You are on page 1of 78

AUTOIMMUNITY A REVIEW

Dissertation submitted to

ANDHRA UNIVERSITY VISAKHAPATNAM In the partial fulfillment of the requirement for the degree of

BACHELOR OF PHARMACY
Submitted by V.K.C. KIRAN PULLELA Regd.No:- 29131955 BADAM SANYASI SETTI Regd.No:- 29131959 BATTULA RAMYAHRUDAYAMALA Regd.No:- 29131904 BANDI BHARATHI Regd.No:- 29131903

Under the guidance of Mr. N.V.V.J.M.Reddy, M.Pharm

VJs College of Pharmacy Diwancheruvu Rajahmundry-533103

CONTENTS
1. AN OVERVIEW OF IMMUNITY 1.1 ANTIGENS AND ANTIGEN RECEPTORS 1.2 MAJOR HISTOCOMPATIBILITY COMPLEX ANTIGENS 1.3 CYTOKINES 1.4 CELLS OF THE IMMUNE SYSTEM 1.5 THE IMMUNE RESPONSE 1.6 ELIMINATION OF INVADERS 1.7 MECHANISMS OF IMMUNE-MEDIATED INJURY 1.8 IMMUNOLOGIC TOLERANCE 2. INTRODUCTION TO AUTOIMMUNITY 2.1 THE BROAD SPECTRUM OF AUTOIMMUNE DISEASES 2.2 LOW-LEVEL AUTOIMMUNITY 2.3 ASPECTS RELATED TO AUTOIMMUNITY 3. PATHOGENESIS OF AUTOIMMUNITY 4. CLASSIFICATION OF AUTOIMMUNE DISEASES 5. SOME COMMON AUTOIMMUNE DISORDERS 6. DIAGNOSIS OF AUTOIMMUNE DISORDERS 6.1 INITIAL LABORATORY EVALUATION 6.2 INFLAMMATORY MARKERS 6.3 AUTOANTIBODIES AND IMMUNOLOGIC STUDIES 6.4 FLOW CYTOMETRY 6.5 CYTOKINE STUDIES 6.6 MHC (HLA) 7. TREATMENT 7.1 IMMUNOSUPPRESSANTS 7.2 IMMUNOSUPPRESSIVE ANTIBODIES 7.3 OTHER IMPORTANT DRUGS 8. LITERATURE REVIEW 9. REFERENCES 1 2 2 3 5 8 13 14 16 18 18 20 20 25 28 29 35 35 36 37 40 40 41 42 42 50 53 56 73

ABBREVIATIONS
AI APC APL BCR CRP CSF CTL DMARDs Autoimmune/Autoimmunity Antigen Presenting Cell Anti Phospho Lipid B- Cell Receptor C - Reactive Protein Colony Stimulating Factors Cytotoxic T Lymphocytes Disease Modifying Anti Rheumatic Drugs

DNA
DTH ELISA ESR GI HIV HLA IBD IDDM IFN Ig IGIV IL ITP mAbs MHC MMF MS NKC NKT NSAID PCR PNAR RA RBC RNA SEM SLE TCR TGF TH TNF UV

Deoxy Ribose Nucleic acid


Delayed Type Hypersensitivity Enzyme Linked Immuno Sorbent Assay Erythrocyte Sedimentation Rate Gastro Intestinal Human Immunodeficiency Virus Human Leucocyte Antigen Inflammatory Bowel Disease Insulin Dependent Diabetes Mellitus Interferon Immunoglobulin Immune Globulin Intravenous Interleukin Idiopathic Thrombocytopenic Purpura Monoclonal Antibodies Major Histocompatibility Complex Mycophenolate Mofetil Multiple Sclerosis Natural Killer Cell Natural Killer T cell Non Steroidal Anti Inflammatory Drug Polymerase Chain Reaction Peanut Agglutinin Receptor Rheumatoid Arthritis Red Blood Cell Ribose Nucleic Acid Scanning Electron Microscope Systemic Lupus Erythematosus T cell Receptor Transforming Growth Factor T Helper Tumour Necrosis Factor Ultra Violet

AUTOIMMUNITY- A REVIEW

1. AN OVERVIEW OF IMMUNITY
The ability of the body to defend itself against specific invading agents such as bacteria, toxins, viruses and foreign tissues is called specific resistance or immunity. Substances that are recognized as foreign and provoke immune responses are called as antigens.1 The immune system is classically composed of two distinct but interrelated components designed to protect against extracellular and intracellular pathogens: Humoral immunity, mediated by soluble antibody proteins, and Cellular immunity, mediated by lymphocytes.2 These cells have the ability to carry out immune responses when properly stimulated. This property is known as immunocompetence.1

Fig 1. Humoral immunity and cellular immunity

VJs College of Pharmacy

Page 1

AUTOIMMUNITY- A REVIEW

B lymphocytes (also called B cells) are the source of antibodies, which participate in immunity either by directly neutralizing extracellular microbes or by activating complement and certain effector cells (neutrophils and macrophages) to kill microorganisms. T lymphocytes (also called T cells) can either directly lyse targets (accomplished by cytotoxic T cells) or orchestrate the antimicrobial immune response of other cells by producing soluble protein mediators called cytokines (made by helper T cells). While B cells and their respective antibodies can recognize and bind to intact antigens, T cells can only "see" antigen that has been processed (proteolytically fragmented into smaller pieces) and presented by other cells.2

1.1 ANTIGENS AND ANTIGEN RECEPTORS1


The antigens are referred to as the substances which have immunogenicity and reactivity. Immunogenicity is the ability to provoke an immune response by stimulating the production of specific antibodies, the proliferation of T cells, or both. Reactivity is the ability of the antigen to react specifically with the antibodies or cells it provoked. The substances with both immunogenicity and reactivity are called as complete antigens. Typically, just certain small parts of a large antigen molecule act as the triggers for immune responses. These small parts are called epitopes or antigenic determinants.

1.2 MAJOR HISTOCOMPATIBILITY COMPLEX ANTIGENS


Located in the plasma membrane of body cells are self-antigens, the major histocompatibility complex (MHC) antigens. These are also called Human Leucocyte Antigens (HLA). Except for identical twins, these are unique for each individual. Thousands to several hundred thousands of MHC molecules mark the surface of the surface of each of the body cells except red blood cells. MHC antigens are the reason that tissues may be rejected when they are transplanted from one person to another. Their normal function is to help T - helper cells recognize that an antigen is foreign, not self.1 T cells can recognize only membrane-bound antigens, and only in the context of "self" histocompatibility molecules; this phenomenon is referred to as MHC restriction.2 These are divided into the following classes: o MHC I- These are built in the plasma membrane of all body cells except red blood cells. In general, MHC I molecules bind to peptides derived from proteins (e.g., viral antigens) synthesized within the cell. Because MHC I molecules are present on virtually all nucleated cells, virally infected cells can be detected and lysed by cytotoxic T cells.1,2

VJs College of Pharmacy

Page 2

AUTOIMMUNITY- A REVIEW

MHC II - The tissue distribution of MHC II-expressing cells is quite restricted. They are constitutively expressed mainly on APC (monocytes, macrophages, and dendritic cells) and B cells. In addition, other cell types, such as vascular endothelial cells, fibroblasts, and renal tubular epithelial cells, are induced to express MHC II by interferon- (IFN-). In general, MHC II molecules bind to peptides derived from proteins (e.g., those derived from extracellular bacteria) synthesized outside the cell. This allows CD4+ T cells to recognize the presence of extracellular pathogens and to orchestrate a protective cytokine-mediated response.1,2

MHC III These proteins include some components of the complement (C2, C3, and Bf); genes for tumor necrosis factor (TNF) and lymphotoxin (TNF-) are also encoded within the MHC. Although genetically linked to class I and II antigens, class III molecules and the cytokine genes do not act as histocompatibility (transplantation) antigens.2

1.3 CYTOKINES
1.3.1. Introduction1,2 Cytokines are low molecular weight polypeptides that are secreted by lymphocytes as well as by effector cells and APCs. They stimulate or inhibit many normal cell functions, such as cell growth and differentiation. They mediate their effects by binding to specific high-affinity receptors on their target cells. Cytokines induce their effects in three ways:
o o o

They act on the same cell that produces them (autocrine effect) They affect other cells in their vicinity (paracrine effect) and They affect cells systemically (endocrine effect)

Cytokines can act in amplifying cascades. Many individual cytokines are produced by several different cell types. For example, IL-1 and TNF can be produced by virtually any cell.

The effects of cytokines are pleiotropic: that is, they act on many cell types, causing many different effects.

Multiple cytokines may induce similar effects, that is, they are redundant.

Cytokines may be antagonistic, and in that fashion they can finely regulate the intensity and type of an immune response.

VJs College of Pharmacy

Page 3

AUTOIMMUNITY- A REVIEW

1.3.2 General Classes of Cytokines2 Cytokines that mediate innate immunity: Included in this group are IL-1, TNF, IL-6, and type 1 interferons. Certain of these cytokines (e.g., interferons) protect against viral infections, while others (e.g., IL-1, TNF, IL-6) initiate nonspecific proinflammatory responses, such as the activation of endothelium and mononuclear inflammatory cells and induction of acute-phase reactant synthesis by the liver. Macrophages are the major source of these cytokines. Cytokines that regulate lymphocyte growth, activation, and differentiation: Within this category are IL-2, IL-4, IL-5, IL-12, IL-15, and transforming growth factor (TGF-). Some, such as IL-2 and IL-4, usually favor lymphocyte growth and differentiation; others, such as IL-10 and TGF-, down-regulate immune responses. Some of these cytokines (e.g., IL-2) fall under the rubric of TH1 cytokines, which direct cell-mediated responses, whereas others (e.g., IL-4, IL-10) are considered to be TH2 cytokines, which antagonize TH1 effects and/or promote certain aspects of humoral immunity. Cytokines that activate inflammatory cells: In this category are IFN- (a TH1 cytokine), TNF, lymphotoxin (TNF-), and migration inhibitory factor. Most of these cytokines are derived from T cells and serve to activate the functions of antigen nonspecific effector cells. Chemokines are cytokines that act to recruit inflammatory cells to sites of injury : These occur in structurally distinct subfamilies, with the two main groups designated as C-C and C-X-C chemokines based on the arrangement of certain cysteine (C) residues. The C-X-C chemokines, which include IL-8, are produced by activated macrophages and tissue cells (e.g., endothelium). C-C chemokines are produced largely by T cells and include monocyte chemoattractant protein 1 (MCP-1) and monocyte inflammatory protein 1 (MIP-1). Cytokines that stimulate hematopoiesis: Several members of this family are called colonystimulating factors (CSFs) because their original characterization was based on their ability to promote the growth of hematopoietic cell colonies from bone marrow precursors. Lymphocytes and bone marrow stromal cells are the major sources of these cytokines. Examples include granulocyte-macrophage (GM)-CSF and granulocyte (G)-CSF, which act on committed progenitor cells, and stem cell factor (also called c-kit ligand), which acts on pluripotent stem cells.

VJs College of Pharmacy

Page 4

AUTOIMMUNITY- A REVIEW

1.4 CELLS OF THE IMMUNE SYSTEM

Fig 2. Cells of the immune system

1.4.1 T Lymphocytes1,2 Thymus-derived, or "T," cells direct the diverse elements of cellular immunity and are also essential for inducing the B cell-derived humoral immunity to many antigens. T cells constitute 60% to 70% of the lymphocytes in circulating blood. Each T cell is genetically programmed to recognize a unique processed peptide fragment by means of a specific T-cell receptor (TCR). T cells exist in the thymus as either CD4 or CD8 cells, which means that, in addition to the antigen receptor, their plasma membrane includes a protein called either CD4 or CD8. These two molecules serve as coreceptors for Tcell stimulation. The CD4- and CD8-expressing T cells (called CD4+ and CD8+, respectively) perform different but overlapping functions. CD4+ T cells are "helper" T cells because they secrete soluble VJs College of Pharmacy Page 5

AUTOIMMUNITY- A REVIEW

molecules (cytokines) that influence virtually all other cells of the immune system. The CD8+ T cells can also secrete cytokines, but they play a more important role in directly killing virus-infected or tumor cells ("cytotoxic" T cells). CD4+ T cells are further divided into two clinically relevant subsets with different functions defined by their cytokine profiles. The so-called TH1 (helper T 1) CD4+ cells characteristically secrete cytokines that help direct cell-mediated immune responses, including macrophage and natural killer cell activation; these TH1 cytokines include interleukin 2 (IL-2) and interferon- (IFN-). In contrast, TH2 (helper T 2) CD4+ cells secrete cytokines (e.g., IL-4, IL-5, and IL-10) that antagonize TH1 effects and/or promote certain aspects of humoral immunity. CD8+ T cells are also divided into analogous subsets that secrete comparable cytokine profiles (called TC1 and TC2 cells) Memory T cells: T cells that remain from a proliferated clone after a cell mediated immune response are termed memory T cells. Should a pathogen bearing the same foreign antigen invade the body later, thousands of memory cells are available to initiate a far swifter reaction than occurred during the first invasion. The second response usually is so fast and so vigorous that the pathogens are destroyed before any signs or symptoms of disease can occur. 1.4.2 B Lymphocytes2,3 Bone marrow-derived, or "B," lymphocytes comprise 10% to 20% of the circulating peripheral lymphocyte population. They are also present in bone marrow, in peripheral lymphoid tissues (lymph nodes, spleen, and tonsils), and in nonlymphoid organs such as the gastrointestinal tract. Stimulation (e.g., by local infection) leads to the formation of a central zone of large, activated B cells in lymphoid follicles, called a germinal center. Upon an encounter with antigen, a mature B cell binds the antigen, internalizes and processes it, and presents its peptide bound to class II MHC to CD4 helper cells, which in turn secrete IL-4 and IL-5. These interleukins stimulate B-cell proliferation and differentiation into memory B cells and immunoglobulin secreting plasma cells. There are five basic immunoglobulin isotypes; IgG, IgM, and IgA constitute more than 95% of circulating antibodies with relatively minimal contributions from IgE and IgD. These immunoglobulins mediate their functions by acting as opsonins to enhance phagocytosis and cellular cytotoxicity and by activating complement to elicit an inflammatory response and induce bacterial lysis. B cells recognize antigen via monomeric surface IgM, the so-called B-cell receptor (BCR). As with T cells, each BCR has a unique antigen specificity. Analogous to the TCR-CD3 complex, BCRs interact with several invariant molecules that are responsible for signal transduction and for complete Bcell activation.

VJs College of Pharmacy

Page 6

AUTOIMMUNITY- A REVIEW

1.4.3 Macrophages2 Macrophages express class II MHC and are therefore central players in the processing and presentation of antigen to CD4+ helper T cells. Because T cells (unlike B cells) cannot be triggered by free antigen, presentation by macrophages or other APCs is obligatory for induction of cell-mediated immunity. Macrophages produce a plethora of cytokines and are therefore important effector cells in certain forms of cell-mediated immunity. These cytokines not only influence T- and B-cell function but also affect other cell types, including endothelium and fibroblasts. Macrophages phagocytose microbes coated by antibody and/or complement; consequently they are important effector elements in humoral immunity. 1.4.4 Dendritic Cells2 Cells with dendritic morphology (i.e., with fine dendritic cytoplasmic processes) occur as two functionally distinct types. Interdigitating dendritic cells: These are nonphagocytic cells that express high levels of MHC class II and costimulatory molecules. The distribution and surface molecule expression of dendritic cells makes them ideally suited for presenting antigens to CD4+ T cells; they are probably the most potent APC for naive T cells. Follicular dendritic cells: As suggested by their name, follicular dendritic cells are primarily localized to the germinal centers of lymphoid follicles in the spleen and lymph nodes. These cells bear Fc receptors for IgG (receptors that bind the constant, or Fc, portion of antibodies) and hence efficiently trap antigen bound to antibodies. Consequently, after an initial antibody response, antigens can persist in this form in lymphoid tissues and facilitate the maintenance of immunologic memory. 1.4.5 Natural Killer (NK) Cells2 Natural Killer (NK) cells are a distinct subset of lymphocytes that act as a first line of defense. They are somewhat larger than small lymphocytes and comprise 10% to 15% of peripheral blood lymphocytes. These cells contain abundant azurophilic granules and are able to lyse a variety of tumor cells, virally infected cells, and some normal cells, without previous sensitization. Although they share some surface markers with T cells, NK cells do not express TCR and are CD3 negative.

VJs College of Pharmacy

Page 7

AUTOIMMUNITY- A REVIEW

1.5 THE IMMUNE RESPONSE


1.5.1 The Innate Immune Response This type of immunity is primitive, does not require priming, and is of relatively low affinity, but is broadly reactive.4 The innate response is activated immediately after infection or injury.5 It is the first line of defense against an invading pathogen (antigen) and includes physical (e.g., skin), biochemical (e.g., complement, lysozyme, interferons), and cellular components (neutrophils, monocytes, macrophages, natural killer [NK], and natural killer-T [NKT] cells).3,4 Fig 3. SEM image of single neutrophil engulfing anthrax bacteria An intact skin or mucosa is the first barrier to infection. When this barrier is breached, destruction of the pathogen is accomplished by biochemical components such as lysozyme (which breaks down the protective peptidoglycan cell wall) and the split products arising from complement activation. Complement components enhance macrophage and neutrophil phagocytosis by acting as opsonins (C3b) and chemoattractants (C3a, C5a) that recruit immune cells to inflammatory sites. The activation of complement eventually leads to pathogen lysis via the generation of a membrane attack complex that creates holes in the membrane and results in leakage of cellular components. Natural killer (NK) and natural killer-T (NKT) cells recruited to the inflammatory site also contribute to the innate response by secreting interferongamma (IFN-), which activates resident tissue macrophages and dendritic cells. 3 Some aspects of the innate response are non-immunological, for example the histamine-induced vascular changes to ultraviolet damage, and some reactions of the neutrophil polymorphs.5 1.5.2 The Adaptive Immune Response The adaptive immune response starts up only after a pathogen has been recognised by the innate system. This type of immunity is antigen-specific, depends upon antigen exposure or priming, and can be of very high affinity.4 The adaptive immune system has a number of characteristics that contribute to its success in eliminating pathogens.3
5

VJs College of Pharmacy

Page 8

AUTOIMMUNITY- A REVIEW

These include the ability to (1) respond to a variety of antigens, each in a specific manner (2) Discriminate between foreign ("non-self") antigen (pathogens) and self-antigens of the host; and (3) Respond to a previously encountered antigen in a learned way by initiating a vigorous memory response.3 The key cells are the lymphocytes, of which there are three main groups B cells, responsible for antibody production, i.e. the humoral immune response T cells, which are important in the induction phase of the immune response and in cell-mediated immune reactions NK cells, which are specialised lymphoid cells that are active in the non-immunological, innate response. 4,5 Miraculously, T and B lymphocytes harbour antigen-specific receptors that recognise and react with virtually all foreign proteins and polysaccharides that we are likely to encounter during our lifetime.5 These cells are important not only in the normal immune response to infection and tumors, but also in transplant rejection and autoimmunity.4 The specific immune response occurs in two phases The Induction Phase: During this phase, antigen is presented to T cells by the antigen presenting cells (APCs), and this is followed by complex interactions of those T cells with B cells and other T cells. The lymphocytes recognize the foreign protein or polysaccharide, undergo clonal expansion, giving rise to a mass of cells that all have the capacity to recognise and respond to that particular antigen. These cells are eventually responsible for the effector phase of the response.5 The Effector Phase: During this phase, these cells differentiate either into plasma cells or into memory cells. The plasma cells produce antibodies (if they are B cells), or are involved in cellmediated immune responses such as activating macrophages or killing virus-infected host cells (if they are T cells). Other cells form an increased population of antigen-sensitive memory cells. Any subsequent exposure to the antigen calls forth a greatly enhanced response.5 1.5.3 Antigen Processing and Presentation1 B cells can recognize and bind to antigens in lymph, interstitial fluid or blood plasma. T cells only recognize fragments of antigenic proteins that are processed and presented in a certain way. In antigenic processing, the antigenic proteins are broken down into peptide fragments that then associate VJs College of Pharmacy Page 9

AUTOIMMUNITY- A REVIEW

with MHC molecules. Next, the antigen - MHC complex is inserted into the plasma membrane of a body cell. The insertion of the complex into the plasma membrane is called antigen presentation. When a peptide fragment comes from a self-protein, the T- cells usually ignore the antigen-MHC complex. If the peptide fragment comes from a foreign protein, T cells recognize the antigen-MHC complex as an intruder and immune response takes place.

Fig 4. Antigen processing and presentation

Processing of exogenous antigens: Foreign antigens that are present in fluids outside body cells are termed exogenous antigens. They include intruders such as bacteria and bacterial toxins, parasitic worms, inhaled pollen and dust, and viruses which have not yet infected a body cell. A special class of cells called antigen presenting cells (APCs) process and present exogenous antigens. APCs include dendritic cells, VJs College of Pharmacy Page 10

AUTOIMMUNITY- A REVIEW

macrophages, and B cells. They are strategically located in places where antigens are likely to penetrate nonspecific defenses and enter the body, such as epidermis and dermis of the skin (Langerhans cells are a type of dendritic cell); mucous membranes that line the respiratory, gastrointestinal, urinary, and reproductive tracts; and lymph nodes. After processing and presenting an antigen, APCs migrate from tissues via lymphatic vessels to lymph nodes. The steps in processing and presenting of an exogenous antigen by an antigen-presenting cell occur as follows: Ingestion of the antigen: APCs ingest antigens by phagocytosis or endocytosis. Ingestion could occur almost anywhere in the body that invaders, such as microbes, have penetrated the nonspecific defenses. Digestion of antigen into peptide fragments: Within the phagosome or endosome proteindigesting enzymes split large antigens into short peptide fragments. Synthesis of MHC - II molecules: At the same time the APC synthesizes MHC-II molecules and packages them into vesicles. Fusion of vesicles: The vesicles containing antigen peptide fragments and MHC-II molecules merge and fuse. Binding of peptide fragments and MHC-II molecules: After the fusion of the two types of vesicles, antigen peptide fragments bind to MHC-II molecules. Insertion of antigen-MHC-II complex into the plasma membrane: The combined vesicle that contains antigen-MHC-II complexes undergoes exocytosis. As a result, the antigen-MHC-II complexes are inserted into the plasma membrane. After processing an antigen, the antigen-presenting cell migrates to lymphatic tissue to present the antigen to T cells that have a compatibly shaped receptors recognize and bind to the antigen fragmentMHC-II complex, triggering either a cell mediated or an antibody mediated immune response. The presentation of exogenous antigen together with MHC-II molecules by antigen presenting cells informs T cells that intruders are present in the body and that combinative action should begin. Processing of endogenous antigens: Foreign antigens that are synthesized inside the body cells are termed endogenous antigens. Such antigens may be viral proteins produced after a virus infects the cells and takes over the cell's metabolic machinery, or abnormal proteins synthesized by a cancerous cell. Fragments of endogenous antigens associate with MHC-I molecules inside infected cells. The resulting endogenous antigen fragment-MHC-I complex then moves to the plasma membrane, where it is presented VJs College of Pharmacy Page 11

AUTOIMMUNITY- A REVIEW

at the surface of the cell. Most cells of the body can process and present endogenous antigens. The display of an endogenous antigen bound to an MHC-I molecule signals that a cell has been infected and needs help. 1.5.4 T-Cell Activation and Clonal Expansion1,2,3 At any given time, most T cells are inactive. The antigen receptors on the surface of the T cells, called T-cell and receptors bind to (TCRs), specific

recognize

foreign antigen fragments that are presented in antigen-MHC

complexes. There are millions of different T cells; each has its own unique TCRs that can recognize a specific antigen-MHC complex.

When an antigen enters the body, only a few T cells have TCRs that can recognize and bind to the antigen. Antigen recognition also involves other surface proteins on T cells, the CD4 or CD8 proteins. These proteins interact with the MHC antigens and help maintain the TCR-MHC coupling. For this reason, they are referred to as coreceptors. Antigen recognition by a TCR with CD4 or CD8 proteins is the first signal in the activation of a T cell. A T cell becomes activated only if it binds to the foreign antigen and at the same time receives a second signal, a process known as costimulation. Of the more than 20 known costimulators, some are cytokines, such as interleukin-2. Other costimulators include pairs of plasma membrane molecules, one on the surface of the T cell (CD28) and a second on the surface of an antigen-presenting cell (CD80 or CD86), that enable the two cells to adhere to one another for a period of time. The need for costimulation may prevent immune responses from occurring accidentally. Different costimulators affect the activated T cell in different ways. Moreover, recognition (antigen binding to a receptor) without costimulation leads to a prolonged state of inactivity called anergy in both T cells and B cells. Once a T cell has received these two signals, it is activated. An activated T cell enlarges and begins to proliferate and to differentiate. The result is a population of identical cells, called a clone, which can recognize the same specific antigen. Before the first exposure to a given antigen, only a few T cells might be able to recognize it, but once an immune VJs College of Pharmacy Page 12 Fig 5. One method of costimulation needed to activate T cells. B7 comes in two forms B7-1 (CD80) and B7-2(CD86)

AUTOIMMUNITY- A REVIEW

response has begun, there are thousands. Activation, proliferation, and differentiation of T cells occur in the secondary lymphatic organs and tissues. Inactive helper T cells recognize exogenous antigen fragments associated with MHC-II molecules at the surface of an APC. With the aid of the CD4 protein, the helper T cell and APC interact with each other, costimulation occurs, and the helper T cell becomes activated. Within hours after costimulation, activated helper T cells start secreting a variety of cytokines. One very important cytokine produced by helper T cells is interleukin-2 (IL-2), which is needed virtually for all immune responses and is the prime trigger of T cell proliferation. IL-2 can act as a costimulator for resting helper T cells or cytotoxic T cells, and it enhances activation and proliferation of T cells, B cells and natural killer cells. Activation of a T helper cell stimulates it to start secreting IL-2, which then acts in an autocrine manner by binding to IL-2 receptors on the plasma membrane of the cell that secreted it. One effect is stimulation of cell division. As the helper T cells proliferate, a positive feedback effect occurs because they secrete more IL-2, which causes further cell division. IL-2 may also act in a paracrine manner by binding to IL-2 receptors ma a neighboring helper T cells, cytotoxic T cells, or B cells. If any of these neighboring cells have already bound an antigen, IL-2 serves as a costimulator. Recognition requires the TCR and CD8 protein to maintain coupling with MHC-I. Following antigenic recognition, costimulation occurs. In order to become activated, cytotoxic T cells require costimulation by interleukin-2 or other cytokines produced by helper T cells. Thus, maximal activation of cytotoxic T cells requires presentation of antigen associated with both MHC-I and MHC-II molecules.

1.6 ELIMINATION OF INVADERS1,3


Cytotoxic T cells are the cells that assault with the foreign invaders in cell-mediated immune responses. They leave secondary lymphatic organs and tissues and migrate to seek out and destroy infected target cells, cancer cells, and transplanted cells. Cytotoxic T cells recognize and attach to target cells. Then, the cytotoxic T cells deliver a "lethal hit" that kills the target cells. Cytotoxic T cells kill infected target body cells much like natural killer cells do. The major difference is that cytotoxic T cells have receptors specific for a particular microbe and thus kill only target body cells infected with one particular type of microbe; natural killer cells can destroy a wide variety of microbe- infected body cells. Cytotoxic T cells have two principal mechanisms for killing infected target cells. VJs College of Pharmacy Page 13

AUTOIMMUNITY- A REVIEW

1. Cytotoxic T cells, using receptors on their surfaces, recognize and bind to infected target cells that have microbial antigens displayed on their surface. The cytotoxic T cells then release granzymes, proteindigesting enzymes that trigger apoptosis. Once the infected cell is destroyed, the released microbes are killed by phagocytes. 2. Alternatively, cytotoxic T cells bind to infected body cells and release two proteins from their granules: perforin and granulysin. Perforin inserts into the plasma membrane of the target cell and creates channels in the membrane. As a result, extracellular fluid flows into the target cell and cytolysis occurs. Other granules in cytotoxic T cells release granulysin, which enters through the channels and destroys the microbes by creating holes in their plasma membranes. Cytotoxic T cells may also destroy target cells by releasing a toxic molecule called lymphotoxin, which activates enzymes in the target cell. These enzymes cause the target cell's DNA fragment and the cell dies. In addition, cytotoxic T cells secrete -interferon, which attracts and activates phagocytic cells, and macrophage migration inhibition factor, which prevents migration of phagocytes from the infection site. After detaching from a target cell, a cytotoxic T cell can seek out and destroy another target cell.

1.7 MECHANISMS OF IMMUNE-MEDIATED INJURY2,3 (HYPERSENSITIVITY REACTIONS)


Whereas the normally functioning immune response can successfully neutralize toxins, inactivate viruses, destroy transformed cells, and eliminate pathogens, inappropriate responses can lead to extensive tissue damage. Hypersensitivity can be classified as antibody-mediated or cell-mediated. Three types of hypersensitivity are antibody-mediated (types IIII), while the fourth is cell-mediated (type IV). Hypersensitivity occurs in two phases: the sensitization phase and the effector phase. Sensitization occurs upon initial encounter with an antigen; the effector phase involves immunologic memory and results in tissue pathology upon a subsequent encounter with that antigen. 1.7.1 Type I Hypersensitivity Immediate, or type I, hypersensitivity is IgE-mediated, with symptoms usually occurring within minutes following the patient's encounter with antigen. It results from cross-linking of membrane-bound IgE on blood basophils or tissue mast cells by antigen. This cross-linking causes cells to degranulate, releasing substances such as histamine, leukotrienes, and eosinophil chemotactic factor, which induce anaphylaxis, asthma, hay fever, or urticaria (hives) in affected individuals.

VJs College of Pharmacy

Page 14

AUTOIMMUNITY- A REVIEW

1.7.2 Type II Hypersensitivity Type II hypersensitivity results from the formation of antigen-antibody complexes between foreign antigen and IgM or IgG immunoglobulins. The associated disorders are autoimmune hemolytic anemia, erythroblastosis fetalis, Goodpasture disease, pemphigus vulgaris etc. 1.7.3 Type III Hypersensitivity Type III hypersensitivity is due to the presence of elevated levels of antigen-antibody complexes that deposit on basement membranes in tissues and vessels. Immune complex deposition activates complement to produce components with anaphylatoxic and chemotactic activities (C5a, C3a, and C4a) that increase vascular permeability and recruit neutrophils to the site of complex deposition. Complex deposition and the action of lytic enzymes released by neutrophils can cause Arthus reaction, serum sickness, systemic lupus erythematosus, and certain forms of acute glomerulonephritis in these individuals. If patients have type III hypersensitivity against a particular antigen, clinical symptoms usually occur 3 to 4 days after exposure to the antigen. 1.7.4 Type IV Hypersensitivity This type of hypersensitivity is also called as Delayed Type Hypersensitivity (DTH). It is cellmediated, and responses occur 23 days after exposure to the sensitizing antigen. DTH is caused by antigen-specific DTH TH1 cells and induces a local inflammatory response that causes tissue damage characterized by the influx of antigen-nonspecific inflammatory cells, especially macrophages. These cells are recruited under the influence of TH1-produced cytokines, which chemoattract circulating monocytes and neutrophils, induce myelopoiesis, and activate macrophages. The activated macrophages are primarily responsible for the tissue damage associated with DTH. Although widely considered to be deleterious, DTH responses are very effective in eliminating infections caused by intracellular pathogens such as Mycobacterium tuberculosis and Leishmania species. Clinical manifestations of DTH include tuberculin and contact hypersensitivities.

VJs College of Pharmacy

Page 15

AUTOIMMUNITY- A REVIEW

1.8 IMMUNOLOGIC TOLERANCE2,6,7


Immunologic tolerance is a state in which an individual is incapable of developing an immune response against a specific antigen. Natural or self-tolerance specifically refers to a lack of immune responsiveness to one's own tissue antigens. Induced tolerance is the tolerance to external antigens can be created by manipulating the immune system. Two broad groups of mechanisms have been forwarded to explain the tolerant state: central tolerance and peripheral tolerance. 1.8.1 Central tolerance This refers to deletion of self-reactive T and B lymphocytes during their maturation in central lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). It is proposed (with experimental confirmation in mice) that many autologous (self-) protein antigens are processed and presented by thymic APCs in association with self-MHC. Any developing T cell that expresses a receptor for such self-antigen is negatively selected (deleted by apoptosis), and the resulting peripheral T-cell pool is thereby depleted of self-reactive cells. As with the case of T cells, deletion of self-reactive B cells also occurs. When developing B cells encounter a membrane-bound antigen during their development in the bone marrow, they undergo apoptosis. Unfortunately, the process of deletion of self-reactive lymphocytes is far from perfect. Many self-antigens are not present in the thymus, and hence T cells bearing receptors for such autoantigens escape into the periphery. There is similar "slippage" in the B-cell system as well, and B cells that bear receptors for a variety of self-antigens, including thyroglobulin, collagen, and DNA, can be readily found in the peripheral blood of healthy individuals. 1.8.2 Peripheral tolerance Self-reactive T cells that escape negative selection in the thymus can potentially wreak havoc unless they are deleted or effectively muzzled. Several back-up mechanisms in the peripheral tissues that silence such potentially autoreactive T cells have been identified: Anergy: This refers to prolonged or irreversible inactivation of lymphocytes induced by encounter with antigens under certain conditions. Activation of T cells requires two signals: recognition of peptide antigen in association with self-MHC molecules on APCs and a set of second costimulatory signals provided by the APCs. If the second costimulatory signals are not delivered, the T cell becomes anergic. Such a cell will be unresponsive even if the relevant antigen is presented again by competent APCs that can deliver costimulation. Because VJs College of Pharmacy Page 16

AUTOIMMUNITY- A REVIEW

costimulatory molecules are not strongly expressed on most normal tissues, the encounter between autoreactive T cells and their specific self-antigens frequently results in anergy. B cells can also become anergic if they encounter antigen in the absence of specific helper T cells. Activation-induced cell death: Another mechanism to prevent uncontrolled T-cell activation during a normal immune response involves apoptosis of activated T cells by the Fas-Fas ligand system. Fas ligand is a membrane protein that is structurally homologous to the cytokine TNF and is expressed chiefly on activated T lymphocytes. Consequently, engagement of Fas by Fas ligand, co-expressed on the same cohort of activated T cells, may function to suppress the immune response by inducing apoptosis of these cells. Theoretically, such activation-induced cell death can also cause the peripheral deletion of autoreactive T cells. Thus, abundant self-antigens would be expected to cause repeated and persistent stimulation of autoreactive T cells in the periphery, leading eventually to their elimination via Fas-mediated apoptosis. Peripheral suppression by T cells: Although activation-induced cell death and anergy are the primary mechanisms of peripheral self-tolerance, additional fail-safe mechanisms exist. Much interest has focused on so-called regulatory T cells, which can modulate the function of other T cells. Although the mechanisms underlying their effects remain elusive, it is known that certain cytokines elaborated by these cells (e.g., IL-10 and transforming growth factor [TGF-]) can dampen a variety of T-cell responses; regulatory T cells also modulate T-cell activity by pathways involving direct cell-cell contact.

VJs College of Pharmacy

Page 17

AUTOIMMUNITY- A REVIEW

2. INTRODUCTION TO AUTOIMMUNITY
Cells from the bodys immune system can on occasion react against normal endogenous proteins and thereby effect a reaction against certain body tissues. This abnormal immune response is termed autoimmunity.8 This phenomenon derives from the activation of self-reactive T and B lymphocytes that generate cell-mediated or humoral immune responses directed against self-antigens.3 Ordinarily, a complex network of feedback loops keeps autoimmune reactions in check. However, under certain circumstances, normal control is lost and the aberrant immune reaction will result in disease. 8 The disease resulting from such an aberrant immune response is termed an autoimmune disease.6 Prominent examples include Coeliac disease, diabetes mellitus type 1 (IDDM), systemic lupus erythematosus (SLE),Multiple Sclerosis, Sjgren's syndrome, Churg-Strauss Syndrome, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, rheumatoid arthritis (RA), lupus and allergies.3,6 Prevalence of autoimmune diseases in the population may be 8% or higher. Autoimmune disorders are diverse with different problems, and have one common feature that they are triggered mostly by foreign or self-proteins and the bodys own immune system is attacking the bodys cells.9 They are highly complex due to MHC genetics, environmental conditions, infectious entities, and dysfunctional immune regulation.3 Autoimmunity is present in everyone to some extent. It is usually harmless and probably a universal phenomenon of vertebrate life. Autoimmune diseases are defined when the progression from benign autoimmunity to pathogenic autoimmunity occurs. This progression is determined by both genetic influences and environmental triggers.10

2.1 THE BROAD SPECTRUM OF AUTOIMMUNE DISEASES10,11


Autoimmune diseases can strike any part of the body, and thus symptoms vary widely and diagnosis and treatment are often difficult. The broad spectrum of autoimmune diseases includes multiple sclerosis and the severe type 1 diabetes mellitus. Some autoimmune diseases such as lupus and pemphigus can be life threatening unless properly diagnosed and treated. Chronic autoimmune disorders like rheumatoid arthritis cripple the patient and also create heavy burdens on patients families. Some types of uveitis may cause blindness. Diseases such as scleroderma require skillful, lifelong treatment. Still other autoimmune diseases, including Graves disease and chronic thyroiditis, can be successfully treated if correctly diagnosed, but they are frequently missed because of their subtle onset. VJs College of Pharmacy Page 18

AUTOIMMUNITY- A REVIEW

For a disease to be regarded as an autoimmune disease, it needs to answer to Witebsky's postulates (first formulated by Ernst Witebsky and colleagues in 1957 and modified in 1993 by Rose and Bona) Direct evidence requires transmissibility of the characteristic lesions of the disease from human to human or human to animal. In the real world, such evidence is attainable at this time only for diseases mediated by autoantibody, since we do not yet have the means for reliably studying T lymphocyte-mediated autoimmune diseases by transfer to animals. Examples of autoimmune diseases that fulfill the criteria of direct evidence are idiopathic thrombocytopenic purpura (in which deliberate human experimentation in the early 1950s showed that the platelet destruction is directly caused by an autoantibody), Graves' disease and myasthenia gravis (in which there are temporary signs of disease in the infant due to transplacental transfer), pemphigus vulgaris and bullous pemphigoid (where the disease can be transmitted from humans to animals by autoantibody). Indirect evidence requires re-creation of the human disease in an animal model. The majority of autoimmune diseases fit in this category. For example, the autoimmune basis of systemic lupus erythematosus is well accepted because of the availability of several genetically determined mouse models which, while not simulating lupus as seen in the clinic, do very closely replicate the serological features and some pathological features. Hashimoto's thyroiditis and multiple sclerosis can be reproduced by immunizing the animal with an antigen analogous to the putative autoantigen of the human disease. Knock-out mice have provided the best models of inflammatory bowel disease; neonatal thymectomy of mice can produce excellent analogs of human oophoritis and autoimmune gastritis. When direct and indirect evidence to define an autoimmune disease are not available, investigators are left with circumstantial evidence, that is, with listing "markers" descriptive of autoimmune disease. Examples of these markers are: positive family history for the same disease, or for other diseases known to be autoimmune presence in the same patient of other known autoimmune diseases presence of infiltrating mononuclear cells in the affected organ or tissue preferential usage of certain MHC class II allele high serum levels of IgG autoantibodies

VJs College of Pharmacy

Page 19

AUTOIMMUNITY- A REVIEW

deposition of antigen-antibody complexes in the affected organ or tissue improvement of symptom with the use of immunosuppressive drugs (such as corticosteroids)

2.2 LOW-LEVEL AUTOIMMUNITY


While a high level of autoimmunity is unhealthy, a low level of autoimmunity may actually be beneficial. First, low-level autoimmunity might aid in the recognition of neoplastic cells by CD8+ T cells, and thus reduce the incidence of cancer. Second, autoimmunity may have a role in allowing a rapid immune response in the early stages of an infection when the availability of foreign antigens limits the response (i.e., when there are few pathogens present). Thus self-MHC recognition (which, if too strong may contribute to autoimmune disease) maintains the responsiveness of CD4+ T cells when foreign antigens are absent.6

2.3 ASPECTS RELATED TO AUTOIMMUNITY


In the prevailing theories about triggers of autoimmune diseases, the trigger does not necessarily need to stay around. For example, a viral infection may trigger the immune response, but the virus need not stay as a chronic infection for the person to develop autoimmunity.9 There are several suspects in the search for triggers. In fact, there is quite a lot of evidence for several types of triggers, so it seems there may be multiple triggers for autoimmune diseases. Some of the suspects include: Age: Autoimmune diseases are seen more often in young adults. However, the elderly have a much higher level of autoantibodies, and get less autoimmune diseases in general.9 Sex: The reasons for the sex role in autoimmunity are unclear. According to the American Autoimmune Related Diseases Association (AARDA), autoimmune diseases that develop in men tend to be more severe. Women appear to generally mount larger inflammatory responses than men when their immune systems are triggered, increasing the risk of autoimmunity. But not all autoimmune diseases show gender bias.6,9 Pregnancy: A history of pregnancy also appears to leave a persistent increased risk for autoimmune disease. It has been suggested that the slight exchange of cells between mothers and their children during pregnancy may induce autoimmunity.6

VJs College of Pharmacy

Page 20

AUTOIMMUNITY- A REVIEW

Genetics: The genes related to immunoglobulins, T-cell receptors and the MHC proteins are liable to recombination which may cause autoimmunity.2,6 Getting one autoimmune disease makes it more likely that the subject is at risk for a second autoimmune disease. Another fact is that the families, siblings, and children of people with an autoimmune disease are at risk of that particular autoimmune disease, and of other autoimmune diseases also. But these risks are not as high as for a true genetic disease. Recent studies have identified an antiphospholipid antibody (APL) that is believed to be a common thread among family members with autoimmune diseases. Among study participants, family members with elevated APL levels showed autoimmune disease, while those with other autoantibodies did not. Family members with elevated APL levels also manifested different forms of autoimmune disease, suggesting that APL may serve as a common trigger for different autoimmune diseases.12 Certain genetically modified animals get autoimmune diseases (e.g. NOD mice get Type 1 diabetes), and this is in fact used to study these diseases in animal models of the disease.9

Infections: An interesting relationship exists between infectious diseases and autoimmune diseases. In areas where multiple infectious diseases are endemic, autoimmune diseases are quite rarely seen. The putative mechanism is that the parasite attenuates the host immune response in order to protect itself.6 But still, some infections are found to be involved in various autoimmune diseases. Viruses: These are probably the most studied candidate for autoimmune diseases. However, results have been somewhat unconvincing. Finding viruses directly inside the autoimmune infection site has been difficult, though perhaps the viral-infected cells are already destroyed, especially if the virus only starts the early phases of autoimmunity. Thus a key question is whether viruses simply initiate autoimmune diseases, or whether they must stay around to continue the autoimmune reaction. It is also unclear if viruses cause their effects because of the immune reaction against the virus specifically, or simply because of the extra inflammation their infection causes at a site. Evidence of viral-autoimmune links is quite strong and there are some autoimmune diseases that can actually be caused by viruses in animal experiments. Some of the diseases with associated viral suspects include: Type 1 Diabetes and Coxsackie B (CVB) virus. Autoimmune hepatitis and hepatitis C virus (HCV) or hepatitis D virus (HDV).

VJs College of Pharmacy

Page 21

AUTOIMMUNITY- A REVIEW

Rheumatoid arthritis and Epstein-Barr virus (EBV). Autoimmune myocarditis in mice and Coxsackie B (CVB) virus. Theiler's myrine encephalomyelitis virus (TMEV) and encephalitis in mice. Herpes simplex virus is also found to be associated with some autoimmune diseases.2,9,13

Bacteria: There is not a strong link between autoimmunity and bacterial infections as a trigger. However, a few examples have been found: Autoimmune myocarditis and Group A streptococcal M bacteria. Autoimmune myocarditis and the syphilis spirochete Treponema pallidum. Streptococcus pyrogenes, Klebsiella species and Borrelia burgdorfeii are also found to be associated with some autoimmune diseases.2, 9,13 Parasites: These are very rarely regarded as an autoimmune disease trigger. However, there are a few rare examples of a relationship between an autoimmune disease and a parasite. Chagas' heart disease and Trypanosoma cruzi. SLE/Sojgren's syndrome and the Ochocerca volvulus (nematode). Pemphigus foliaceous and the Simulium nigraimanum (blackfly).9,13

Diet9 - There are some examples where the presence of a particular substance in the diet might possibly be related to an autoimmune disease. Cow's milk and Type 1 diabetes: Somewhat controversial, but there is some evidence of an association between cow's milk and Type 1 diabetes. This idea is tied to the idea of molecular mimicry theory as the underlying cause, because a particular sequence of milk protein matches the proteins of the islet cells. Celiac disease and gluten: There is a clear relationship between gluten (in wheat) and celiac disease. But is this a trigger of celiac disease or a secondary issue.

VJs College of Pharmacy

Page 22

AUTOIMMUNITY- A REVIEW

Chemicals9 - There are examples where toxins and chemicals have been linked to AI diseases in humans and laboratory animals. Scleroderma and metals: the risk of scleroderma to miners is high, particular silica; other possible metals involved are mercury, copper, iron. Mercury and kidney autoimmunity in rats. Iodine and autoimmune thyroiditis: if not causal, at least contributes to the development of AI. Silicone breast implants and SLE.

Drugs3,9 - There have been some examples of medications that may trigger autoimmunity as a side effect. In these drug-induced autoimmune states, IgG antibodies bind to drug-modified tissue and are destroyed by the complement system or by phagocytic cells with Fc receptors. Fortunately these to drugs usually subside within several months after the offending drug is withdrawn. Immunosuppressive therapy is warranted only when the autoimmune response is unusually severe. These are included under Type-II drug allergies. Systemic lupus erythematosus following hydralazine or procainamide therapy. Autoimmune hemolytic anemia resulting from methyldopa administration. Thrombocytopenic purpura due to quinidine. "Lupoid hepatitis" due to cathartic sensitivity. Cytochrome antibodies and tienilic acid. Acetylcholine receptor antibodies and D-penicillamine. Halothane causes autoimmunity through creating a new antigen in the liver. Agranulocytosis is caused due to a variety of drugs.

Cancers9 - Rarely, a cancer can cause an autoimmune disease. There are two methods: Immune system tumors: Direct tumor of an immune organ such as the thymus or bone marrow (i.e. a thymoma or lymphoma). However, autoimmune disease is very rare from

VJs College of Pharmacy

Page 23

AUTOIMMUNITY- A REVIEW

these disorders, so it seems that despite their importance to the immune system, a failure at these sites is not the only problem required for autoimmune disease to result. Paraneoplastic autoimmune disorders: Though very rare, there are a few types of autoimmune disease that are caused by cancers of a different part of the body. These are called "paraneoplastic" autoimmune disorders. Examples include: Cancer Associated Retinopathy (CAR): An autoimmune reaction against the eye retina, caused by some types of cancers, typically lung cancer. The mechanism of paraneoplastic autoimmunity is believed to be that the cancer causes a hidden antigen to be shown to the immune system. This antigen is attacked, but by coincidence, this antigen is also at another body site (e.g. the retina), and the immune system mistakenly attacks the retina as an innocent bystander. Radiation9 - UV light may damage cells and release new antigens. However, there are few examples of possible relationships between radiation and autoimmunity. Immune abnormalities9 - Because autoimmunity is related to the immune system, various abnormalities of the immune system have been considered as possible triggers or causal factors. Thymus abnormalities9 - Neonatal thymectomy causes oophoritis and autoimmune gastritis in mice. Chronic infections or inflammation9 - An infection causes heightened immune response as a natural course. It is therefore plausible that a chronic inflammation could possibly cause autoimmunity, or if not actually cause, at least provide an environment in which it would flourish. Cells9 - One strange method of causing autoimmunity is to be injected with the cells of the body. This can sometimes upset the balance of the immune system. Some examples include: Brain autoimmunity from rabies vaccinations, which were once made from brain emulsions. Encephalitis in monkey brains after injection with monkey brain cells.

Mitochondrial disorders9 - Not a general theory of AI, but a possible factor in MS. The genetic mitochondrial disorder Leber's Hereditary Optic Neuropathy has been associated with MS, but no clear link between mitochondria and MS has been found as yet.

VJs College of Pharmacy

Page 24

AUTOIMMUNITY- A REVIEW

3. PATHOGENESIS OF AUTOIMMUNITY 2,3,6


Breakdown of one or more of the mechanisms of self-tolerance can unleash an immunologic attack on tissues that leads to the development of autoimmune diseases. Immunocompetent cells are undoubtedly involved in mediating the tissue injury, but the precise influences that initiate their reactions against self are not known. More than one defect might be present in each disease, and the defects vary from one disorder to the other. Furthermore, the breakdown of tolerance and initiation of autoimmunity involves the interaction of complicated immunologic, genetic, and microbial factors. Here the initiating immunologic mechanisms (mostly attributable to failure of peripheral tolerance) are discussed. Failure of Activation-Induced Cell Death: Persistent activation of potentially autoreactive T cells may lead to their apoptosis via the Fas-Fas ligand system. It therefore follows that defects in this pathway may allow persistence and proliferation of autoreactive T cells in peripheral tissues. Breakdown of T-Cell Anergy: Potentially autoreactive T cells that escape central deletion are rendered anergic when they encounter self-antigens in the absence of costimulation. Such anergy may be broken if normal cells that do not usually express costimulatory molecules can be induced to do so. In fact, such induction may occur after infections or in other circumstances where there is tissue necrosis and local inflammation. Bypass of B-Cell Requirement for T-Cell Help: Many self-antigens have multiple determinants, some recognized by B cells, others by T cells. Antibody response to such antigens occurs only when potentially self-reactive B cells receive help from T cells, and tolerance to such antigens may be associated with deletion or anergy of helper T cells in the presence of fully competent specific B cells. Therefore, this form of tolerance may be overcome if the need for tolerant helper T cells is bypassed or substituted. One way to accomplish this is if the T-cell epitope of a self-antigen is modified, allowing recognition by helper T cells that were not deleted. These could then cooperate with the B cells, leading to the formation of autoantibodies. Such modification of the T-cell determinants of an autoantigen may result from complexing with drugs or microorganisms. Failure of T-Cell-Mediated Suppression: The possibility that diminished regulatory (suppressor) T-cell function might result in autoimmunity is quite attractive. Molecular Mimicry: Some infectious agents share epitopes with self-antigens, and an immune response against such microbes will elicit similar responses to the cross-reacting self-antigen. For VJs College of Pharmacy Page 25

AUTOIMMUNITY- A REVIEW

example, rheumatic heart disease sometimes follows streptococcal infection because antibodies to streptococcal M protein cross-react with cardiac glycoproteins. Molecular mimicry may also apply to T-cell epitopes. Dendritic cell apoptosis: immune system cells called dendritic cells present antigens to active lymphocytes. Dendritic cells that are defective in apoptosis can lead to inappropriate systemic lymphocyte activation and consequent decline in self-tolerance. T-Cell-B-Cell discordance: A normal immune response is assumed to involve B and T cell responses to the same antigen. However, if the B-cell recognizes an antigen, endocytoses and processes a protein which is different from the antigen, and presents it to the T-cell, it may result in autoimmunity. Cytokine Dysregulation: Some cytokines like IL-4, IL-10 and TGF- etc., seem to have a role in prevention of exaggeration of pro-inflammatory immune responses. Any dysregulations may lead to autoimmunity. Polyclonal Lymphocyte Activation: Tolerance in some cases is maintained by anergy. Autoimmunity may nevertheless occur if such self-reactive but anergic clones are stimulated by antigen-independent mechanisms. Several microorganisms and their products are capable of causing polyclonal (i.e., antigen-nonspecific) activation of B cells. Idiotype Cross-Reaction: Idiotypes are antigenic epitopes found in the antigen-binding portion (Fab) of the immunoglobulin molecule. Plotz and Oldstone presented evidence that autoimmunity can arise as a result of a cross-reaction between the idiotype on an antiviral antibody and a host cell receptor for the virus in question. In this case, the host-cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host cells. Aberrant B cell receptor-mediated feedback: A feature of human autoimmune disease is that it is largely restricted to a small group of antigens, several of which have known signaling roles in the immune response [DNA, C1q, IgGFc, Ro, Con. A receptor, Peanut agglutinin receptor (PNAR)]. This fact gave rise to the idea that spontaneous autoimmunity may result when the binding of antibody to certain antigens leads to aberrant signals being fed back to parent B cells through membrane bound ligands. These ligands include B cell receptor (for antigen), IgG Fc receptors, CD21, which binds complement C3d, Toll-like receptors 9 and 7 (which can bind DNA and nucleoproteins) and PNAR.

VJs College of Pharmacy

Page 26

AUTOIMMUNITY- A REVIEW

Inappropriate expression of class II MHC molecules on the membranes of cells that normally do not express class II MHC (e.g., islet cells). Increased expression of MHC II may increase presentation of self-peptides to T helper cells, which in turn induce CTL, TDTH, and B-lymphocyte cells that react against self-antigens.

Release of Sequestered Antigens: Regardless of the exact mechanism by which self-tolerance is achieved (deletion or anergy), it is clear that induction of tolerance requires interaction between a given antigen and the immune system. Thus, any self-antigen that is completely sequestered during development is likely to be viewed as foreign if subsequently introduced to the immune system. Spermatozoa and ocular antigens fall into this category. The mere release of antigens is not sufficient to cause autoimmunity; the inflammation associated with the tissue injury is also essential for the up-regulation of costimulatory pathways that are critical for the induction of an immune response.

Exposure of Cryptic Self and Epitope Spreading: It has been recently appreciated that "molecular sequestration" of antigens is much more common than is anatomic sequestration. Thus, each self-protein has relatively few antigenic determinants (epitopes) that are effectively processed and presented to T cells. During development, most T cells capable of reacting to such dominant epitopes are either deleted in the thymus or rendered anergic in the periphery. By contrast, a large number of self-determinants are not processed and therefore are not recognized by the immune system; thus, T cells specific for such "cryptic" self-epitopes are not deleted. It follows that such T cells could cause autoimmune diseases if the cryptic epitopes are somehow subsequently presented to them in an immunogenic form.

In any event, it is postulated that regardless of the initial trigger of an autoimmune response (e.g., infection with a cross-reacting microbe, release of a sequestered antigen, failure of suppressor T cells), the progression and chronicity of the autoimmune response is maintained by recruitment of autoreactive T cells that recognize normally cryptic self-determinants. The induction of such autoreactive T cells is sometimes referred to as epitope spreading because the immune response "spreads" to determinants that were initially not recognized.

VJs College of Pharmacy

Page 27

AUTOIMMUNITY- A REVIEW

4. CLASSIFICATION OF AUTOIMMUNE DISEASES 6


Autoimmune diseases can be broadly divided into systemic and organ-specific or localised autoimmune disorders, depending on the principal clinical and pathologic features of each disease. Systemic autoimmune diseases include SLE, Sjgren's syndrome, scleroderma, rheumatoid arthritis, and dermatomyositis. These conditions tend to be associated with autoantibodies to antigens which are not tissue specific. Thus although polymyositis is more or less tissue specific in presentation, it may be included in this group because the autoantigens are often ubiquitous tRNA synthetases. Local syndromes6 which affect a specific organ or tissue: o Endocrinologic: Diabetes mellitus type 1 Hashimoto's thyroiditis Addison's disease o Gastrointestinal: Coeliac disease Crohn's Disease Pernicious anaemia o Dermatologic: Pemphigus vulgaris Vitiligo o Haematologic: Autoimmune haemolytic anaemia Idiopathic thrombocytopenic purpura o Neurological: Myasthenia gravis Guillain-Barre syndrome Sometimes it is hard to distinguish between the above two classes of diseases, as there may be several overlapping features.

VJs College of Pharmacy

Page 28

AUTOIMMUNITY- A REVIEW

5. SOME COMMON AUTOIMMUNE DISORDERS 14,15


Systemic Lupus Erythematosus (SLE) This is a serious and potentially fatal autoimmune disease occurring predominantly in women. The disorder is found worldwide, although its incidence is higher in some ethnic groups such as Afro Caribbean and Chinese. The bodys immune system attacks connective tissue, causing severe inflammation. As connective tissue is widely distributed, the skin and many organs are affected. Recent research suggests that the autoimmune response is triggered by a failure in the bodys mechanism for clearing up the debris of dead cells. The affected person lacks an enzyme called DNase 1 which degrades DNA. Symptoms include Fig 6. SLE- Parts affected and symptoms

Fever, Weight loss, Hair loss, Mouth sores, Fatigue,

Butterfly rash across the nose and cheeks, Rashes on other parts of the body, Painful or swollen joints and muscle pain, Sensitivity to the sun, Chest pain, Headache, dizziness, seizure, memory problems, or change in behavior. Sjgrens Syndrome A disorder of connective tissue, with dryness of the mouth (xerostomia) and dryness of the eye (kerato conjunctivitis sicca) occurring in association with Rheumatoid Arthritis. It can occur independently of rheumatoid disease. The lack of tears gives rise to symptoms of dryness and grittiness of the eyes; the dry mouth can occasionally be so severe as to cause a dysphagia. The disease is due to the autoimmune destruction of the salivary glands and the lacrimal glands. The disorder is usually associated with specific HLA antigen. Other symptoms include sores in the mouth, Loss of sense of taste, Severe dental cavities, Hoarse Fig 7. Sjgrens syndrome- symptoms voice, Fatigue, Joint swelling or pain, Swollen glands, Cloudy eyes. VJs College of Pharmacy Page 29

AUTOIMMUNITY- A REVIEW

Scleroderma This is a rare autoimmune disease. Scleroderma circumscriptum (morphoea) affects the skin, usually of the trunk, producing indurated plaques which resolve over many years. The more serious systemic form of scleroderma usually begins with Raynauds Disease (This is a condition in which the circulation becomes suddenly obstructed in outlying parts of the body), eventually producing a deforming hardening and clawing of the hands. Later the face and sometimes the internal organs, particularly the gastrointestinal tract and kidneys, may be affected. Fingers and toes turn white, red, or blue in response to heat and cold. Other symptoms include skin that looks shiny on the hands and forearm, tight and mask-like facial skin, sores on the fingers or toes, trouble swallowing, weight loss, diarrhea or constipation, shortness of breath. Rheumatoid Arthritis (RA) Rheumatoid Arthritis is a chronic inflammation of the synovial lining of several joints, tendon sheaths or bursae which is not due to sepsis or a reaction to uric acid crystals. It is distinguished from other patterns of inflammatory arthritis by the symmetrical involvement of a large number of peripheral joints; by the common blood-finding of rheumatoid factor antibody; by the presence of bony erosions around joints; and, in a few, by the presence of subcutaneous nodules with Fig 8. One of the symptoms of scleroderma

necrobiotic (decaying) centers. There is a major immunogenetic predisposition to rheumatoid arthritis in people carrying the HLA-DR4 antigen. The symptoms Fig 9. Joint showing Rheumatoid Arthritis may be seen. VJs College of Pharmacy Page 30 include painful, stiff, swollen, and deformed joints, reduced movement and function. Fatigue, Fever, Weight

loss, Eye inflammation, and lung disease, Lumps of tissue under the skin, often the elbows and anemia

AUTOIMMUNITY- A REVIEW

Insulin-Dependent Diabetes Mellitus (IDDM; Type 1 Diabetes) Insulin-dependent diabetes occurs as a result of autoimmune destruction of beta cells within the pancreas. Genetic influences are important and individuals with certain HLA tissue types (HLA DR3 and HLA DR4) are more at risk. Subjects are prone to severe deficiency or absence of insulin production. Insulin therapy is essential to prevent ketosis a disturbance of the bodys acid/base balance and an accumulation of ketones in the tissues. The onset is most commonly during childhood, but can occur at any age. Symptoms are acute and weight loss is common. Other symptoms include polydipsia, polyuria, Feeling very hungry or tired, impaired wound healing, Dry and itchy skin, paraesthesia, having blurry eyesight etc. Hashimotos Disease This is a condition in which the whole of the thyroid gland is diffusely enlarged and firm. It is one of the diseases produced by autoimmunity. The enlargement is due to diffuse infiltration of lymphocytes and increase of fibrous tissue. This form of goiter appears in middle-aged women, does not give rise to symptoms of thyrotoxicosis (A disorder of the thyroid gland in which excessive amounts of thyroid hormones are secreted into the bloodstream), and tends to produce myxedema (the Fig 11. Hashimotos disease- Symptoms skin and subcutaneous tissues thicken and result in a coarse appearance). The symptoms include Fatigue, Weakness, Weight gain, Sensitivity to cold, Muscle aches and stiff joints, Facial swelling and Constipation. Fig 10. Mechanism of IDDM

VJs College of Pharmacy

Page 31

AUTOIMMUNITY- A REVIEW

Crohn's Disease This is a chronic inflammatory bowel disease (IBD) which has a protracted, relapsing and remitting course. This is an autoimmune condition; it may last for several years. There are many similarities with ulcerative colitis; sometimes it can be hard to differentiate between the two conditions. A crucial difference is that ulcerative colitis is confined to the colon, whereas Crohns disease can affect any part of the gastrointestinal tract, including the mouth and anus. The sites most commonly affected in Crohns disease (in order of frequency) are terminal ileum and right Fig 12. Crohns disease - Symptoms

side of colon, just the colon, just the ileum and finally the ileum and jejunum. The whole wall of the affected bowel is edematous and thickened, with deep ulcers a characteristic feature. Ulcers may even penetrate the bowel wall, with abscesses and fistulas developing. Another unusual feature is the presence in the affected bowel lining of islands of normal tissue. Other symptoms include abdominal pain, Diarrhea (which may be bloody), Rectal bleeding, Fever, Weight loss, Fatigue and Mouth ulcers. Vitiligo This is a disease in which small or large areas of skin lose their pigment and become white because of a reduction in the bodys production of melanin. The hair may be similarly affected. This probably is a consequence of an

autoimmune mechanism; vitiligo is associated with other autoimmune diseases such as thyroiditis and Addisons disease. There is no cure; the vitiliginous skin must be protected from sunburn. Fig 13. Vitiligo - Symptoms Other symptoms include white patches on areas exposed to the sun, on armpits, genitals, and rectum; early greying of hair, Loss of color inside the mouth. VJs College of Pharmacy Page 32

AUTOIMMUNITY- A REVIEW

Idiopathic thrombocytopenic purpura (ITP) This is an autoimmune disorder in which blood platelets are destroyed. This disturbs the bloods coagulative properties and spontaneous bleeding (purpura) occurs into the skin. The disease may be acute in children but most recover without treatment. Adults may develop a more serious, chronic variety which requires treatment with corticosteroids and sometimes splenectomy. Should the disease persist despite these treatments, intravenous immunoglobulin or Fig 14. Leg of a person affected with ITP

immunosuppressive drugs are worth trying. Should the bleeding be or become life-threatening, concentrates of

platelets should be administered. Symptoms include very heavy menstrual period, tiny purple or red dots on the skin that might look like a rash, easy bruising, nosebleed or bleeding in the mouth. Myasthenia gravis It is a classic example of an autoimmune disease. The body develops antibodies which interfere with the working of the nerve endings in muscle that are acted on by acetylcholine. It is acetylcholine that transmits the nerve impulses to muscles: if this transmission cannot be effected, as in myasthenia gravis, then the muscles are unable to contract. Not only the voluntary muscles, but those connected with the acts of swallowing, breathing, and the like, become progressively weaker. The thymus gland plays the major part in the cause of myasthenia gravis, possibly by being the source of the original acetylcholine receptors to which the antibodies are being formed. The symptoms include double vision, trouble keeping a steady gaze, drooping eyelids, Trouble Fig 15. Some of the muscles which can be affected by Myasthenia Gravis swallowing, Weakness or paralysis, Muscles that work better after rest, Drooping head.

VJs College of Pharmacy

Page 33

AUTOIMMUNITY- A REVIEW

Multiple Sclerosis (MS) Multiple sclerosis is a progressive disease of the brain and spinal cord, which, although slow in its onset, in time may produce marked symptoms such as paralysis and tremors, and may ultimately result in a severely disabled invalid. The disorder consists of hardened patches, from the size of a pin-head to that of a pea or larger, scattered here and there irregularly through the brain and spinal cord. Each patch is made up of a mass of the connective tissue (neuroglia), which should be present only in sufficient amount to bind the nerve-cells and fibres Fig 16. Multiple Sclerosis Parts affected

together. In the earliest stage, the insulating sheaths (myelin) of the nerve-fibres in the hardened patches break up, are absorbed, and leave the nerve-fibres bare, the connective tissue being later formed between these. The symptoms include weakness and trouble with coordination, balance, speaking, and walking; Paralysis, Tremors; Numbness and tingling feeling in arms, legs, hands, and feet. Symptoms vary because the location and extent of each attack vary.

VJs College of Pharmacy

Page 34

AUTOIMMUNITY- A REVIEW

6. DIAGNOSIS OF AUTOIMMUNE DISORDERS 6,16


The hallmark of autoimmune diseases generally involves the presence of self-reactive T cells, autoantibodies, and inflammation. Examining patients for potential autoimmune diseases is fraught with difficulty because no one laboratory test establishes such a diagnosis. In several systemic disorders, serological assays which can detect specific autoantibodies can be employed. Localized disorders are best diagnosed by immunofluorescence of biopsy specimens. Typically, multiple laboratory tests are needed and include basic studies like the following complete blood count (CBC) comprehensive metabolic panel measurement of acute-phase reactants immunologic studies Serology flow cytometry cytokine analysis HLA typing erythrocyte sedimentation rate (ESR)

Although some tests might be nonspecific, such as the erythrocyte sedimentation rate (ESR), they are useful for assessing disease activity. These tests can be useful in the diagnosis and management of patients with autoimmune diseases and help in providing a prognosis or indicating the severity of organ involvement or damage.

6.1 INITIAL LABORATORY EVALUATION


General: Characteristic findings can include a normochromic normocytic anemia indicating the chronicity or severity of disease. Common hematologic parameters also include an increased or decreased platelet count, white blood cell (WBC) count, or both. Serum protein levels are helpful to screen for abnormal increases of immunoglobulin levels. Disease specific: Leukopenia and thrombocytopenia are common in patients with systemic lupus erythematosus (SLE). Autoimmune hepatitis can be manifested by increases in transaminase, bilirubin, and serum protein levels. VJs College of Pharmacy Page 35

AUTOIMMUNITY- A REVIEW

Coagulation studies, such as a prolongation of the activated partial thromboplastin time, the prothrombin time, or both that do not correct with mixing studies, suggest an inhibitor of the clotting process is present, as seen in the antiphospholipid (APL) syndrome.

Hypercalcemia can be observed in approximately 30% of patients with sarcoidosis. An increase in muscle enzyme levels (creatinine kinase [CK], alanine transaminase [ALT], and aspartate aminotransferase [AST]) can be seen in autoimmune inflammatory myopathies (dermatomyositis [DM], polymyositis [PM], and inclusion body myositis [IBM]).

Urinalysis is commonly used to assess renal injury (glomerulonephritis and interstitial nephritis) and will show proteinuria, hematuria, or active sediment (WBC casts or red blood cell [RBC] casts).

Many other illnesses can be tested similarly.

6.2 INFLAMMATORY MARKERS


Serum proteins that are produced in response to inflammation can be referred to as inflammatory markers. These proteins are mainly produced by the liver in response to stress and can also be called acute-phase reactants. Proinflammatory cytokines, such as IL-1, IL-6, and TNF-, induce synthesis of some acute-phase reactants that include C-reactive protein (CRP), fibrinogen, and haptoglobin. The inflammatory markers are not diagnostic of inflammation but reflect abnormalities that are seen in autoimmune diseases, infections, malignancies, and other illnesses. ESR: The ESR is the measure of the quantity of RBCs that precipitate in a tube in a defined time and is based on serum protein concentrations and RBC interactions with these proteins. Inflammation causes an increase in the ESR. Multiple factors influence the ESR and include the patient's age, sex, RBC morphology, hemoglobin concentration, and serum level of immunoglobulin. The sample must be handled appropriately and processed within a few hours to ensure test accuracy. Although the ESR is not a diagnostic test, it can be used to monitor disease activity and treatment response and signal that inflammatory or infectious stress is present. CRP: CRP/CRP high sensitivity was discovered and named for its reactivity to the C polysaccharide in the cell wall of Streptococcus pneumoniae. CRP, an innate immune protein, helps opsonize pathogens for phagocytosis and activates the complement system. The magnitude of inflammation directly relates to the concentration of CRP. Levels of less than 0.2 mg/dL are considered normal, whereas those greater than 1.0 mg/dL are suggestive of inflammation, infection, or both. VJs College of Pharmacy Page 36

AUTOIMMUNITY- A REVIEW

Ferritin: Serum ferritin is a storage protein for iron, and its synthesis is regulated by intracellular iron, cytokines (TNF-, IL-1, and IL-6), products of oxidative stress, and growth factors. Increased levels can indicate acute or chronic sepsis, inflammation, or malignancy. Diseases such as adult Still disease, systemic-onset juvenile idiopathic arthritis (JIA), hemophagocytic lymphohistiocytosis, and iron-overload diseases, including hemochromatosis or hemosiderosis, should be considered with increased ferritin levels.

Less common indicators of inflammatory states: Ceruloplasmin is the major copper-containing protein in the blood that plays a role in iron metabolism, and its concentration is increased in patients with acute and chronic inflammatory states, pregnancy, lymphoma, RA, and Alzheimer disease. Fibrinogen is a hemostatic coagulation factor produced in response to tissue injury. Fibrinogen synthesis is controlled at the transcriptional level and is increased in the presence of inflammation and stress that is mediated by IL-6. Haptoglobin is produced in response to tissue injury. Increased levels of haptoglobin can be seen during inflammation, malignancy, surgery, trauma, peptic ulcer disease, and ulcerative colitis. Decreased levels might indicate chronic liver disease or anemia. Albumin is a serum protein synthesized by the liver that aids body tissues in maintaining the oncotic pressure necessary for proper body fluid distribution. The average amount of albumin in the plasma is approximately 300 to 400 g, and about 15 g is produced by the liver per day. Although the rate of synthesis can double in situations of rapid albumin loss, as seen in glomerulonephritis or inflammatory bowel disease, serum levels will decrease.

6.3 AUTOANTIBODIES AND IMMUNOLOGIC STUDIES


Autoantibodies are used to diagnose many autoimmune diseases. The presence of an autoantibody in a patient does not ensure a diagnosis of an autoimmune disease. But the levels of autoantibodies are measured to determine the progress of the disease. Many different methods were used to test for the presence of an autoantibody. Today, testing is principally done with enzyme immunosorbent assays because of cost-saving measures with mechanization. ELISA: The ELISA is an immunometric method for detecting and measuring specific antibodies. In a typical double-antibody sandwich ELISA, an antibody that is attached to the bottom of a well provides both antigen capture and immune specificity while another antibody linked to an enzyme VJs College of Pharmacy Page 37

AUTOIMMUNITY- A REVIEW

provides detection and acts as an amplification factor. This allows for accurate and sensitive detection of the antigen of interest. ELISAs permit measurement of only 1 antigen at a time for a given aliquot of sample. Rheumatoid factor and anticyclic citrullinated peptide antibody: Rheumatoid factor (RF) is an autoantibody that reacts to the Fc portion of polyclonal IgG, although it can be any class of immunoglobulin. Most assays detect the IgM RF. Rheumatoid factor is helpful in evaluating the patients with suspected Rheumatoid arthritis, Sjgren syndrome, SLE, and cryoglobulinemia; in pulmonary diseases, such as interstitial fibrosis and silicosis; and in various infectious diseases. Antinuclear antibody: Autoantibodies to nuclear antigens are a diverse group of antibodies that react against nuclear, nucleolar, or perinuclear antigens. Classically, the antinuclear antibody (ANA) hallmarks the serologic diagnosis of SLE. SLE, Sjgren syndrome, RA, mixed connective tissue disease, scleroderma can be found out by this method. Antidouble-stranded DNA: Autoantibodies to double-stranded DNA (dsDNA) are an important marker used in the diagnosis and monitoring of SLE. Antibodies to dsDNA are highly specific for SLE. Antiextractable nuclear antigen: The extractable nuclear antigens consist of the Smith antigen, ribonucleoprotein (RNP) or U1RNP, anti-SSA (Ro), and anti-SSB (La). SLE, systemic sclerosis, mixed connective tissue disease, Sjgren syndrome, subcutaneous lupus erythematosus and neonatal lupus can be diagnosed with this method. Antisignal recognition particle, antiJo-1, anti- Mi-2 and anti-PM/Scl: Antisignal recognition particle (anti-SRP), antiJo-1, antiMi-2 and anti-PM/Scl are termed myositis-specific antibodies because of the high specificity to the autoimmune idiopathic inflammatory myopathies (IIMs). Anti-neutrophil cytoplasmic antibody (myeloperoxidase and proteinase 3): Anti-neutrophil cytoplasmic antibodies (ANCAs) react with cytoplasmic granules of neutrophils. Vasculitis, Wegener granulomatosis, microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), inflammatory bowel disease, SLE, rheumatoid arthritis, and juvenile idiopathic arthritis (JIA) can be diagnosed. Complement: The complement cascade is a complex, tightly regulated series of proteolytic enzymes, regulatory proteins, and cell-surface receptors that mediate and augment both the complement, humoral, and cellular immune response. Immunoglobulins (quantitative and qualitative): Measuring total quantitative immunoglobulin levels, is a key component to any immunologic evaluation. The immunoglobulin levels reflect B-cell function (humoral production and T-cell interaction), and serum immunoglobulin levels aid in disease detection.

VJs College of Pharmacy

Page 38

AUTOIMMUNITY- A REVIEW

Cryoglobulins: Cryoglobulins are immunoglobulins that precipitate reversibly in cold temperatures. In disease states these antibodies can bind with complement proteins and other peptides to form immune complexes and cause tissue damage. Multiple myeloma, Waldenstrom macroglobulinemia, lymphoproliferative disorders, hepatitis C, small-vessel vasculitis, purpura, ulcerations, Raynaud phenomenon, arthralgias, proteinuria, and renal failure are associated with Cryoglobulins. Lupus anticoagulant/anticardiolipin/aPL autoantibodies: In patients with autoimmune disease, serum antibodies that inhibit or prolong in vitro clinical laboratory coagulation tests are termed aPL antibodies (also called anti-cardiolipin antibodies, anti-phospholipid antibodies or lupus anticoagulant) because they are directed against phospholipids and phospholipid-binding proteins. The existence of these antibodies is associated with the antiphospholipid antibody syndrome (APS). The auto antibodies for some autoimmune diseases are tabulated below. AUTOANTIBODY Anti-dsDNA Anti-Sm Anti-ribosomal P Anti-topoisomerase I (Scl-70) Anti-CCP (citrulline-modified proteins) Anti-SS-A/Ro Anti-SS-B/La Anti-U1-RNP Anti-PM-Scl Anti-Jo-1 Anti-thyroglobulin (TGA) Anti-thyroid peroxidase enzyme (TPO) Insulin and glutamic acid decarboxylase Type 1 Diabetes Mellitus Polymyositis or Dermatomyositis Thyroiditis Mixed Connective Tissue Disease (MCTD) Scleroderma Rheumatoid Arthritis Sjgrens Syndrome (Sjs) AUTOIMMUNE DISEASE Systemic Lupus Erythematosus (SLE)

autoantibodies Anti-mitochondrial autoantibody Primary Billiary Cirrhosis Table-117 Organ-specific diseases are associated with autoantibodies specific to the main affected organ, like in, in and in. The autoantibodies may represent a status of disease activity or predict a future pathogenic condition. VJs College of Pharmacy Page 39

AUTOIMMUNITY- A REVIEW

6.4 FLOW CYTOMETRY


Flow cytometry is a technique in which particles or tagged cells flow through laser light so that populations of particles/cells can be counted and phenotyped by using cell characteristics and surface proteins. When evaluating a patient with a suspected immunodeficiency, flow cytometry is crucial to determine the quantitative number of immune cells (typically T, B, and natural killer cells). Flow cytometric testing reveals numbers of cells and does not indicate cellular function.

Fig 17. Schematic diagram of flow cytometry

6.5 CYTOKINE STUDIES


Cytokines are molecules secreted by a variety of cells that function in cellular communication. Laboratory testing of cytokines is laborious because of the labile nature of these small molecules. Laboratory methods commonly used to assay cytokine levels include flow cytometry and ELISA. Cytokines that influence inflammation include IL-1, IL-6, and TNF-. There is extensive evidence that these cytokines promote inflammation and therefore have become targets for therapy. Rheumatoid Arthritis is the best example of an autoimmune illness in which anti-TNF therapy has revolutionized the natural history of the disease. Targeting TNF with proteins (fusion produced or mAbs) that antagonize TNF action results in dramatic improvement of disease activity. In fact, Rheumatoid Arthritis is the prototypic autoimmune disease in which the efficacy of anticytokine therapy is best demonstrated. VJs College of Pharmacy Page 40

AUTOIMMUNITY- A REVIEW

Currently, anti-TNF, antiIL-1, and antiIL-6 therapies have all proved to be effective in treating Rheumatoid Arthritis.

6.6 MHC (HLA)


HLA is synonymous with MHC. MHC classes I and II genes are the major genetic determinants of susceptibility to many autoimmune diseases. MHC class I molecules include HLA-A, HLA-B, and HLAC. MHC class II molecules include HLA-DR, HLA-DQ, and HLA-DP. Detection of HLA type can be done routinely and can be assayed by using several methods that include gel electrophoresis, PCR, ELISA, and newer methods using high-throughput detection of nucleic acid. Many antigens of the MHC, especially of HLA class I and II, have been associated with rheumatic disorders.

VJs College of Pharmacy

Page 41

AUTOIMMUNITY- A REVIEW

7. TREATMENT
Treatments for autoimmune disease have traditionally been immunomodulatory, antiinflammatory (steroids), or palliative. Non-immunological therapies, such as hormone replacement treat outcomes of the auto aggressive response, thus these are palliative treatments. Steroidal or NSAID treatment limits inflammatory symptoms of many diseases.6 Lifestyle and dietary modifications often help in managing these diseases. The important drugs that are used in the treatment of autoimmune diseases are briefly described.

7.1 IMMUNOSUPPRESSANTS
Immunosuppressive agents are often employed in debilitating cases of autoimmune disease to curb the production of autoantibodies. 7.1.1 GENERAL PRINCIPLES OF IMMUNOSUPPRESSIVE THERAPY 8 Before describing individual drugs, it is important to consider three principles of immunosuppressive therapy. (1) Primary immune responses are more readily inhibited than are secondary responses. Therefore, components of the primary phase of the immune response, such as processing, proliferation, and differentiation, will be the most sensitive to drug action. Drugs that are effective in suppressing an immune response in an unsensitized person generally will show much less effect, if any, in a sensitized individual. Once a population of memory cells has been established, immunosuppressive drugs show little effectiveness. (2) Not all immune responses are equally affected by immunosuppressive drugs. Cellular and humoral immunity may be affected differentially. Additionally, the different classes of immune globulins in a humoral response may be variably affected. (3) Beneficial effects other than immunosuppression may result from therapy with these drugs. In particular, the anti-inflammatory properties of certain of these drugs may be valuable because inflammation often accompanies the immune response. If only an inflammatory reaction is present, a true anti-inflammatory drug, such as a corticosteroid, that is devoid of the many side effects of immunosuppressive agents should be used.

VJs College of Pharmacy

Page 42

AUTOIMMUNITY- A REVIEW

Fig 18. Immune reaction and immunosuppressants VJs College of Pharmacy Page 43

AUTOIMMUNITY- A REVIEW

7.1.2 CORTICOSTEROIDS Corticosteroids (Glucocorticoids) were the first hormonal agents recognized as having lympholytic properties.3 prednisone or prednisolone is employed for autoimmune conditions. The exact mechanism responsible for the immunosuppressive action of the corticosteroids is unclear. The T lymphocytes are affected most. The steroids are able to rapidly reduce lymphocyte populations by lysis or redistribution. On entering cells, they bind to the glucocorticoid receptor. The complex passes into the nucleus and regulates the translation of DNA. Among the genes affected are, those involved in inflammatory responses.18 Although corticosteroids possess immunosuppressive properties, their real value is in controlling the inflammation that can accompany transplantation and autoimmune disorders. 8 Administration of glucocorticoids has no toxic effect on proliferating myeloid or erythroid stem cells in the bone marrow.3 Clinical uses: Corticosteroid therapy alone is successful in only a limited number of autoimmune diseases, such as idiopathic thrombocytopenia, hemolytic anemia, and polymyalgia rheumatica.8 High dose pulses of intravenous methylprednisolone sodium succinate are used to reverse acute exacerbations of selected autoimmune disorders. Glucocorticoids are used routinely to treat autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, systemic dermatomyositis, psoriasis and other skin conditions, asthma and other allergic disorders, inflammatory bowel disease, inflammatory ophthalmic diseases, autoimmune hematologic disorders, and acute exacerbations of multiple sclerosis.4 Unwanted effects: The use of these agents is associated with numerous adverse effects. For example, they are diabetogenic, and they can cause hypercholesterolemia, cataracts, osteoporosis, and hypertension on prolonged use.18 7.1.3 IMMUNOPHILIN LIGANDS CYCLOSPORINE Cyclosporine is a compound first found in fungus. It consists of a cyclic peptide of 11 amino acid residues with potent immunosuppressive activity.5 The molecule is very lipophilic and essentially is not soluble in water. It can be administered intravenously, orally, or by injection.8 The actions of relevance to immunosuppression are:

Decreased clonal proliferation of T cells, primarily by inhibiting IL-2 synthesis and possibly also by decreasing expression of IL-2 receptors.

VJs College of Pharmacy

Page 44

AUTOIMMUNITY- A REVIEW

Reduced induction, and clonal proliferation, of cytotoxic T cells from CD8+ precursor T cells. Reduced function of the effector T cells that are responsible for cell-mediated responses (e.g. decreased delayed-type hypersensitivity).

Some reduction of T cell-dependent B-cell responses. Exhibits a high degree of specificity in its actions on T cells without significantly impairing B cell activity.5,8

The main action is a relatively selective inhibitory effect on IL-2 gene transcription, although a similar effect on interferon (IFN)- and IL-3 has also been reported.5 Normally, interaction of antigen with a T-helper cell receptor results in increased intracellular Ca2+, which in turn stimulates a phosphatase, calcineurin; this activates various transcription factors that initiate IL-2 transcription. Cyclosporine binds to cyclophilin, a cytosolic protein member of the immunophilins (a group of proteins that act as intracellular receptors for such drugs). The drug- immunophilin complex binds to and inhibits calcineurin, thereby preventing activation of Th cells and production of IL-2.5 Clinical uses: Higher doses of cyclosporine are often required to suppress autoimmune disorders. It has a beneficial effect on the course of rheumatoid arthritis, uveitis, insulin dependent diabetes, systemic lupus erythematosus, and psoriatic arthropathies in some patients.8 Cyclosporine is an alternative to methotrexate for the treatment of severe, active rheumatoid arthritis. It can also be used for patients with recalcitrant psoriasis that does not respond to other therapies.18 It is a second line drug in autoimmune diseases, like severe rheumatoid arthritis, uveitis, bronchial asthma, inflammatory bowel disease, dermatomyositis, etc. and in psoriasis, especially to suppress acute exacerbations.19 Unwanted effects: Many of the adverse effects caused by Cyclosporine are dose dependent; therefore, it is important to monitor blood levels of the drug. The commonest and most serious unwanted effect of cyclosporine is nephrotoxicity, which is thought to be unconnected with calcineurin inhibition. Reduction of the dosage can result in reversal of nephrotoxicity in most cases, although nephrotoxicity may be irreversible in 15% of patients. Hyperlipidemia, Hyperkalemia, Hepatotoxicity and hypertension can also occur. Less important unwanted effects include anorexia, lethargy, hirsutism, tremor, paraesthesia (tingling sensation), gum hypertrophy (especially when coprescribed with calcium antagonists for hypertension), glucose intolerance and gastrointestinal disturbances. Cyclosporine has no depressant effects on the bone marrow.5,18 Transient liver dysfunction, and unwanted hair growth are also observed.8

VJs College of Pharmacy

Page 45

AUTOIMMUNITY- A REVIEW

TACROLIMUS 3,5,18 Tacrolimus is a macrolide antibiotic of fungal origin (soil fungus) with a very similar mechanism of action to cyclosporine, but considerably more potency. The main difference is that the internal receptor for this drug is not cyclophilin but a different immunophilin termed FKBP-12 (FK-binding protein). The tacrolimus-FKBP complex inhibits calcineurin. Clinical uses: An ointment preparation has been approved for moderate to severe atopic dermatitis that does not respond to conventional therapies. It is also used in the therapy of psoriasis. Unwanted effects: similar to those of cyclosporine but are more severe. The incidence of nephrotoxicity and neurotoxicity is higher, but that of hirsutism is lower. Nephrotoxicity and neurotoxicity (tremor, seizures, and hallucinations) tend to be more severe in patients, who are treated with tacrolimus than in patients treated with cyclosporine, but careful dose adjustment can minimize this problem. Gastrointestinal disturbances and metabolic disturbances (hyperglycemia) can occur. Thrombocytopenia and hyperlipidemia have been reported but respond to reducing the dosage. SIROLIMUS 3,20 Sirolimus is derived from Streptomyces hygroscopicus and binds immunophilins and inhibits calcineurin. It does not block interleukin production by activated T cells but instead blocks the response of T cells to cytokines. It is a potent inhibitor of B-cell proliferation and immunoglobulin production. Clinical uses: Topical sirolimus is also used in some dermatologic disorders such as psoriasis. Unwanted effects: Toxicities of sirolimus can include profound myelosuppression (especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, and headache. 7.1.4 MYCOPHENOLATE MOFETIL (MMF) 3,5 Mycophenolate mofetil is a semisynthetic derivative of a fungal antibiotic. In the body, it is converted to mycophenolic acid, which restrains proliferation of both T and B lymphocytes and reduces the production of cytotoxic T cells by inhibiting inosine monophosphate dehydrogenase, an enzyme crucial for de novo purine biosynthesis in both T and B cells (other cells can generate purines through another pathway), so the drug has a fairly selective action. Clinical uses: applications for MMF include lupus nephritis, rheumatoid arthritis, and some dermatologic disorders.

VJs College of Pharmacy

Page 46

AUTOIMMUNITY- A REVIEW

Unwanted effects: Toxicities include gastrointestinal disturbances (nausea and vomiting, diarrhea, abdominal pain) headache, hypertension and reversible myelosuppression (primarily neutropenia). 7.1.5 THALIDOMIDE 3 Thalidomide inhibits angiogenesis and has anti-inflammatory and immunomodulatory effects. It inhibits TNF-, reduces phagocytosis by neutrophils, increases production of IL-10, alters adhesion molecule expression, and enhances cell-mediated immunity via interactions with T cells. Clinical uses: Thalidomide has been used for many years in the treatment of some manifestations of leprosy and has been reintroduced in the USA for erythema nodosum leprosum; it is also useful in management of the skin manifestations of lupus erythematosus. Unwanted effects: The most important toxicity is teratogenesis. Other adverse effects of thalidomide include peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, and increased risk of deep vein thrombosis. 7.1.6 CYTOTOXIC AGENTS AZATHIOPRINE 5,8,18 Azathioprine interferes with purine synthesis and is cytotoxic. It is widely used for immunosuppression. This drug is metabolised to give mercaptopurine, a purine analogue that inhibits DNA synthesis. Both cell-mediated and antibody-mediated immune reactions are depressed by this drug. Azathioprine is a relatively powerful anti-inflammatory agent. Although its beneficial effect in various conditions is principally attributable to its direct immunosuppressive action, the anti-inflammatory properties of the drug play an important role in its overall therapeutic effectiveness. Clinical uses: Azathioprine has applications in certain disorders with autoimmune components, most commonly rheumatoid arthritis. It is as effective as cyclophosphamide in the treatment of Wegeners granulomatosis. Unwanted effects: The main unwanted effect is depression of the bone marrow. Other toxic effects are nausea and vomiting, skin eruptions and a mild hepatotoxicity. The drug has little effect on suppressing a chronic immune response. It has been shown to be mutagenic in animals and humans and carcinogenic in animals.

VJs College of Pharmacy

Page 47

AUTOIMMUNITY- A REVIEW

MERCAPTOPURINE 3 Mercaptopurine produces immunosuppression by interfering with purine nucleic acid metabolism at steps that are required for the wave of lymphoid cell proliferation that follows antigenic stimulation. The purine analogs are thus cytotoxic agents that destroy stimulated lymphoid cells. Although continued messenger RNA synthesis is necessary for sustained antibody synthesis by plasma cells, these analogs appear to have less effect on this process than on nucleic acid synthesis in proliferating cells. Cellular immunity as well as primary and secondary serum antibody responses can be blocked by this cytotoxic agent. Clinical uses: These antimetabolites have been used with some success in the management of acute glomerulonephritis and in the renal component of systemic lupus erythematosus. They have also proved useful in some cases of rheumatoid arthritis, Crohn's disease, and multiple sclerosis. The drugs have been of occasional use in prednisone-resistant antibody-mediated idiopathic thrombocytopenic purpura and autoimmune hemolytic anemias. Unwanted effects: The chief toxic effect of azathioprine and mercaptopurine is bone marrow suppression, usually manifested as leukopenia, although anemia and thrombocytopenia may occur. Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur, with the gastrointestinal symptoms seen mainly at higher dosages. Hepatic dysfunction, manifested by very high serum alkaline phosphatase levels and mild jaundice, occurs occasionally, particularly in patients with preexisting hepatic dysfunction. CYCLOPHOSPHAMIDE 3,8,19 This is an alkylating agent which forms covalent linkages with the macromolecules such as DNA, RNA and enzymes. This property accounts for its cytotoxic effect. This drug has more marked effect on B cells and humoral immunity compared to that on T cells and cell-mediated immunity. Clinical uses: In rheumatoid arthritis, it is rarely used, only when systemic manifestations are marked. Low doses are occasionally employed for maintenance therapy in pemphigus, systemic lupus erythematosus and idiopathic thrombocytopenic purpura. In smaller doses, it has been effective against autoimmune disorders (including systemic lupus erythematosus) and in patients with acquired factor XIII antibodies and bleeding syndromes, autoimmune hemolytic anemia, antibody-induced pure red cell aplasia, and Wegener's granulomatosis. Unwanted effects: Treatment with large doses of cyclophosphamide carries considerable risk of pancytopenia and hemorrhagic cystitis. Other adverse effects of cyclophosphamide include nausea, vomiting, cardiac toxicity, and electrolyte disturbances. VJs College of Pharmacy Page 48

AUTOIMMUNITY- A REVIEW

LEFLUNOMIDE 5,8 Leflunomide has a relatively specific inhibitory effect on activated T cells. It gives rise to a metabolite that inhibits de novo synthesis of pyrimidines by inhibiting dihydroorotate dehydrogenase. Clinical uses: It is approved in the treatment of rheumatoid arthritis. Unwanted effects: Diarrhea occurs in approximately one-third of patients taking this drug; indigestion, nausea, and vomiting occur in about 10%. Other common adverse effects include weight changes, headache, skin rashes, pruritus, and reversible alopecia and hepatic enzyme elevation. Although leflunomide acts as an immunosuppressive, it does not appear to cause significant bone marrow depression. METHOTREXATE 8,19 Methotrexate competitively inhibits the binding of folic acid to the enzyme dihydrofolate reductase. This enzyme catalyzes the formation of tetrahydrofolate, as follows: Folic acid (FH2)
dihydrofolate reductase

tetrahydrofolate (FH4)

Tetrahydrofolate is in turn converted to N5, N10- methylenetetrahydrofolate, which is an essential cofactor for the synthesis of thymidylate, purines, methionine, and glycine. The major mechanism by which methotrexate brings about cell death appears to be inhibition of DNA synthesis through a blockage of the biosynthesis of thymidylate and purines. Clinical uses: methotrexate has been used as an immunosuppressive agent in severe rheumatoid arthritis. It has been used as a first line drug in many autoimmune diseases like rapidly progressing rheumatoid arthritis, severe psoriasis, pemphigus, myasthenia gravis, uveitis, chronic active hepatitis. Unwanted effects: Myelosuppression is the major dose-limiting toxicity associated with methotrexate therapy. Gastrointestinal toxicity may appear in the form of ulcerative mucositis and diarrhea. Nausea, alopecia, and dermatitis are common with high-dose methotrexate. Methotrexate is a potent teratogen and abortifacient.

VJs College of Pharmacy

Page 49

AUTOIMMUNITY- A REVIEW

VINCRISTINE 3,8 Vincristine binds avidly to tubulin, a class of proteins that form the mitotic spindle during cell division. The drugs cause cellular arrest in metaphase during mitosis, and cell division cannot be completed. Clinical uses: useful in idiopathic thrombocytopenic purpura refractory to prednisone. Unwanted effects: Neurological toxicity is the major dose-limiting toxicity of vincristine.

7.2 IMMUNOSUPPRESSIVE ANTIBODIES


Introduction 3 The development of hybridoma technology by Milstein and Kohler in 1975 revolutionized the antibody field and radically increased the purity and specificity of antibodies used in the clinic and for diagnostic tests in the laboratory. Hybridomas consist of antibody-forming cells fused to immortal plasmacytoma cells. Hybrid cells that are stable and produce the required antibody can be subcloned for mass culture for antibody production. Large-scale fermentation facilities are now used for this purpose in the pharmaceutical industry. More recently, molecular biology has been used to develop monoclonal antibodies. Combinatorial libraries of cDNAs encoding immunoglobulin heavy and light chains expressed on bacteriophage surfaces are screened against purified antigens. The result is an antibody fragment with specificity and high affinity for the antigen of interest. This technique has been used to develop antibodies specific for viruses (e.g., HIV), bacterial proteins, tumor antigens, and even cytokines. Several antibodies developed in this manner are in clinical trials. Other genetic engineering techniques involve production of chimeric and humanized versions of murine monoclonal antibodies in order to reduce their antigenicity and increase the half-life of the antibody in the patient. Murine antibodies administered as such to human patients evoke production of human antimouse antibodies (HAMA), which clear the original murine proteins very rapidly. Humanization involves replacing most of the murine antibody with equivalent human regions while keeping only the variable, antigen- specific regions intact. Chimeric mouse-human antibodies have similar properties with less complete replacement of the murine components. The current naming convention for these engineered substances uses the suffix "umab" or "zumab" for humanized antibodies, and "imab" or "ximab" for chimeric products. These procedures have been successful in reducing or preventing HAMA production for many of the antibodies discussed below. Monoclonal antibodies against T-cell surface proteins are increasingly being used in the clinic for autoimmune disorders and in transplantation settings.

VJs College of Pharmacy

Page 50

AUTOIMMUNITY- A REVIEW

IMMUNE GLOBULIN INTRAVENOUS (IGIV) 3 This immunoglobulin preparation (usually IgG) is prepared from pools of thousands of healthy donors, and no specific antigen is the target of the "therapeutic antibody." Rather, one expects that the pool of different antibodies will have a normalizing effect upon the patient's immune networks. It has also brought about good clinical responses in systemic lupus erythematosus and refractory idiopathic thrombocytopenic purpura. Possible mechanisms of action of IGIV include a reduction of T helper cells, increase of suppressor T cells, decreased spontaneous immunoglobulin production, Fc receptor blockade, increased antibody catabolism, and idiotypic-anti-idiotypic interactions with "pathologic antibodies." Although its precise mechanism of action is still controversial, IGIV brings undeniable clinical benefit to many patients with a variety of immune syndromes. MONOCLONAL ANTIBODIES (MABS) Recent advances in the ability to manipulate the genes of immunoglobulins have resulted in development of a wide array of humanized and chimeric monoclonal antibodies directed against therapeutic targets. The only murine elements of humanized monoclonal antibodies are the complementarity-determining regions in the variable domains of immunoglobulin heavy and light chains. Complementarity-determining regions are primarily responsible for the antigen-binding capacity of antibodies. Chimeric antibodies typically contain antigen-binding murine variable regions and human constant regions. The following are brief descriptions of the engineered antibodies that have been approved by the FDA.3 Anti-TNF- MABs

Adalimumab is a completely human IgG1 approved for use in rheumatoid arthritis. Like the other anti- TNF- biologicals, adalimumab blocks the interaction of TNF- with TNF receptors on cell surfaces; it does not bind TNF- .3 This recombinant human IgG1 monoclonal antibody was created by phage display technology and is approved for use in rheumatoid arthritis.4

Etanercept is a dimeric fusion protein composed of human IgG1 constant regions (CH2, CH3 , and hinge, but not CH1 ) fused to the TNF receptor. Etanercept binds to both TNF- and TNF- and appears to have effects similar to that of infliximab, i.e., inhibition of TNF--mediated inflammation, but its half-life is shorter due to its physical form (fusion protein) and the route of

VJs College of Pharmacy

Page 51

AUTOIMMUNITY- A REVIEW

injection (subcutaneously, twice weekly). Etanercept is approved for adult RA, polyarticularcourse juvenile RA, and psoriatic arthritis. It may be used in combination with methotrexate.3,8

Infliximab is a human-mouse chimeric IgG1 monoclonal antibody possessing human constant (Fc) regions and murine variable regions. Infliximab is currently approved for use in Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis.3,4

ABATACEPT 3 Abatacept is a recombinant fusion protein composed of the extracellular domain of cytotoxic Tlymphocyte-associated antigen 4 (CTLA-4) fused to human IgG Fc. CTLA-4 is a costimulatory molecule found on T cells that binds to CD80 and CD86 on antigen presenting cells. This fusion protein blocks activation of T cells by binding to CD80 or 86 so that CD28 on T cells cannot bind and stimulate the T cell and lead to cytokine release. Abatacept is approved for patients with severe rheumatoid arthritis who have failed other DMARDS. Patients should not take other anti-TNF drugs or anakinra while taking abatacept. ALEFACEPT 3 Alefacept is an engineered protein consisting of the CD2-binding portion of leukocyte-functionassociated antigen-3 (LFA-3) fused to a human IgG1 Fc region (hinge, CH1, and CH2), approved for the treatment of plaque psoriasis. It inhibits activation of T cells by binding to cell surface CD2, inhibiting the normal CD2/LFA-3 interaction. Treatment of patients with alefacept also results in a dose-dependent reduction of the total number of circulating T cells, including those that predominate in psoriatic plaques. Therefore, T-cell counts of patients receiving alefacept must be monitored, and the drug discontinued if CD4 lymphocyte levels fall below 250 cells/ L. EFALIZUMAB 3 Efalizumab is a recombinant humanized anti-CD11a monoclonal antibody approved for the treatment of adult patients with severe psoriasis. Binding of efalizumab to CD11a (the alpha subunit of LFA-1) inhibits the interaction of LFA-1 on all lymphocytes with intercellular adhesion molecule-1 (ICAM-1), thereby inhibiting the adhesion, activation, and migration of lymphocytes into skin. Efalizumab is administered by subcutaneous injection. OMALIZUMAB3 Omalizumab is an anti-IgE recombinant humanized monoclonal antibody that is approved for the treatment of allergic asthma in adult and adolescent patients whose symptoms are refractory to inhaled VJs College of Pharmacy Page 52

AUTOIMMUNITY- A REVIEW

corticosteroids. The antibody blocks the binding of IgE to the high-affinity Fc receptor on basophils and mast cells, which suppresses IgE-mediated release of type I allergy mediators such as histamine and leukotrienes. Total serum IgE levels may remain elevated in patients for up to 1 year after administration of this antibody.

7.3 OTHER IMPORTANT DRUGS


CHLORAMBUCIL 3,19 It has relatively weak immunosuppressant action which is sometimes utilised in autoimmune diseases. Chlorambucil, probably through its metabolite phenyl acetic acid mustard, cross-links DNA, thereby preventing cell replication. Clinical uses: Chlorambucil is used in rheumatoid arthritis Behet's disease, systemic lupus erythematosus, vasculitis, and other autoimmune disorders. Unwanted effects: The most common toxicity is dose-related bone marrow suppression. Infertility with azoospermia and amenorrhea also occurs. The risk of neoplasia is increased, with the relative risk of leukemia increased about tenfold compared with the general population, especially after more than 3 years of use. GOLD COMPOUNDS 3 Gold compounds were first proved to be effective in a large double-blind trial in 1960. Because of their toxicity, they are used infrequently today. Their intramuscular formulations (aurothiomalate and aurothioglucose) contain 50% elemental gold. The oral formulation (auranofin) contains 29% elemental gold. Gold alters the morphology and functional capabilities of human macrophages possibly its major mode of action. As a result, monocyte chemotactic factor-1, interleukin-8, interleukin-1 production, and vascular endothelial growth factor (VEGF) are all inhibited. Intramuscular gold compounds also alter lysosomal enzyme activity, reduce histamine release from mast cells, inactivate the first component of complement, and suppress the phagocytic activities of polymorphonuclear leukocytes. Oral gold (auranofin) also inhibits release of prostaglandin E2 and leukotriene B4. Clinical uses: Gold is effective for active rheumatoid arthritis and has been shown to slow radiologic progression of the disease. It has also been used in Sjgren's syndrome and juvenile rheumatoid arthritis. In Japan, gold is used to treat asthma. The oral form of gold is effective in rheumatoid arthritis. VJs College of Pharmacy Page 53

AUTOIMMUNITY- A REVIEW

Unwanted effects: Pruritic skin rashes occur, sometimes associated with eosinophilia. Stomatitis and a metallic taste in the mouth are common. Hematologic abnormalities occur, including thrombocytopenia, leukopenia, and pancytopenia. Aplastic anemia, while very rare, may be fatal. Some patients may develop proteinuria that may progress to nephrotic syndrome. Rare toxicities include enterocolitis, cholestatic jaundice, peripheral neuropathy, and pulmonary infiltrates. Corneal gold deposition occurs but has little clinical import. Nitritoid reactions (sweating, flushing, and headaches) can occur, especially with gold thiomalate, and are presumably due to the vehicle rather than the gold salts. INTERLEUKIN-1 ANTAGONISTS 8 Anakinra is the first antirheumatic agent that acts by blocking the action of IL-1. This drug was recently approved for the treatment of moderately to severely active rheumatoid arthritis in adults who have not responded to therapy with one or more DMARDs. Anakinra may be used alone or in combination with DMARDs other than the TNF antagonists. Anakinra is a nonglycosylated form of the human IL-1 receptor antagonist (IL-1ra). It is produced in a recombinant Escherichia coli expression system and has an additional methionine residue at its amino terminus. In rheumatoid arthritis patients, the amount of naturally occurring IL-1ra in the synovial fluid is not sufficient to counteract the high levels of locally produced IL-1. Anakinra acts as a competitive antagonist of the type 1 IL-1 receptor and decreases the pain and inflammation produced by IL-1. It is administered as a daily subcutaneous injection. Unwanted effects: The most common adverse reactions to anakinra are redness, bruising, pain, and inflammation at the injection site. Neutropenia may occur, and the risk of serious infection is somewhat elevated, particularly in asthmatic patients. SULFASALAZINE 8 Sulfasalazine is approved for the treatment of rheumatoid arthritis and ulcerative colitis. It is also used to treat ankylosing spondylitis and Crohns disease. Sulfasalazine is a prodrug of which 70% is converted by colon bacteria to two active metabolites, sulfapyridine and 5-aminosalicylic acid (mesalamine). Sulfapyridine has antibacterial activities, and 5aminosalicylic acid is anti-inflammatory. Unwanted effects: Mild to moderate side effects, including nausea, vomiting, abdominal pain, diarrhea, anorexia, and headache, occur in up to 33% of patients taking this drug. Skin rash and discoloration, fever, reversible male infertility, and liver enzyme elevation occur less frequently. Rare hematological VJs College of Pharmacy Page 54

AUTOIMMUNITY- A REVIEW

abnormalities, such as agranulocytosis, aplastic anemia, hemolytic anemia, neutropenia, or other blood dyscrasias, can be fatal. Hypersensitivity reactions occur rarely. HYDROXYCHLOROQUINE 3,18 Hydroxychloroquine is an antimalarial agent with immunosuppressant properties. It is thought to suppress intracellular antigen processing and loading of peptides onto MHC class II molecules by increasing the pH of lysosomal and endosomal compartments, thereby decreasing T-cell activation. Because of these immunosuppressant activities, hydroxychloroquine is used to treat some autoimmune disorders. Clinical uses: It is used in the treatment of rheumatoid arthritis and systemic lupus erythematosus. Unwanted effects: Skin rashes and pruritus are common adverse effects of the 4-aminoquinoline antimalarials, as are GI effects. The most serious toxic reaction is irreversible retinopathy with resultant blindness. Severe hematological toxicity (neutropenia, thrombocytopenia, aplastic anemia) is rare.

Along with the above drugs, many other drugs are used. In most of the cases, drugs which provide symptomatic relief are used. These drugs vary from disease to disease. In spite of the treatment taken by the patient, many other lifestyle modifications are to be done to improve the quality of life of the persons suffering from autoimmune disorders. These include balanced diet, stress reduction, exercise etc. Apart from this, the family members of the patients suffering from autoimmune disorders are to be counseled regarding the care to be taken.

VJs College of Pharmacy

Page 55

AUTOIMMUNITY- A REVIEW

8. LITERATURE REVIEW
1. AUTOANTIGENS IN SYSTEMIC AUTOIMMUNITY: CRITICAL PARTNER IN

PATHOGENESIS A.Rosen & L. Casciola-Rosen Abstract: Understanding the mechanisms of human autoimmune rheumatic diseases presents a major challenge, due to marked complexity involving multiple domains, including genetics, environment and kinetics. In spite of this, the immune response in each of these diseases is largely specific, with distinct autoantibodies associated with different disease phenotypes. Defining the basis of such specificity will provide important insights into disease mechanism. Accumulating data suggest an interesting paradigm for antigen selection in autoimmunity, in which target tissue and immune effector pathways form a mutually reinforcing partnership. In this model, distinct autoantibody patterns in autoimmunity may be viewed as the integrated, amplified output of several interacting systems, including: (i) the specific target tissue, (ii) the immune effector pathways that modify antigen structure and cause tissue damage and dysfunction, and (iii) the homeostatic pathways activated in response to damage (e.g. regeneration differentiation cytokine effects). As unique antigen expression and structure may occur exclusively under these amplifying circumstances, it is useful to view the molecules targeted as neo-antigens, that is, antigens expressed under specific conditions, rather than ubiquitously. This model adds an important new dynamic element to selection of antigen targets in autoimmunity, and suggests that the amplifying loop will only be identified by studying the diseased target tissue in vivo. Journal of Internal Medicine 265; 625631 DOI: 10.1111/j.1365-2796.2009.02102.x 2. SEX DIFFERENCES IN AUTOIMMUNE DISEASES Rhonda Voskuhl Abstract: Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, rheumatoid arthritis and Hashimotos thyroiditis. This increased susceptibility in females compared to males is also present in animal models of autoimmune diseases such as spontaneous SLE in (NZBxNZW)F1 and NZM.2328 mice, experimental autoimmune encephalomyelitis (EAE) in SJL mice, thyroiditis, Sjogrens syndrome in MRL/Mp-lpr/lpr mice and diabetes in non-obese diabetic mice. Indeed, being female confers a greater VJs College of Pharmacy Page 56

AUTOIMMUNITY- A REVIEW

risk of developing these diseases than any single genetic or environmental risk factor discovered to date. Understanding how the state of being female so profoundly affects autoimmune disease susceptibility would accomplish two major goals. First, it would lead to an insight into the major pathways of disease pathogenesis and, secondly, it would likely lead to novel treatments which would disrupt such pathways. Biology of Sex Differences 2011, 2:1 3. EPITOPE SPECIFICITY AND SIGNIFICANCE IN SYSTEMIC AUTOIMMUNE DISEASES Michael Mahler and Marvin J. Fritzler Abstract: Autoimmune diseases are characterized by self-reactive immune processes mediated by B and T cells. These disorders exhibit a spectrum of clinical features that range from local or organ specific to systemic diseases. Although a variety of putative mechanisms that trigger the loss of tolerance and thus the genesis of autoimmunity have been identified, for the most part the precise mechanisms remain illusive. Nevertheless, it is widely appreciated that autoantibodies are useful both in the diagnosis of autoimmune disorders and as molecular biological tools to study cellular processes in which the target antigens are involved. Several methods and technologies, including protein fragments, synthetic peptides, phage display, or structural analyses have been developed for the characterization of the specificity of the autoimmune reactions. The present review provides an overview of the autoantibody epitopes in systemic autoimmune diseases as they relate to the clinical relevance and applications of certain autoepitopes and the technologies that are used to classify and identify them. Annals of the New York Academy of Sciences 1183 (2010) 267287 4. SELF-TOLERANCE AND AUTOIMMUNITY IN A REGULATORY T CELL MODEL H.K. Alexander, L.M. Wahl Abstract: The class of immunosuppressive lymphocytes known as regulatory T cells (Tregs) has been identified as a key component in preventing autoimmune diseases. Although Tregs have been incorporated previously in mathematical models of autoimmunity, we take a novel approach which emphasizes the importance of professional antigen presenting cells (pAPCs). We examine three possible mechanisms of Treg action (each in isolation) through ordinary differential equation (ODE) models. The immune response against a particular autoantigen is suppressed both by Tregs specific for that antigen and by Tregs of arbitrary specificities, through their action on either maturing or already mature pAPCs or on autoreactive effector T cells. In this deterministic approach, we find that qualitative long-term behaviour is predicted by the basic reproductive ratio R0 for each system. When R0 < 1, only the trivial VJs College of Pharmacy Page 57

AUTOIMMUNITY- A REVIEW

equilibrium exists and is stable; when R0 > 1, this equilibrium loses its stability and a stable non-trivial equilibrium appears. We interpret the absence of self-damaging populations at the trivial equilibrium to imply a state of self-tolerance, and their presence at the non-trivial equilibrium to imply a state of chronic autoimmunity. Irrespective of mechanism, our model predicts that Tregs specific for the autoantigen in question play no role in the systems qualitative long-term behaviour, but have quantitative effects that could potentially reduce an autoimmune response to subclinical levels. Our results also suggest an important role for Tregs of arbitrary specificities in modulating the qualitative outcome. A stochastic treatment of the same model demonstrates that the probability of developing a chronic autoimmune response increases with the initial exposure to self-antigen or autoreactive effector T cells. The three different mechanisms we consider, while leading to a number of similar predictions, also exhibit key differences in both transient dynamics (ODE approach) and the probability of chronic autoimmunity (stochastic approach). Bulletin of Mathematical Biology (2010) DOI 10.1007/s11538-010-9519-2 5. AUTOIMMUNE DISEASE IN THE ERA OF THE METAGENOME Amy D. Proal, Paul J. Albert, Trevor G. Marshall Abstract: Studies of autoimmune disease have focused on the characteristics of the identifiable antibodies. But as our knowledge of the genes associated with the disease states expands, we understand that humans must be viewed as super organisms in which a plethora of bacterial genomes a metagenome - work in tandem with our own. The NIH has estimated that 90% of the cells in Homo sapiens are microbial and not human in origin. Some of these microbes create metabolites that interfere with the expression of genes associated with autoimmune disease. Thus, we must re-examine how human gene transcription is affected by the plethora of microbial metabolites. We can no longer assume that antibodies generated in autoimmune disease are created solely as autoantibodies to human DNA. Evidence is now emerging that the human microbiota accumulates during a lifetime, and a variety of persistence mechanisms are coming to light. In one model, obstruction of VDR nuclear-receptortranscription prevents the innate immune system from making key antimicrobials, allowing the microbes to persist. Genes from these microbes must necessarily impact disease progression. Recent efforts to decrease this VDR-perverting microbiota in patients with autoimmune disease have resulted in reversal of autoimmune processes. As the NIH Human Microbiome Project continues to better characterize the human metagenome, new insights into autoimmune pathogenesis are beginning to emerge. VJs College of Pharmacy Page 58

AUTOIMMUNITY- A REVIEW

Autoimmunity Reviews, (C) Copyright 2009 Elsevier doi:10.1016/j.autrev.2009.02.016 6. ASIA - AUTOIMMUNE/INFLAMMATORY SYNDROME INDUCED BY ADJUVANTS Yehuda Shoenfeld, Nancy Agmon-Levin Abstract: The role of various environmental factors in the pathogenesis of immune mediated diseases is well established. Of which, factors entailing an immune adjuvant activity such as infectious agents, silicone, aluminium salts and others were associated with defined and non-defined immune mediated diseases both in animal models and in humans. In recent years, four conditions: siliconosis, the Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena were linked with previous exposure to an adjuvant. Furthermore, these four diseases share a similar complex of signs and symptoms which further support a common denominator. Thus, we review herein the current data regarding the role of adjuvants in the pathogenesis of immune mediated diseases as well as the amassed data regarding each of these four conditions. Relating to the current knowledge we would like to suggest to include these comparable conditions under a common syndrome entitled ASIA, Autoimmune (Auto inflammatory) Syndrome Induced by Adjuvants. Journal of Autoimmunity 36 (2011) 4-8 doi:10.1016/j.jaut.2010.07.003 7. OPPORTUNISTIC AUTOIMMUNE DISORDERS Yi-chi M. Kong, Wei-Zen Wei, and Yaron Tomer Abstract: Rapid advances in our understanding of the immune network have led to treatment modalities for malignancies and autoimmune diseases based on modulation of the immune response. Yet therapeutic modulation has resulted in immune dysregulation and opportunistic autoimmune sequelae, despite prescreening efforts in clinical trials. This review focuses on recent clinical data on opportunistic autoimmune disorders arising from three immunotherapeutic modalities: (1) systemic immunomodulators, including interferon- (also used to treat hepatitis C patients) and interferon-; (2) monoclonal antibodies to CTLA-4 and CD52, and (3) hematopoietic stem cell transplantation. Uncategorized predisposing factors in these patients include major histocompatibility complex and gender genetics, prevalence of different autoimmune diseases, prior chemotherapy, underlying disorder (e.g., hepatitis C), and preconditioning regimens as part of organ and stem cell transplants. Not unexpectedly, VJs College of Pharmacy Page 59

AUTOIMMUNITY- A REVIEW

the prevalent autoimmune thyroid disease surfaced frequently. Our combination models to study the balance between thyroid autoimmunity and tumor immunity upon regulatory T-cell perturbation are briefly described. Annals of the New York Academy of Sciences.1183 (2010) 222236 8. RECENT ADVANCES IN DIAGNOSTIC TECHNOLOGIES FOR AUTOIMMUNE DISEASES Mario Plebani et al. Abstract: The investigation of autoimmunity provides an interest challenge in omics research and, particularly, proteome research, as autoimmune diseases are common disorders of unsolved etiology that occur in a wide range of manifestations, in all of which tissues and organs are attacked by the body's own immune system. Autoantibodies are a hallmark of many autoimmune diseases and the presence of autoantibodies is a distinctive and key characteristic of autoimmune diseases. Conventionally, the study of autoimmune response has always been conducted by analysing the presence and/or concentration of individual antibodies in biological fluids. New proteomic techniques allow the simultaneous identification/measurement of different autoantibodies in sera of patients suffering from autoimmune diseases. The possibility of simultaneously measuring a number of correlated analytes appears to be very interesting for analytical reasons (reduced volumes of biological samples, reagents and low costs), logistical/managerial reasons, and pathophysiological reasons (combination of markers in diseaseoriented or organ-oriented profiling). In particular, we describe data collected by using high-throughput techniques such as antigen microarrays and mass spectrometry for antibody profiling. While recently collected data demonstrate satisfactory analytical sensitivity and reproducibility, some issues such as standardization and data interpretation have to be solved before the introduction of these new and promising techniques into clinical practice. Autoimmunity Reviews 8 (2009) 238243 doi:10.1016/j.autrev.2008.07.032 9. STEM CELL TREATMENT FOR PATIENTS WITH AUTOIMMUNE DISEASE BY SYSTEMIC INFUSION OF CULTURE-EXPANDED AUTOLOGOUS ADIPOSE TISSUE DERIVED MESENCHYMAL STEM CELLS Jeong Chan Ra et al

VJs College of Pharmacy

Page 60

AUTOIMMUNITY- A REVIEW

Abstract: Prolonged life expectancy, life style and environmental changes have caused a changing disease pattern in developed countries towards an increase of degenerative and autoimmune diseases. Stem cells have become a promising tool for their treatment by promoting tissue repair and protection from immune-attack associated damage. Patient-derived autologous stem cells present a safe option for this treatment since these will not induce immune rejection and thus multiple treatments are possible without any risk for allogenic sensitization, which may arise from allogenic stem cell transplantations. Here we report the outcome of treatments with culture expanded human adipose-derived mesenchymal stem cells (hAdMSCs) of 10 patients with autoimmune associated tissue damage and exhausted therapeutic options, including autoimmune hearing loss, multiple sclerosis, polymyotitis, atopic dermatitis and rheumatoid arthritis. For treatment, we developed a standardized culture-expansion protocol for hAdMSCs from minimal amounts of fat tissue, providing sufficient number of cells for repetitive injections. High expansion efficiencies were routinely achieved from autoimmune patients and from elderly donors without measurable loss in safety profile, genetic stability, vitality and differentiation potency, migration and homing characteristics. Although the conclusions that can be drawn from the compassionate use treatments in terms of therapeutic efficacy are only preliminary, the data provide convincing evidence for safety and therapeutic properties of systemically administered AdMSC in human patients with no other treatment options. The authors believe that exvivo- expanded autologous AdMSCs provide a promising alternative for treating autoimmune diseases. Further clinical studies are needed that take into account the results obtained from case studies as those presented here. Journal of Translational Medicine 2011, 9:181 10. INVERSE VACCINATION, THE OPPOSITE OF JENNERS CONCEPT, FOR THERAPY OF AUTOIMMUNITY L. Steinman Abstract: DNA-based vaccines to induce antigen-specific inhibition of immune responses in human autoimmune diseases represent the inverse of what Jenner intended when he invented vaccination. Jenners vaccine induced antigen-specific immunity to small pox. DNA vaccines for autoimmunity have been developed in preclinical settings, and now tested in human trials. The first two clinical trials, one in relapsing remitting multiple sclerosis, and the other in type 1 diabetes indicate that specific inhibition of antigen-specific antibody and T-cell responses is attainable in humans. Further development of this approach is ongoing. This new version of immunization termed inverse vaccination when applied to autoimmune diseases, may allow targeted reduction of unwanted antibody and T-cell responses to

VJs College of Pharmacy

Page 61

AUTOIMMUNITY- A REVIEW

autoantigens, while leaving the remainder of the immune system intact. The method of specifically reducing a pathological adaptive autoimmune response is termed inverse vaccination. Journal of Internal Medicine 2010: 267; 441451 doi: 10.1111/j.1365-2796.2010.02224.x 11. CLINICAL STEM CELL THERAPIES FOR SEVERE AUTOIMMUNE DISEASES J. A. Snowden et al. Abstract: Severe autoimmune diseases (ADs) are major source of disability and reduced quality of life and may result in shortened life expectancy, particularly in treatment-resistant patients. For several decades, allogeneic and autologous haematopoietic stem cell transplantation (HSCT) has been the focus of scientific investigation as a potential means of delivering one-off intensive treatment in severe ADs. Improvements in the clinical safety of HCST were followed by its increasing use in recent years as an experimental treatment for severe and resistant ADs. European and North American registries have accumulated between one and two thousand procedures. Retrospective analyses and prospective studies have demonstrated the feasibility, safety and initial efficacy data in various ADs. Profound cell biological changes induced by HSCT leading to stabilization or reversal of organ damage have been characterized. These have also shed light on basic disease mechanisms and support investigation of more specific cellular therapy in ADs. There is clear potential for harnessing a profound immunological effect through HSCT. However, there is a need for an ongoing balance against evolving non-transplant treatments for ADs. Ideally, these issues should be resolved in phase III studies, in which HSCT approaches are compared with the best comparator. Transfusion Medicine, 2009, 19, 223234 doi: 10.1111/j.1365-3148.2009.00927.x 12. NEW INSIGHTS INTO T CELL BIOLOGY AND T CELL-DIRECTED THERAPY FOR AUTOIMMUNITY, INFLAMMATION, AND IMMUNOSUPPRESSION Scott M. Steward-Tharp et al. Abstract: T cell-directed therapies have become mainstays in the management of various autoimmune diseases and organ transplantation. The understanding of T cell biology has expanded greatly since the development of most agents currently in use. Here we discuss important recent discoveries pertaining to T helper cell differentiation, lineage commitment, and function. Within this context, we examine existing T VJs College of Pharmacy Page 62

AUTOIMMUNITY- A REVIEW

cell-directed therapies, including new agents being evaluated in clinical and preclinical studies. We also use recent findings to speculate on novel targets. Annals of the New York Academy of Sciences. 1183 (2010) 123148 13. THERAPEUTIC ANTIBODIES FOR AUTOIMMUNITY AND INFLAMMATION Andrew C. Chan and Paul J. Carter Abstract: The development of therapeutic antibodies has evolved over the past decade into a mainstay of therapeutic options for patients with autoimmune and inflammatory diseases. Substantial advances in understanding the biology of human diseases have been made and tremendous benefit to patients has been gained with the first generation of therapeutic antibodies. The lessons learnt from these antibodies have provided the foundation for the discovery and development of future therapeutic antibodies. Here we review how key insights obtained from the development of therapeutic antibodies complemented by newer antibody engineering technologies are delivering a second generation of therapeutic antibodies with promise for greater clinical efficacy and safety. NATURE Reviews | Immunology Volume 10 May 2010 doi:10.1038/nri2761 14. MERCURY AND SILVER INDUCE B CELL ACTIVATION AND ANTI-NUCLEOLAR AUTOANTIBODY PRODUCTION IN OUTBRED MOUSE STOCKS: ARE ENVIRONMENTAL FACTORS MORE IMPORTANT THAN THE SUSCEPTIBILITY GENES IN CONNECTION WITH AUTOIMMUNITY? M. Abedi-Valugerdi Abstract: Environmental and predisposing genetic factors are known to play a crucial role in the development of systemic autoimmune diseases. With respect to the role of environmental factors, it is not known how and to what extent they contribute to the initiation and exacerbation of systemic autoimmunity. In the present study, I considered this issue and asked if environmental factors can induce autoimmunity in the absence of specific susceptible genes. The development of genetically controlled mercury- and silver-induced B cell activation and anti-nucleolar autoantibodies (ANolA) production in genetically heterozygous outbred Institute of Cancer Research (ICR), Naval Medical Research Institute (NMRI) and Black Swiss mouse stocks were analysed. Four weeks of treatment with both mercury and silver induced a strong B cell activation characterized by increased numbers of splenic antibody-secreting VJs College of Pharmacy Page 63

AUTOIMMUNITY- A REVIEW

cells of at least one or more immunoglobulin (Ig) isotype(s) in all treated stocks. The three stocks also exhibited a marked increase in the serum IgE levels in response to mercury, but not silver. More importantly, in response to mercury a large numbers of ICR (88%), NMRI (96%) and Black Swiss (100%) mice produced different levels of IgG1 and IgG2a ANolA (a characteristic which is linked strictly to the H-2 genes). Similarly, but at lower magnitudes, treatment with silver also induced the production of IgG1 and IgG2a ANolA in 60% of ICR, 75% of NMRI and 100% of Black Swiss mice. Thus, the findings of this study suggest that long-term exposure to certain environmental factors can activate the immune system to produce autoimmunity per se, without requiring specific susceptible genes. Clinical and Experimental Immunology, 155: 117124 doi:10.1111/j.1365-2249.2008.03801.x 15. PROTEOMIC APPROACH TO AUTOIMMUNE DISORDERS: A REVIEW Vandana D Pradhan, Neha R Deshpande and K Ghosh Abstract: Proteomics is the study of structural and functional endowment of cells, tissues or organs. This science brings together powerful toolsphysical separation techniques like 2-D electrophoresis and mass spectroscopy. It also includes various monoclonal antibodies and other probes coupled with which analysis is done by systems biology approach using modern software. Various statistical, probabilistic, humanistic and artificial neural network algorithms and at the same time incorporating elements of chaos and fractal theories are used to study the interactions of multitude of proteins in the cell. This allows separation of large background noise of high concentration proteins inside the cell from pathobiologically and aetiologically relevant protein molecules present in nano, femto or even atto molar concentrations. Pattern recognition algorithms in modern proteomic techniques will help in understanding aetiopathogenesis of disease, discovering diagnostically and prognostically important biomarkers and molecular targets for future drug discovery. These techniques will have important applications in autoimmune disorders and other disorders which are in general difficult to manage. The present review shows how proteomic approach can illuminate various facets of these groups of elusive disorders in near future. Indian Journal of Biotechnology, Vol 9, January 2010, pp 13-17 16. DEVELOPMENT OF TLR INHIBITORS FOR THE TREATMENT OF AUTOIMMUNE DISEASES Franck J. Barrat and Robert L. Coffman VJs College of Pharmacy Page 64

AUTOIMMUNITY- A REVIEW

Abstract: The innate immune system is a critical element of protection from invading pathogens. The specific receptors that recognize various components of the pathogens trigger signals that result in the production of proinflammatory cytokines as well as the activation of antigen-presenting cells, which activate the adaptive immune system. The discovery of the Toll-like receptors (TLRs) as important components of pathogen recognition has brought new understanding of the key signaling molecules involves in innate immune activation. Interestingly, it appears that most TLRs can recognize self-ligands as well and that mechanisms are required to discriminate between self and non-self ligands. One of these mechanisms is the expression of all the nucleic acid-specific TLR in endosomal compartments and not on the cell surface. Inappropriate activation of TLRs by self-components can result in sterile inflammation or autoimmunity. For example, TLR7 and TLR9 activation by endogenous RNA and DNA, transported to the endosomes in the form of immune complexes or noncovalently associated with cationic peptides, could be an important mechanism involved in promoting diseases such as systemic lupus erythematosus and psoriasis. In this review, we discuss the rationale for self-recognition by TLR7 and TLR9 as an important part of the development of lupus and other autoimmune diseases. We describe novel inhibitors of these receptors and provide evidence to support their use as novel therapeutic agents for autoimmunity. Immunological Reviews 2008 Vol. 223: 271283 17. OXIDATIVE STRESS, ALTERED-SELF AND AUTOIMMUNITY Ivan C. Gerling Abstract: It is well known that oxidative stress can induce production of free radicals that can modify proteins. The hypothesis presented here is that the target antigens in autoimmune diseases, such as type 1 diabetes mellitus, are not normal self proteins but rather self proteins that have been altered by free radicals, produced as a result of oxidative stress in the target cells. The observation that disease often occurs only in a single tissue, even when other tissues contain the same antigen, could be explained if both the presence of the antigen and severe oxidative stress is required, before tissue destruction occurs. Furthermore, the cyclic nature of tissue destruction and problems with detecting robust high affinity autoreactivity to self-antigens may be easier to understand if we presume that pathological autoreactivity is targeting redoxmodified self antigens, while assays to unmodified self only measure its cross-reactivity to normal self antigens. The Open Autoimmunity Journal, 2009, 1, 33-36

VJs College of Pharmacy

Page 65

AUTOIMMUNITY- A REVIEW

18. THE ROLE OF NUCLEAR FACTOR-B IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES: A LINK BETWEEN GENES AND ENVIRONMENT Alina Kuryowicz and Janusz Nauman Abstract: Although autoimmune diseases are relatively common, mechanisms that lead to their development remain largely unknown. Nuclear factor-B (NF-B), as a key transcription factor involved in the regulation of immune responses and apoptosis, appears to be a good candidate for studies on the pathogenesis of autoimmunity. This review presents how perturbations of the NF-B signaling pathway may contribute to self-tolerance failure, initiation of autoimmune inflammatory response as well as its persistent maintenance and therefore to the development of common autoimmune diseases including rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, thyroid autoimmune diseases, systemic lupus erythematosus as well as inflammatory bowel diseases and psoriasis. A special emphasis is put on the genetic variations in the NF-B related genes and their possible association with susceptibility to autoimmune diseases, as well as on the therapeutic potential of the NF-B targeted strategies in the treatment of autoimmunity. Acta Biochimica Polonica; Vol. 55 No. 4/2008, 629647 19. CYTOCHROME-P450 ENZYMES AND AUTOIMMUNITY: EXPANSION OF THE RELATIONSHIP AND INTRODUCTION OF FREE RADICALS AS THE LINK MR Namazi Abstract: The Cytochrome-P-450 enzymes (CYP) are among the most important xenobioticmetabolizing enzymes, which produce reactive oxygen species (ROS) as the result of metabolizing xenobiotics. ROS are believed to play important roles in the pathophysiology of autoimmune diseases. ROS can alter the structure of cellular antigens to produce a "neo-antigen" which could mount an autoimmune response against the original antigen through molecular mimicry. ROS are involved in apoptosis, activation of antigen presenting cells and initiation or amplification of diverse immunologic reactions. Taking all these facts together, it could be speculated that CYP may be involved in the initiation and/or amplification of autoimmune phenomena. Journal of Autoimmune Diseases 2009, 6:4 doi:10.1186/1740-2557-6-4

VJs College of Pharmacy

Page 66

AUTOIMMUNITY- A REVIEW

20. TOCILIZUMAB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS AND OTHER SYSTEMIC AUTOIMMUNE DISEASES: CURRENT PERSPECTIVES AND FUTURE

DIRECTIONS Atsushi Ogata and Toshio Tanaka Abstract: Interleukin (IL)-6 is a cytokine featuring redundancy and pleiotropic activity. While IL-6, when transiently produced, contributes to host defense against acute environmental stress, continuous dysregulated IL-6 production plays a significant pathological role in several systemic autoimmune diseases. In response to the expectation that IL-6 blockade would constitute a novel therapeutic strategy for the treatment of these diseases, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Clinical trials have verified the efficacy and the safety of tocilizumab for patients with rheumatoid arthritis, resulting in approval of this innovative biologic for the treatment of rheumatoid arthritis in more than 90 countries worldwide. Pathological analyses of the effect of IL-6 on the development of autoimmune diseases and a considerable number of case reports and pilot studies have also indicated the beneficial effects of this antibody on other systemic autoimmune diseases, including systemic lupus erythematosus, systemic sclerosis, polymyositis, and large-vessel vasculitis. International Journal of Rheumatology; Volume 2012, Article ID 946048 doi:10.1155/2012/946048 21. NATURAL KILLER CELLS AND AUTOIMMUNITY Anthony R French and Wayne M Yokoyama Abstract: Autoimmune diseases are often characterized as clinical syndromes caused by the inappropriate activation of T or B cells resulting in systemic or organ-specific damage. However, studies support a role for the innate immune system, and in particular natural killer (NK) cells, in stimulating or suppressing autoimmunity. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells in modulating T and B cell-mediated autoimmunity. Arthritis Research & Therapy 2004, 6:8-14 DOI 10.1186/ar1034 22. AMPLIFICATION OF AUTOIMMUNE DISEASE BY INFECTION David N Posnett and Dmitry Yarilin VJs College of Pharmacy Page 67

AUTOIMMUNITY- A REVIEW

Abstract: Reports of infection with certain chronic persistent microbes (herpes viruses or Chlamydiae) in human autoimmune diseases are consistent with the hypothesis that these microbes are reactivated in the setting of immunodeficiency and often target the site of autoimmune inflammation. New experimental animal models demonstrate the principle. A herpes virus or Chlamydia species can be used to infect mice with induced transient autoimmune diseases. This results in increased disease severity and even relapse. The evidence suggests that the organisms are specifically imported to the inflammatory sites and cause further tissue destruction, especially when the host is immunosuppressed. We review the evidence for the amplification of autoimmune inflammatory disease by microbial infection, which may be a general mechanism applicable to many human diseases. We suggest that patients with autoimmune disorders receiving immunosuppressing drugs should benefit from preventive antiviral therapy. Arthritis Research & Therapy 2005, 7:74-84 DOI 10.1186/ar1691 23. IMMUNE-REGULATORY MECHANISMS IN SYSTEMIC AUTOIMMUNE AND RHEUMATIC DISEASES Yuya Takakubo and Yrjo T. Konttinen Abstract: Systemic autoimmune and rheumatic diseases (SAIRDs) are thought to develop due to the failure of autoimmune regulation and tolerance. Current therapies, such as biologics, have improved the clinical results of SAIRDs; however, they are not curative treatments. Recently, new discoveries have been made in immune tolerance and inflammation, such as tolerogenic dendritic cells, regulatory T and B cells, Th 17 cells, inflammatory and tolerogenic cytokines, and intracellular signaling pathways. They lay the foundation for the next generation of the therapies beyond the currently used biologic therapies. New drugs should target the core processes involved in disease mechanisms with the aim to attain complete cure combined with safety and low costs compared to the biologic agents. Re-establishment of autoimmune regulation and tolerance in SAIRDs by the end of the current decade should be the final and realistic target. Clinical and Developmental Immunology; Volume 2012, Article ID 941346 doi:10.1155/2012/941346 24. ALTERNATIVE SPLICING IN MULTIPLE SCLEROSIS AND OTHER AUTOIMMUNE DISEASES

VJs College of Pharmacy

Page 68

AUTOIMMUNITY- A REVIEW

Irina Evsyukova et al. Abstract: Alternative splicing is a general mechanism for regulating gene expression that affects the RNA products of more than 90% of human genes. Not surprisingly, alternative splicing is observed among gene products of metazoan immune systems, which have evolved to efficiently recognize pathogens and discriminate between self and non-self, and thus need to be both diverse and flexible. In this review we focus on the specific interface between alternative splicing and autoimmune diseases, which result from a malfunctioning of the immune system and are characterized by the inappropriate reaction to self-antigens. Despite the widespread recognition of alternative splicing as one of the major regulators of gene expression, the connections between alternative splicing and autoimmunity have not been apparent. We summarize recent findings connecting splicing and autoimmune disease, and attempt to find common patterns of splicing regulation that may advance our understanding of autoimmune diseases and open new avenues for therapy. RNA Biology 7:4, 462-473; July/August 2010 25. TOLL-LIKE RECEPTORS IN SYSTEMIC AUTOIMMUNE DISEASE Ann Marshak-Rothstein Abstract: Toll-like receptors (TLRs) have a crucial role in the early detection of pathogen associated molecular patterns and the subsequent activation of the adaptive immune response. Whether TLRs also have an important role in the recognition of endogenous ligands has been more controversial. Numerous in vitro studies have documented activation of both autoreactive B cells and plasmacytoid dendritic cells by mammalian TLR ligands. The issue of whether these in vitro observations translate to an in vivo role for TLRs in either the initiation or the progression of systemic autoimmune disease is a subject of intense research; data are beginning to emerge showing that this is the case. Nature Reviews-Immunology; Volume; November 2006 doi:10.1038/nri1957 26. B-CELL TARGETING IN RHEUMATOID ARTHRITIS AND OTHER AUTOIMMUNE DISEASES Jonathan C. W. Edwards and Geraldine Cambridge Abstract: B-cell-targeted therapy for autoimmune disease emerged from theoretical proposition to practical reality between 1997 and 1998, with the availability of the B-cell depleting monoclonal antibody VJs College of Pharmacy Page 69

AUTOIMMUNITY- A REVIEW

rituximab. Since then, a score of autoantibody-associated disorders have been treated, with most convincing evidence of efficacy seen in subjects with rheumatoid arthritis. Several classes of B-celltargeted agent are now under investigation. From the outset, a major goal of B-cell targeting has been the re-establishment of some form of immunological tolerance. In some subjects, the observed improvement of disease for years following therapy fuels hope that this goal might ultimately be achievable. Nature Reviews-Immunology; Volume 6; May 2006 doi:10.1038/nri1838 27. THE DOUBLE-EDGED SWORD OF AUTOIMMUNITY: LESSONS FROM MULTIPLE SCLEROSIS Anne Lise K. Hestvik Abstract: The relationship between immune responses to self-antigens and autoimmune disease is unclear. In contrast to its animal model experimental autoimmune encephalomyelitis (EAE), which is driven by T cell responses to myelin antigens, the target antigen of the intrathecal immune response in multiple sclerosis (MS) has not been identified. Although the immune response in MS contributes significantly to tissue destruction, the action of immunocompetent cells within the central nervous system (CNS) may also hold therapeutic potential. Thus, treatment of MS patients with glatiramer acetate triggers a protective immune response. Here we review the immunopathogenesis of MS and some recent findings on the mechanism of glatiramer acetate (GA). Toxins 2010, 2, 856-877 doi:10.3390/toxins2040856 28. SYSTEMIC AUTOIMMUNE DISORDERS IN CELIAC DISEASE Alessio Fasano Abstract: The current literature did not clearly establish which of the two theories explain the comorbidity between celiac disease and other autoimmune disorders. There is, however, growing evidence that the loss of the intestinal barrier function typical of celiac disease could be responsible of the onset of other autoimmune disease. This concept implies that the autoimmune response can be theoretically stopped and perhaps reversed if the interplay between autoimmune predisposing genes and trigger(s) is prevented or eliminated by a prompt diagnosis and treatment.

VJs College of Pharmacy

Page 70

AUTOIMMUNITY- A REVIEW

Current Opinion in Gastroenterology 2006, 22:674679 29. MECHANISMS OF B CELL AUTOIMMUNITY IN SLE Thomas Dorner et al. Abstract: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is known to be associated with polyclonal B-cell hyper-reactivity. The underlying causes of the diffuse B-cell overreactivity are unclear, but potential candidates include (a) intrinsic hyper reactivity leading to polyclonal B-cell activation with disturbed activation thresholds and ineffective negative selection; (b) lack of immunoregulatory functions; (c) secondary effects of an overactive inflammatory environment, such as overactive germinal center and ectopic follicular activity; and/or (d) disturbed cytokine production by non-B immune cells. These mechanisms are not mutually exclusive and may operate to varying extents and at varying times in SLE. Phenotypic and molecular studies as well as the results of recent clinical trials have begun to provide new insights to address these possibilities. Of importance, new information has made it possible to distinguish between the contribution played by abnormalities in central checkpoints that could lead to a pre-immune repertoire enriched in autoreactive B cells, on the one hand, and the possibility that autoimmunity arises in the periphery from somatic hypermutation and abnormal selection during T cell dependent B-cell responses on the other. There is an intriguing possibility that apoptotic material bound to the surface of follicular dendritic cells positively selects autoreactive B cells that arise from non-autoreactive B-cell precursors as a result of somatic hypermutation and thereby promotes the peripheral emergence of autoimmunity. Arthritis Research & Therapy 2011, 13:243 30. LEPTIN IN AUTOIMMUNITY: MANY QUESTIONS, SOME ANSWERS G. Matarese et al. Abstract: It has recently become apparent that several molecules involved in the control of metabolism also play an important function in the regulation of immune responses. Among those molecules, the adipocyte-derived cytokine leptin has been shown to significantly influence innate and adaptive immune responses both in normal and in pathological conditions. For example, levels of leptin are typically low in infection and high in autoimmunity, both systemically and at the site of inflammation. Moreover, in addition to its long-known effects on the promotion of T helper 1 immune responses and cell-mediated immunity, leptin has more recently been found capable to constrain proliferation of regulatory T cells. As such, leptin represents not only a link between metabolism and immune responses in general but also a VJs College of Pharmacy Page 71

AUTOIMMUNITY- A REVIEW

pivotal modulator of the magnitude of selected mechanisms of peripheral immunity in relation to body fat mass. We review here the most recent advances on the role of leptin in the control of immune tolerance and critically discuss how strategies aimed at neutralizing the leptin axis could represent innovative tools for the therapy of autoimmune disorders. Tissue Antigens 70, 8795 doi: 10.1111/j.1399-0039.2007.00886.x

VJs College of Pharmacy

Page 72

AUTOIMMUNITY- A REVIEW

9. REFERENCES
1. Gerard J. Tortora, Bryan Derrickson. Principles of Anatomy and Physiology. 11th ed.. John Wiley and Sons, Inc. ; 2007; p.820-828 2. Kumar, Kotran, Robbins. ROBBINS BASIC PATHOLOGY. 7th ed.. (Electronic edition) Elsevier Inc.; 2007; p.104-112; p.125-130 3. Bertram G Katzung Basic and Clinical Pharmacology. 10th ed.. (Electronic edition) The Mc Graw-Hill Companies, Inc.; 2006; p.1072-1081; p. 1654-1690 4. Goodman and Gilmans The Pharmacological basis of Therapeutics. 11th ed.. (Electronic edition) The Mc Graw-Hill Companies, Inc.; 2006; Chapter 52 (Immunosuppressants, Tolerogens and Immunostimulants) 5. H.P.Rang, M.M.Dale, J.M.Ritter, R.J.Flower. Rang and Dales Pharmacology. 6th ed.. Churchill Livingstone Elsevier; 2009; p.202-212; p.242-245 6. Retrieved from http://www.en.wikipedia.org/Autoimmunity 7. Retrieved from http://www.en.wikipedia.org/Immune tolerance 8. Charles R. Craig, Robert E. Stitzel Modern Pharmacology with Clinical Applications. 5th ed.. (Electronic edition); p.432-438; p.657-661 9. Retrieved from http://www.cidpusa.org [Official website of cidpUSA Foundation] 10. Retrieved from http://www.autoimmune.pathology.jhmi.edu [Official website of Autoimmune Disease Research Center, John Hopkins Medical Institutions, USA] 11. Retrieved from http://www.en.wikipedia.org/Autoimmune diseases 12. Retrieved from http://www.enotes.com/Autoimmunity and Autoimmune disorders 13. A.M. Ercolini, S.D.Miller. The Role of Infections in Autoimmune disease. Clinical and Experimental immunology. 2008; 155: 1-15 14. Blacks Medical Dictionary 41st ed.. Edited by Dr. Harvey Marcovitch; A & C Black Publishers limited; 2005 15. Retrieved from http://www.womenshealth.gov.in/Autoimmune diseases: Overview 16. Christine Castro, Mark Gourley,MD. Diagnostic testing and interpretation of tests for autoimmunity. The Journal of Allergy and Clinical Immunology, Vol.125, Issue 2, Supplement 2, 2010; p. S238-S247; retrieved from http://www.jaconline.org 17. Ilza Salamuni. Laboratory diagnosis of autoimmune diseases new technologies, old dilemmas. Biochemia Medica 2010;20(1):45-56; retrieved from http://www.biochemia-medica.com

VJs College of Pharmacy

Page 73

AUTOIMMUNITY- A REVIEW

18. Finkel, Richard; Clark, Michelle A.; Cubeddu, Luigi X. Lippincott's Illustrated Reviews: Pharmacology. 4th ed.. ; Lippincott Williams and Wilkins; 2009; p. 489-497 19. K.D.Tripathi Essentials of Medical Pharmacology 6th ed.. JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD. ; 2009; p. 837-842 20. A to Z Drug Facts. Books@Ovid; 2003 Facts and Comparisons, David S. Tatro (Electronic edition)

IMAGES
Fig 1. Image retrieved from http://www.studentconsult.com Fig 2. Image retrieved from http://www.hms.alltech.com Fig 3. Image retrieved from http://www.en.wikipedia.org/Immune system Fig 4. Image retrieved from http://www.actanaturae.ru Fig 5. Image retrieved from http://www.users.rcn.com Fig 6. Image retrieved from http://www.healthcentral.com Fig 7. Image retrieved from http://www.moondragon.org Fig 8. Image retrieved from http://www.reidhosp.adam.com Fig 9. Image retrieved from http://www.bccorefitness.com Fig 10. Image retrieved from http://www.dtc.ucsf.edu Fig 11. Image retrieved from http://www.endocrinesurgery.ucla.edu Fig 12. Image retrieved from http://www.nlm.nih.gov Fig 13. Image retrieved from http://www.healthcentral.com Fig 14. Image retrieved from http://www.skinerrors.com Fig 15. Image retrieved from http://www.ghi.com Fig 16. Image retrieved from http://www.healthur.com VJs College of Pharmacy Page 74

AUTOIMMUNITY- A REVIEW

Fig 17. Image retrieved from http://www.sanidadanimal.info Fig 18. Heinz Lllmann, Albrecht Ziegler, Klaus Mohr, Detlef Bieger. Color Atlas of Pharmacology. 2nd ed.. ; Thieme Stuttgart; 2000; p.301

VJs College of Pharmacy

Page 75