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Index Innate immunity Immune cells and Organs Antigens Antibodies Immunoglobulin Gene expression and organisation Antibody

and Antigen interaction Complement system T cell Maturation, Activation and differentiation B Cell Maturation, Activation and differentiation Cytokines Cell mediated immunity Antigen presentation Hypersensitivity Autoimmunity Immune related diseases

Innate immunity Non specific immunity Its not long lasting defense system like adaptive immunity, but provides immediate defense against infection. First line of defense against foreign organisms Cell involve in innate immunity are mast cells, phagocytic cells like macrophages, neutrophiles, dendritic cells, basophiles and eosinophiles, natural killer cells, T cells. Barriers which prevent the entry or growth of microorganisms inside the body: Skin, Phagocytic cells, Antibacterial proteins such as defensin, Psoriasin. Psoriasin is a small protein with potent antibacterial activity against E.Coli. Anatomical barriers are skin which defense against the microorganism through the sweat, desquamation, flushing and organic acids. GI tract, which has defensin, gut flora, thiocynate, bile acids, gastric juice, and peristalsis. Airway and lungs has surfactant, mucociliary elevator. Eyes have tears. Nasopharynx has mucus, saliva, lysozyme. C- Reactive protein belongs to family of pentameric proteins called pentraxins, which bind ligands in a calcium dependent reaction. BPI (bactericidal/permeability-increasing protein) is 55 kDa proteins that bind with high affinity to LPS in the walls of gram negative bacteria and cause damage to the bacteriums inner membrane. iNOS (inducible nitric oxide synthetase), an enzyme that oxidizes L- arginine to yield Lcitrulline and Nitric oxide (NO). ROS species production Oxygen O2 .O2H2O2 HClO-

Oxygen is converted to superoxide anion by NADPH phagosome oxidase, and then Superoxide anion is converted to hydrogen peroxide by superoxide dismutase. Then with addition of chlorine ion, hydrogen peroxide is converted to hypochlorite by myeloperoxidase. Natural killer cells produce interferon gamma and TNF alpha. These cytokines stimulate the maturation of dendritic cells. INFG is a mediator of macrophage activation and regulator of T helper cells development.

NOD proteins Cytosolic and has two members in this family i.e. NOD1 and NOD2, which recognize products derived from bacterial peptidoglycans. NOD1 binds to the tripeptide products of peptidoglycans (NAM and NAG) breakdown and NOD2 recognizes muramyl dipeptide, derived from the degradation of peptidoglycan from gram positive bacterial cell walls. NOD1 recognizes meso-diaminopimellic acid (meso-DAP) in Gram ve bacteria and NOD2 senses intracellular muramyl dipeptide (MDP) in S. Pneumoniae and M.tuberculosis. Mutation of NOD2 is associated with crohns disease or Blau syndrome. TOLL LIKE RECEPTOR (TLR) Membrane spanning proteins that share a common structural element in their extracellular region, repeating segments of 24 to 29 amino acids containing the sequence xLxxLxLxx. These structural motifs are called leucine rich repeats. The intracellular domain of TLR is called TIR domain. TLR1 ligand is Triacyl lipopeptides and a target microbe is mycobacteria. TLR2 ligand is peptidoglycans, GPI linked proteins, lipoproteins and zymosan. Target molecules are gram positive bacteria, trypanosomes, mycobacteria, yeasts and other fungi. TLR3 double stranded RNA (dsRNA) and target microbes are viruses. TLR4 LPS and F-protein and target microbes are Gram ve and respiratory syncytial virus (RSV) TLR5 TLR6 TLR7 TLR8 flagellin and target is bacteria. diacyl lipopeptides and zymosan. Mycobacteria, yeast and fungi. single stranded RNA (ssRNA) and viruses. single stranded RNA (ssRNA) and viruses.

TLR9 CpG unmethylated dinucleotides, dinucleotides, herpesvirus infection. Bacterial DNA and some herpesvirus TLR10 and TLR11 unknown

Immune organs and cells Primary lymphoid organs Thymus Bone marrow Secondary lymphoid organs Lymph nodes Spleen Various Mucosa associated lymphoid tissues (MALT) like GALT site for mature lymphocytes to interact with antigen. maturation of lymphocytes takes places.

Thymus

It is the site for T cell development and maturation. Bilobed organ situated above the heart. Each lobe is surrounded by a capsule and divided into lobules, which are separated from each other by strands of connective tissue called trabeculae. Each lobule is organized into two compartments: cortex which is densely packed with immature T cells called Thymocytes whereas the inner compartment or medulla is sparsely populated with thymocytes. Both the compartments consist of epithelial cells, dendritic cells, and macrophages which make up the framework of the organ and contribute to the growth and maturation of thymocytes. Function of thymus: to generate and select a repertoire of T cells that will protect the body from infection. As thymocytes develop, enormous diversity of T cell receptors is generated by gene rearrangement. It produces some T cells with receptors capable of recognizing

antigen MHC complexes. But only small portion of cells survive and rest will undergo apoptosis. Bone marrow It is a complex tissue that is the site of haematopoiesis and a fat depot. Hematopoietic cells are generated here move through the walls of blood vessels and enter the bloodstream, which carries them out of the marrow and distributes these various cell types to the rest of the body. It is site of B cell origin and development. Immature B cells proliferate and differentiated within the Bone marrow and stromal cells within the bone marrow interact directly with the B cells and secrete various cytokines that are required for development. Lymphatic system lymphoid follicles: primary follicle network of follicular dendritic cells and small resting B cells. After antigenic challenge, a primary follicle becomes secondary follicle a ring of concentrically packed B lymphocytes surrounding a center (the germinal center) in which one finds a focus of proliferating B lymphocytes and an area that contains nondividing B cells and some helper T cells interspersed with macrophages and follicular dendritic cells. Lymph nodes and spleen capsules. surrounded by fibrous

MALT less organized lymphoid tissue found in various body sites.

Lymph node: Encapsulated bean shaped structures containing a reticular network packed with lymphocytes, macrophages and dendritic cells. They are organised in such a way to encounter antigens that enter the tissue spaces. Cortex outermost layer contains B cells mostly, macrophages and follicular dendritic cells arranged in primary follicles. After antigenic challenge, the primary follicles enlarge into secondary follicles, each containing germinal center. Paracortex it is beneath cortex which is populated largely by T cells and also contains dendritic cells that migrated from tissue to the node. Medulla more sparsely populated with lymphoid lineage cells, and of those present, many are plasma cells actively secreting antibody molecules.

Lymph nodes traps the antigens from local tissues.

Spleen: Present in the high left abdominal cavity. It is large ovoid, plays a major role in mounting immune responses to antigens in the blood stream. Spleen filters the blood and traps the blood borne antigens. So it responds to systemic infections. It is not supplied by lymphatic vessels, instead antigens and cells are carried into spleen through splenic artery. It is surrounded by capsules from which a number of projections extend into the interior to form a compartmentalized structure. Two compartments: Red pulp: network of sinusoids populated by macrophages, numerous red blood cells, and few lymphocytes. Defective and old RBCs are destroyed and removed. White pulp: it surrounds a branches of splenic artery forming a periarteriolar lymphoid sheath (PALS) populated mainly by T cells. Primary lymphoid follicles are attached to PALS. Marginal zone contains lymphocytes and macrophages. Antigens are trapped in marginal zone by dendritic cells, which then carry it to the PALS. And also lymphocytes enter through the same route as of the antigen. MALT (mucosa associated lymphoid tissue) The vulnerable membrane surface of digestive, respiratory and urogenital systems are defended by a group of organized lymphoid tissues called MALT. Respiratory epithelium bronchus associated lymphoid tissue (BALT) Gut- associated lymphoid tissue (GALT)

Epithelium of the digestive tract

MALT includes tonsils, and appendix. M cells carry the antigen from lumina of the tracts to the underlaying MALT. They are flattened epithelial cells lacking the microvilli that characterize the rest of the mucous epithelium. They have deep invagination, or pocket in the basolateral, plasma membrane which is filled with a cluster of B cells, T cells and Macrophages.

Immune cells Hematopoietic stem cells Stem cells progenitor cells lymphoid and myeloid progenitor cells immune cells

They all grow, differentiate and matured on a mesh like scaffold called stromal cells, which includes fat cells, endothelial cells, fibroblasts and macrophages. It influence the differentiation of HSC by providing hematopoietic inducing microenvironment (HIM) consisting of cellular matrix and factors that promote growth and differentiation. Many of these hematopoietic growth factors are soluble agents that arrive at their target cells by diffusion, where as others are membrane bound molecules on the surface of stromal cells that require cell to cell contact between the responding cells and the stromal cells. Transcription factors in hematopoiesis GATA-1 GATA-2 PU-1 Bmi-1 Ikaros Oct-2 erythroid erythroid, myeloid, lymphoid

erythroid (maturational stage), myeloid (later stage), lymphoid all hematopoietic lineages lymphoid B lymphoid (differentiation of B cells into plasma cells)

Natural killer cells: CD16 is present on the membrane of NK cells which can bind to the specific antibody of the target cells. NKT cells have T cell receptors. They interact with MHC like molecule called CD1. Dendritic cells Langerhans dendritic cells Interstitial DCs lymph nodes skin interstitial space of the organs except brain

lymph node and spleen

Monocyte derived DCs Plasmacytoid DCs presentation.

blood stream into tissue

plasmacytoid cells plays important role in innate immunity and antigen

Follicular dendritic cells Not for APC, not from bone marrow, do not express any MHC molecules They are present in lymphoid follicles which are rich in B cells. B cells interaction with follicular cells will provide maturation and diversification of B cells.

Antigens Epitopes antigenic determinants

B cell epitope on native proteins generally are composed of hydrophilic amino acids on the protein surface that are topographically accessible to membrane bound or free antibody. Sequential epitopes each containing 6-8 contiguous amino acids were found in sperm whale myoglobin. Each of these epitopes is on the surface of the molecule at bends between - helical regions. Non sequential epitopes residues that constitutes these epitopes are far apart in the primary amino acid sequence but close together in the tertiary structure of the molecule. Immunologically active regions of an immunogen that bind to antigen specific membrane receptors on lymphocytes or to secreted Ab. Haptens antigenic small molecules but incapable by themselves of inducing a specific immune response Tolerance antibody does not mount immunity of the self antigen.

Immunogens have > 100,000 dalton molecular size < 5 kDa or 10 kDa is considered poor immunogens Adjuvants Substances when mixed with antigens and injected with it inorder to enhance the immunogenicity of that antigen Alum aluminium potassium sulfate precipitates the antigen and injected into the organism. This results in the slow release of antigen from the site. Alum also increases antigen size. Freunds incomplete adjuvant contains antigen in aqueous solution, mineral oil and an emulsifying agent such as mannide monooleate which disperses the oil into small droplets surrounding the antigen. The antigen is then released very slowly from the site of injection. Antibody CDR complementarity determining region

Hypervariable region form the antigen binding site of the antibody molecule, because antigen binding site is complementary to the structure of the epitope. 3 VL and 3 VH CDR region is on the loops connecting the strands of the VH and VL domains. The remainder of the VL and VH domains exhibit far less variation; these stretches are called framework regions (FRs). FRs act as the scaffold that supports the six loops. CDRs bind antigen

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The hing region is rich in proline residues and is flexible giving IgG, IgD and IgA segmental flexibility. IgG there are four subclasses based on heavy chain i.e. IgG1, IgG2, IgG3, IgG4 with either or light chains. IgG1, IgG3, IgG4 IgG3 that cross the placenta and protect the fetus.

complement activator followed by IgG1 and IgG2 is less efficient. IgG4 cant do

IgG1, IgG3 bind with high affinity to Fc receptors on phagocytic cells and thus mediate opsonisation. IgG4 IgM intermediate affinity for Fc receptors and IgG2 has an extremely low affinity. membrane bound Ab on B cells. It is secreted by plasma cells as pentamer.

10 antigen binding site It is the first class produced in a primary response to an antigen and it is also the first immunoglobulin to be synthesized by the neonate. Because of its pentameric structure with 10 antigen binding sites, serum IgM has a higher valency than the other isotypes. It does not diffuse well and therefore found in very low concentration in intercellular tissue fluids. IgA it is predominant in saliva, tears, and mucus of the bronchial, genitourinary and digestive tracts. In serum, they exist in monomer, but polymeric forms are seen with J chain in it. Poly Ig receptor helps in the transportation of dimeric IgA from the submucosa region to lumen through the epithelial vesicle transport. Breast milk contains IgA. IgE mediate immediate hypersensitivity reactions that are responsible for the symptoms of hay fever, asthma, hives etc. P-K reaction: the serum from allergic patient is injected into the non allergic patient and finally if the wheal and flare reaction occurs, then it means the person is susceptible to hypersensitivity. IgE binds to Fc receptors on the membranes of blood basophils and tissue mast cells. Cross linkage of receptor bound IgE by allergen induces basophils and mast cells to translocate their granules to the plasma membrane and release their contents to the extracellular environment, a process known as degranulation. Isotype constant regions determinants that collectively define each heavy chain class and subclass and each light chain type and subtype within a species

Allotype Idiotype

allele of the antibody chains found in the individual. it arise from the sequence of heavy and light chain variable regions.

Immunoglobulin gene organisation and expression Gene segments light chain and V, J and C gene segment segment encode the variable region of the light chains. the rearranged VJ

chain Multigene family 5 V segment and 3 J segment is separated by a non coding DNA sequence in unrearranged germ line DNA. 2V, 3J, 3C 30V, 4J, 7C Multigene family mouse Multigene family Human 85 V, 5 J and 1C 40 V, 5 J and 1C

chain Multigene family mouse chain Multigene family human

Heavy chain V, D, J and C gene segments VDJ gene segments encode the variable region of the heavy chain. Human Multigene family chromosome 14 39 V (upstream) from 23 D gene segments from 6 J gene segment (downstream) followed by series of C gene segment (C,C,C,C,C). In each gene family, C gene segment encode for constant region. Each V segment is preceded at its 5 end by a small exon that encodes a short signal or leader (L) peptide that guides the heavy or light chain through the endoplasmic reticulum.

Antibody and antigen interaction Avidity Strength of multiple interactions between a multivalent antibody and antigen. It is the measure that the affinity for quantifying the binding capacity of an antibody within biological systems. Cross reactivity antigen-antibody reactions are highly specific, in some cases antibody elicited by one antigen can cross react with an unrelated antigen. It occurs if two different antigens share an identical or very similar epitope. glycolipids expressed on the red blood cells. A type individual ABO blood group antigens have anti B antibodies, B type individuals have anti A antibody and type O individuals has anti A and anti B antibodies.

Complement system Activities of complement system Lysis, opsonisation, activation of inflammatory response, clearance of immune complexes They are produced by liver hepatocytes and small amount by blood monocytes, macrophage, and epithelial cells. Zymogens are inactive form of complement proteins and they are activated by proteolytic cleavage which removes the inhibitory fragment and exposes the active site of molecule. There are three pathways of complement activity 1. Classical pathway 2. Alternative pathway 3. Lectin pathway The common among all these pathways is the formation of MAC (membrane attacking complex). 1. Classical pathway The activation starts with formation of soluble antigen antibody complexes or with the binding of antibody to antigen on a suitable target. IgM and IgG activate the complement pathway and initial stage of activation involves components C1, C2, C3, and C4 which are present in plasma in functionally inactive forms. Fc portion of IgM conformational change on binding of antigen. Exposure site on IgM for C1 complement protein to bind. C1 consists of C1qr2s2 held together in a complex stabilized by calcium ions. C1q molecule 18 polypeptide chains that associate to form six collagen like triple helical arms, tips of which bind to exposed C1q binding sites in CH2 domain of the antibody molecule. Each C1r and C1s monomer contains a catalytic domain and an interaction domain, the latter facilitates interaction with C1q or with each other. After the C1q is bound to Fc binding sites, a conformational changes induce C1r to become a active serine protease enzyme C1r* which then cleaves C1s to a similar active enzyme C1s*. C1s* two substrates C4 and C2. The C4 is glycoprotein contains three polypeptide chains , , and . C4 is activated when C1s* hydrolyzes a small fragment C4a from the amino terminus of chain, exposing a binding site on the larger fragment (C4b). The C4b fragment attaches to the target surface in the vicinity of C1 and the C2 proenzyme then attaches to the exposed binding site on C4b, where the C2 is then cleaved by the neighbouring C1s*, the small fragment C2b diffuses away. The resulting C4b2a* complex is called C3 convertase. C3 convertase converts C3 into active form. C4a is an anaphylatoxin or mediator of inflammation which does not participate directly in the lytic function of the complement cascade. Similarly C3a and C5a is also an anaphylatoxin.

The C3 component consists of two polypeptide chains and . Hydrolysis of a short fragment C3a from the amino terminus of chain by the C3 convertase generates C3b. Some C3b component binds to C4b2a* complex to form a trimolecular complex called C5 convertase (C4b2a3b*). C3b component of this complex binds C5 and alters its conformation allowing C4b2a* component to cleave C5 into C5a, which diffuses away and C5b which attaches to C6 and initiates formation of the membrane attack complex. C3b sometimes function as opsonin and promote phagocytosis. C3b may also bind directly to cell membranes.

2. Alternative pathway It happens similar to the classical pathway, but it does without the antigen antibody complexes for initiation. Since, it is a component of innate immunity. It involves four serum proteins C3, factor B, factor D and properdin. Serum C3 gets cleaved into C3a and C3b on the microbial cell surface. The C3b bind to either foreign surface antigens or to the host cell. But on the host cell is not affected by C3b binding because host cell surface is having high sialic acid which contributes to rapid inactivation of bound C3b molecules on host cells. Then another serum protein called factor B forms complex with C3b and it is stabilized by Mg2+. Now this complex serve as a substrate for factor D, which convert them into C3bBb* complex. The complex is having C3 convertase activity which is limited half life unless the serum protein properdin binds to it. Now the C3 convertase cleaves the C3 into C3b and C3a. C5 convertase is formed by the binding of C3b to the C3 convertase (C3bBbC3b). C5 convertase generates C5a and C5b. C5b is used for MAC.

3. Lectin pathway Lectins are proteins that recognize and bind to specific carbohydrate targets. Lectin activates complements binds to mannose residues. Lectin pathway is activated by the binding of mannose binding lectin to mannose residues on glycoproteins or carbohydrates on the surface of microorganisms, including bacteria such as salmonella, listeria and neisseria strains. MBL is a collectin family acute phase proteins and its concentration increases during inflammatory responses. Its function in the complement pathway is similar to that of C1q, which it resembles in structure. After MBL binds to the carbohydrates residues on the surface of cell or pathogen, MBL associated serine proteases, MASP-1 and MASP-2 bind to MBL. Now the active complex formed by this association causes cleavage and activation of C4 and C2. MASP-1 and MASP-2 are structurally similar to C1r and C1s and mimic their activity.

4. MAC formation C5b, C6, C7, C8, and C9 which interact sequentially to form a macromolecular structure called the membrane attack complex (MAC). It forms a large channel on the membrane of the target cell enabling ions and small molecules to diffuse freely across the membrane. C3b and C4b binding facilitates opsonisation. Complement system neutralize viral infectivity. Regulation of complement system form complex with C1r2s2 causing it to dissociate from C1q C1 inhibitor and preventing further activation of C4 or C2. C3b is hydrolysed once it moves away at 40 nm distance from the C4b2a* or C3bBb* convertase enzymes. C3 convertase activity is regulated by proteins which contain repeating amino sequences of about 60 residues termed short consensus repeats (SCRs). All this proteins are encoded in single location on chromosome 1 in humans, known as the regulators of complement activation (RCA) gene cluster. RCA proteins prevent C3 convertase assembly and it includes proteins like C4b binding protein (C4bBP), and two membrane bound proteins, complement receptor type 1 (CR1) and membrane cofactor protein (MCP). Each of these regulatory proteins binds to C4b and prevents its association with C2a. Once the regulatory proteins binds to C4b, another regulatory protein factor I cleaves the C4b into bound C4d and soluble C4c. In other case, MCP, CR1 and Factor H binds to C3b and prevents it association with factor B. After this, Factor I cleaves C3b into a bound iC3b and release C3c fragment. Decay accelerating factor (DAF or CD55) which is a glycoprotein covalently anchored to a glycophospholipid membrane protein has the ability to dissociate C3 convertase. Homologous restriction factor (HRF) or membrane inhibitor of reactive lysis (MIRL or CD59). CD59 protects cells from nonspecific complement mediated lysis by binding to C8 preventing assembly of poly C9 and its insertion into plasma membrane.

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Hypersensitivity reactions Hypersensitivity inappropriate and damaging immune response symptoms manifest within minutes or hours after a sensitized recognition of delay of symptoms until days after exposure

Immediate hypersensitivity recipient encounters antigen. Delayed type hypersensitivity

Gell and coomb classification of hypersensitivity Type I IgE mediated hypersensitivity

Ag induces cross linking of IgE bound to mast cells and basophils with release of vasoactive mediators. The allergens induce humoral antibody response resulting in the generation of antibody secreting plasma cells and memory cells. The plasma cells secrete IgE in response to the activation of allergen specific Th2 cells. This class of antibody binds with high affinity to Fc receptors on the surface of tissue mast cells and blood basophils. The coated mast cells and basophils are said to be sensitized. Later exposure to the same allergen cross links the membrane bound IgE on sensitized mast cells and basophils, causing degranulation of these cells. The principle effects vasodilation and smooth muscle contraction. Atopy is hereditary predisposition to the development of immediate hypersentivity reactions against common environment antigens. List of diseases by Type I hypersensitivity Systemic anaphylaxis Localized hypersensitivity reactions Asthma Allergic rhinitis Food allergies Atopic dermatitis Type II Antibody mediated cytotoxic hypersensitivity

Antibody bound to a cell surface antigen can activate the complement system, creating pores in the membrane of foreign cells or it can mediate cell destruction by ADCC. Transfusion reaction: anti B isohemagglutinins binds to the B blood cells and mediate their destructions by means of Complement mediated lysis. Antibodies to other blood group antigens may result from repeated blood transfusions because minor allelic differences in these antigens can stimulate antibody production. Eg: ABO blood group antigens Haemolytic disease of newborn During first pregnancy the child born with Rh antigen and during delivery the rupture of placenta will lead to mixing of fetus blood with mother and therefore, antibodies will be produced against the child Rh antigens. Now during the second pregnancy if the child has Rh antigen, then the mothers memory B cells will produce antibodies against the fetus Rh antigen and finally leads to the destruction of RBCs causing erythroblastosis fetalis. But

currently the mother is treated with Rhogam which prevent the B cell activation and memory cell formation against Rh antigen. Drug induced haemolytic anaemia Penicillin induces all types of hypersentivity. Some drug protein complexes induce antibody production and therefore binding of Ab to the RBC induces complement system. Type III immune complex mediated hypersensitivity

Reaction of antigen with antibody generated immune complexes. When these complexes are deposited in tissue very near the site of antigen entry, a localized reaction develops. The reactions develop when immune complexes activate the complement systems array of immune effector molecules. Type IV delayed type hypersensitivity

DTH when some subpopulations of activated Th cells encounter certain types of antigens, they secrete cytokines that induce a localized inflammatory reaction. Sensitization phase the APC presents the antigen to the Th cells and secretes cytokines and activates macrophages and Th1 cells. Effector phase macrophages. the Th1 sensitized cells secretes cytokines and activates the resting

Example: poison oak which contains pentadecacatechol which enters through the skin and gets processed in langherhans cells (APC). Th1 is sensitized and activates tissue macrophages.

Autoimmunity Tolerance preventing self reactive lymphocytes

Central tolerance deletes T and B cell clones before the cells are allowed to mature if they possess receptors that recognize self antigens with greater than a low threshold organs, bone marrow and thymus. If central tolerance is not proper, then self reactive immune cells travel through the secondary lymphoid tissues where there are additional safe guard known as peripheral tolerance, which renders lymphocytes in secondary lymphoid tissues inactive or anergic. Autoimmunity priate response of the immune system against self components

Receptor editing the antigen specific V region is edited with a different V region gene segment switched for the autoreactive V gene segment via VDJ recombination. Anergy unresponsiveness to antigenic stimulus

Regulatory T cells are component of peripheral tolerance. Treg cells downregulate autoimmune processes and they have unique subset of CD4+ T cells that express high level of IL-2R chain (CD25). Certain cells upregulate the transcription factor Foxp3 and then develop into Treg cells capable of suppressing reaction to self antigens. Antigen sequestration is means to protect self antigens. Organ specific autoimmune diseases Hashimotos thyroiditis Middle aged women produce auto antibodies and sensitized Th1 cells specific for thyroid antigens. An attending DTH response is characterized by an intense infiltration of the thyroid gland by lymphocytes, macrophages and plasma cells, which form lymphocytic follicles and germinal centers. The ensuing inflammatory response causes a goiter, or visible enlargement of the thyroid gland, a physiological response to hypothyroidism. Autoimmune anaemia Pernicious anaemia is caused by auto antibodies to intrinsic factor; a membrane bound intestinal protein on gastric parietal cells.

Cytokines Low molecular weight regulatory proteins or glycoproteins secreted by WBCs and various other cells in the body in response to a number of stimuli. They assist in regulating the development of immune effector cells, and some possess direct effector function on their own. Properties of cytokines They bind to specific receptors on the membrane of target cells, triggering signal transduction pathways that ultimately alter gene expression in the target cells. It exhibits the attributes of pleiotropy, redundancy, synergy, antagonism, and cascade induction which permit them to regulate cellular activity in a coordinated interactive way. They have a molecular mass of less than 30 kDa. Cytokines belong to four groups: the hematopoietin family, interferon family, the chemokine family, and tumor necrosis factor family.

Cytokines in innate immunity 1. 2. 3. 4. 5. 6. Interleukin 1 (IL-1) Tumor necrosis factor- (TNF-) Interleukin 12 (IL-12) Interleukin 6 (IL-6) Interferon (IFN-) Interferon (IFN-)

Cytokines in adaptive immunity 1. 2. 3. 4. 5. Interleukin 2 (IL-2) Interleukin 4 (IL-4) Interleukin 5 (IL-5) Transforming growth factor (TGF-) Interferon (IFN-)

Cytokine receptors Cytokine exert their biological effects by binding to specific receptors expressed on the membrane of responsive target cells. Cytokine family 1. Immunoglobulin superfamily receptors Receptors for IL-1 are an example for this family and IL-1 comes in two forms i.e. IL-1 and IL-1. There are two different receptors for IL-1: type I IL-1R expressed on many cell types and type2 IL-1R is limited to B cells. The binding of IL-1 to the type 2 IL-1R does not initate responses typical of IL-1 suggesting that type 2 IL-1R is a decoy meant to remove IL-1 thereby preventing its bind to type 1 receptors. IL-1 is a proinflammatory cytokine. IL-18 is related to IL-1 uses the same receptor. 2. Class I cytokine receptor family (hematopoietin receptor family)

They have conserved amino acid sequence motifs in the extracellular domain consisting of four positionally conserved cysteine residues (CCCC) and a conserved sequence of tryptophan-serine-tryptophan serine. The receptors for all the cytokines classified as hematopoietins belongs to class I cytokine receptor family. IL-2 and about 13 interleukins as well as several colony stimulating factors and growth hormones bind to the receptors of this family

Subfamilies of class I type receptors GM-CSF GM-CSF, IL-3 and IL-5 (common subunit): induce eosinophiles proliferation and basophile degranulation with release of histamines. IL-6 receptors IL-6, IL-11, CNTF, LIF/OSM (common gp130 subunit) IL-2 receptors IL-2, IL-15, IL-7, IL-9, IL-4 (common subunit) 3. Class II cytokine receptor family (interferon receptor family) They possess the conserved CCCC motif but lacks the WSXWS motif present in class I cytokine receptors. 12 receptors chains that in their various assortments bind no fewer than 27 different cytokines, including six members of the IL-10 family, 17 type I interferons, one type II interferon, and three members of the recently described interferon family, including IL-28a, IL-28b and IL-29. 4. TNF receptor family 1. The receptors are rich in cysteine and trimerize following cytokine binding. It include TNF receptor, lymphotoxin and nerve growth factor receptor and cell surface associated molecules CD40 and CD95 (Fas). 5. Chemokine receptor family IL-2R It is a trimeric receptor comprises three distinct subunits the ,, and chains. The and chains belong to the class I cytokine receptor family, whereas the chain has a quite different structure and is not a member of this family. They occur in three forms that exhibit different affinities for IL-2: the low affinity monomeric IL-2R activated Th and Tc cells, the intermediate- affinity dimeric IL2R expressed in NK cells, resting T cells, and the high affinity trimeric IL-2R activated Th and Tc cells. Cytokines in helper T cells Th1 (++) 1. IFN 2. IL-2 3. TNF 4. TNF 5. GM-CSF 6. IL3 Th2 (++) 1. 2. 3. 4. 5. 6. TNF (+) GM-CSF (+) IL3 IL4 IL5 IL6

Antigen presentation Major histocompatibility complex (MHC) Class I MHC genes Encodes glycoproteins expressed on the surface of nearly all nucleotide cells; the major function of class I gene products is presentation of peptide antigen to Tc cells. Class II MHC genes Encodes glycoproteins expressed primarily on antigen presenting cells, where they present processed antigenic peptides to Th cells. Class III MHC genes Encode in addition to other products various secreted proteins that have immune functions including components of the complement system and molecules involved in inflammation. MHC is referred to HLA complex in human and H-2 complex in mouse. Class I MHC molecule It has a glycoprotein heavy chain and small protein light chain. It contains 45kDa chain associated noncovalently with a 12 kDa 2 microglobulin molecule. The chain is a transmembrane glycoprotein encoded by polymorphic genes within the A,B, and C regions of Human HLA complex and within K and D regions in mouse H-2 complex. 2 microglobulin is a protein encoded by a highly conserved gene located on a different chromosome.

The peptide binding cleft is located on top surface of the class I MHC molecule and it is large enough to bind a peptide of 8-10 amino acids.

Class II MHC molecule Contain two different polypeptide chains 33 kDa chain and 28 kDa chain which associated by noncovalent interactions. They are membrane bound glycoproteins that contain external domains, a transmembrane segment and a cytoplasmic anchor segment.