SUD UU renieeeneneeeneeeeeneeneeneeeeeesnemeemnemennneeeeneenmeeeeeinneeneReeRREREEEEEEneeeeeentene IMMUNITY ‘The immune system protects us from invading pathogenic microorganisms and cancer. the state of protection from infectious disease — has both a less specific or Immunity INNATE and a more specific or ADAPTIVE component. INNATE IMMUNITY This provides the first line of defence against infection. It is a rapid response (minutes); it is not specific to a particular pathogen. It has no memory and does not confer long-lasting immunity to the host. It has 4 main components and is found in all classes of plant and animal life. Coltular defences 2) 0.9, neutrophils, TY macrophages, natural kllor coll, Natural barriers 4g. skin, mucous membranes NK-T cells, mast cells Soluble mediators Pattern-recognition molecules 0g. kinins, g 14) 0g. toll-ike receptors ~ cytokines, TLA4 recognises LPS complement, on gram-negative interferon bacteria ADAPTIVE IMMUNITY This provides a specific immune response directed at an invading pathogen. Following exposure to a foreign organism there is an initial EFFECTOR RESPONSE that eliminates posure to the same foreign organism induces a or neutralizes a pathogen. Later re-e3 MEMORY RESPONSE with a more rapid immune reaction that eliminates the pathogen and prevents disease. This response is found only in vertebrates. Tt has been known from historical times that a person who has recovered from an infectious disease, e.g. smallpox, is most unlikely to suffer from it again — even when exposed maximally — although he would remain susceptible to other infections, Subsequent exposures Smallpox Healthy First > Smallpox (2) exposure to-- to 1 Smallpox Memory Y { Y response NO DISEASE | Effector y response y Chickenpox, Measles, ——> DISEASE ete. That is, during the recovery period he has ACQUIRED SPECIFIC IMMUNITY to smallpox but not to other unrelated infections. Note: This immunity may extend to related infections: the use of the immunity against smallpox conferred by world-wide vaccination with cowpox (pioneered by Jenner in the 18th century) has completely eliminated smallpox throughout the world. Scanned with CamScannerTHE ADAPTIVE IMMUNE RESPONSE ADAPTIVE IMMUNE RESPONSE EFFECTOR RESPONSE MEMORY RESPONSE First attack of infecting agent ‘Subsequent contact with ‘same infecting agent [Intecting agent ic a, [Specie inmune memory (Of variable duration but ‘may last many years [necting aoe (eee Tecagntion a angen { faapid activation and ampltication (clinical oF subclinical i.e. no symptoms) of immune response _4 _Vory rapid destruction of antigen No disease ANTIGENS ~ Substances that can be recognised by the immunoglobulin receptor of B cells or the T cell receptor when complexed with MHC are called ANTIGENS. They are usually part of infectious agents such as bacteria and some viruses although other foreign materials are also antigenic. Most antigens are proteins but some large carbohydrate molecules such as lipopolysaccharides will induce antibody formation. EPITOPES are the immunologically active regions of an antigen that bind to specific membrane receptors on. INTER- lymphocytes or to secreted antibodies. * INTER-RELATIONSHIP OF INNATE & B and T cells recognise different ADAPTIVE IMMUNITY epitopes on the same antigenic INNATE IMMUNITY molecule. B cells usually recognise soluble antigen (exogenous). Freya defenses Epitopes recognised by T cells are [Watwalbarios | GK oes often internal peptides that are exposed by processing with antigen- Presenting cells (endogenous). Scanned with CamScannerCELLULAR BASIS OF THE ADAPTIVE IMMUNE RESPONSE ‘The main cells of the adaptive immune response are the lymphocytes. They are indistinguishable by light microscopy using conventional stains but can be sepai surface proteins on T and B cells. a In man, to reach functional maturity, stem cells are processed mainly in the bone marrow. (First associated with the Bursa of Fabricius in the bowel of chicken) ». called B lymphocytes rrated by the presence of different Stem cells in MARROW —__. In man and other mammals, to reach functional maturity, stem cells are processed in the Thymus --- . called T lymphocytes lymphocytes in the blood ‘The introduction of an antigen results in activation and proliferation of the: takes place in the lymphoid tissues. lymphocyte populations. This activity *Resting’ B cell In germinal centre (not — inblood) Blast 1 cells | mere a ™“e SPECIFICALLY SENSITISED LYMPHOCYTES (i) Cytotoxic activity. (ii) Production of messenger mediators (cytokines). The end result of the T cell respons? is the formation of CELLULAR IMMUNITY st intracellular org: ome bacteria (e.g. 78 anisms: ~ protection again e.g. viruses and s Scanned with CamScannerGENETIC INFLUENCES ON THE IMMUNE RESPONSE ‘The MAJOR HISTOCOMPATIBILITY complex, also known as the human leucocyte antigen (HLA), has an important role in the IMMUNE RESPONSE and DISEASE. ‘The genes controlling the system are in 2 major groups (Class I and Class I) on ‘CHROMOSOME 6: each group has 3 genes which are highly polymorphic (i.e. show great variation within individual members of the same animal species). The multiple alleles of each gene encode for surface membrane glycoproteins. HLA locus A c B DR DQ DP Ss ——_ Class | MHC expressed on nearly all nucleated cells Class Il MHC expressed on all antigen presenting cells (macrophages, dendritic cells, B cells) Consist of a dimer of 2 different chains each with 2 domains Consist of 3 domains complexed to a B, — microglobulin molecule. Both have an ANTIGEN BINDING ~ CLEFT - By microglobulin |, By Cell surface membrane The important roles of HLA are: (Presentation of peptides from foreign antigens to T lymphocytes Class I antigens to cytotoxic T cells (normally CD8 +ve) Class II antigens to helper T cells (normally CD4 +ve). i) They are the main stimulus to graft rejection in incompatible hosts. (The better the HLA match, the better the chance of graft survival.) (iii) There is a strong association with diseases ~ especially auto-immune disorders 107). Fae most striking example is ankylosing spondylitis where >90% of patients carry the allele HLA B27. (iv) They control individual resistance/susceptibility to certain infections, e.g, HLA B52 is associated with resistance to HIV infection. Scanned with CamScannerCELLULAR IMMUNITY Activation of T cells requires the involvement of ANTIGEN PRESENTING CELLS. Within these cells, foreign antigen is proteolytically digested to short peptides and then presented with HLA molecules to the T cell which possesses a specific receptor for that antigen. Exogenous antigen ‘Antigen presenting cell e.g. Streptococcus is processed with Endogenous antigen class Il MHC eg. intracellular bacteria such s as Mycobacterium tuberculosis > are processed with class | MHC ae Antigen = processing of antigen 9 Class! and presentation at & MHC cell surface © D4 + T cytotoxic Thelf velper cell cell Activation and CLONAL expansion (each new cell same specific immune potential) Activated Activated Thelper cell cytotoxic T lymphocyte ion of cytokines Activation and B-cell Activation of other proliferation of (eg.1L-2) inflammatory cells other T cells Macrophages (e.9. IFNy) (eg. IL-2) Neutrophils Eosinophils (e.g. IL-5) Mast cells Killing of altered self-cells e.g. virus-infected or ‘tumour cells Scanned with CamScannerCYTOKINES The chemical messengers of immune system are known as CYTOKINES. These small proteins are produced by virtually all cells of the innate and adaptive immune system, particularly CD4+ lymphocytes. The quantity and type of cytokine can positively and negatively regulate cells and cytokine effect is in turn controlled by expression or down-regulation of cytokine receptors on the cell surface. CYTOKINES INVOLVED IN INNATE IMMUNITY — Prostaglandins ——» Fever Hypothalamus Tha Acuto phase protein, IL [> Secreted by —> Acute ==> — eg. C-reactive ice macrophages phase protein, Fibrinogen response Liver Ca — Leucocytosis Bone marrow Antiviral state in all cells macrophages and fibroblasts ENB L» Secreted by aXe Increased MHC Class | expression NK cell activation Scanned with CamScannerCYTOKINES INVOLVED IN ADAPTIVE IMMUNITY ‘The immune response to a particular pathogen must induce an appropriate set of effector functions that can eliminate the pathogen from the host. Differences in cytokine secretion patterns among T helper cells are determinants of the type of immune response made to a particular antigenic challenge. Accordingly the cytokines secreting T helper cells are currently divided into 4 subsets: Antigen presenting cell Naive COE" T colt Activated CD4* T call can iflerentiate nto 1 of 4 subsets 2 wie N @. J ‘\ 22s ™m oS ‘Treg cell @® © Tre col Thi? colt wz mea waz t z IFRS Ls. ce i a | | ae ‘Autoimmune disease sanmememesin ar scgy 2 Penny Bol cs aah ceovena: "+ artct io Allergic 2. Activation of eyotoxie cals e.g. vial infection reaction Virus Eosinopht = Hlintn infected activation infection . C; col Eosinophil basic protein ‘The balance between the two main subsets determines disease outcome, e.g. tuberculoid leprosy is characterised by a THI response (destructive granulomas, few parasites). In Jepromatous leprosy there is a TH2 response (disseminated disease, many parasites). Scanned with CamScannerHUMORAL IMMUNITY BASIC STRUCTURE OF IMMUNOGLOBULIN ‘The basic immunoglobulin is a protein molecule consisting of 2 identical LIGHT chains and two identical HEAVY chains. Each light chain is bound to a heavy chain by a disulphide bond. Similarly disulphide bridges link the two heavy and light chain combinations to form the basic four chain structure. 4y 2 Hinge cegion H + allows better 3 4 nem gntigen /m 1 and 2 are heavy chains. Differences in structure allow separation of five | main Ig classes ~ 9G; A; Enzymatic M; D; E.3 and 4 are light digestion chains. They exist in two (papain) forms - Kappa (x) and | Lambda (). In any one molecule both chains are Fc is the constant part of the either kor molecule and does not Fe participate in antigen binding: (fragment Fay are the variable parts Secondary effects after antigen crystaline) of the molecule and are binding has occured include: the site of antigen binding, = complement activation Fab the variation in amino acid = chemotaxis / al content allowing a wide - opsonisation. range of specific activity. ANTIBODY MEDIATED EFFECTOR FUNCTIONS, 1. Opsonisation Fe receptors on macrophages and neutrophils can bind the Fe of Ig molecule resulting in phagocytosis of the antigen-antibody complex. 2. Complement Activation IgM and IgG subclasses can activate the complement system. 3. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) The linking of antibody bound to target cells (e.g. virus infected cells) with the Fe receptors of natural killer (NK) cells, enables the NK cell to recognise and kill the target cell. 4. Crossing of Epithelium (Transcytosis) The delivery of antibody to the mucosal surfaces of the eyes, nose, mouth, bronchi and gut, as well as transport to breast milk, requires the movement of immunoglobulin across epithelium, a process called transcytosis. 5. Activation of Mast Cells, Eosinophils, Basophils This is unique to IgE (see p.102). Scanned with CamScannerIMMUNOGLOBULINS ANTIBODY CLASSES AND ACTIVITIES These groups are named according to the composition of the heavy chains. IgM (heavy chain = 11) is a polymer, joined by J chains, of five identical Ig molecules, therefore called macroglobulin. Although in low concentration in the blood, 0.5-2 mg/ml, it is the main Ig on the surface of B lymphocytes (before conversion to plasma cells). It is the first immunoglobulin class produced and is active in the primary response. It neutralises viruses. In combination with complement, it is actively bactericidal and is especially effective in bacteraemia. / Note: The numerous (10) antigen- binding sites increase its efficiency. ‘The natural blood group antibodies, anti-A and anti-B are M globulins. IgG IgG (heavy chain = 7) is a single molecule with two antigen binding sites. <7>—— This is the most abundant class of immunoglobulin, with a concentration in blood of 8-16 mg/ml. There are 4 subclasses IgG1, IgG2, IgG3 and IgG4. Of its several activities the important ones are: 17 1, Passive transfer of IgG (IgG1, 2. Neutralisation of virus and toxins. IgG3, and IgG4) from mother to Virus or toxin baby occurs via the placenta and Specific colostrum. The immunity only neutralising Cell protected by antibody blocking effect of antibody Surface receptor for virus or toxin lasts a few months. 3. Opsonisation (IgG1 and IgG3). See Transplacental Colostrum, rich in passage of IgG IgG, absorbed from page 36. alimentary tract into 4, Complement Activation (IgG3, IgG1 and the blood stream of TgG2). See page 99. the neonate Scanned with CamScannerIMMUNOGLOBULINS IgA IgA (heavy chain = a) occurs in the blood (1.5-4 mg/ml) where its function is unknown. It is the predominant immunoglobulin in secretions of eyes, nose, mouth, bronchi and gut. Its function is to protect mucous surfaces from antigenic attack and prevent access of foreign substances to the circulation and general immune system. It may neutralise toxins and prevent binding to mucous surfaces. IgA is a single molecule in the serum. ao ‘The diagram illustrates the local production of IgA in the gut. In secretions, the IgA _Locally sited LUMEN molecule is plasma cell : 2 mer of ty [su 2 identical 7° ws 2) » fo samen Bi dommeyeran Binds to secretion. Part of receptor still rec allowing attached ecretory passage component) protects through 7 IgA from digestion. epithelial cell a IgD (heavy chain A) of uncertain function: concentration in blood very low probably * because it is not secreted by plasma cells. Like IgM it is present on the surface of B lymphocytes prior to transformation. (heavy chain €) — a single molecule similar to IgG and IgA. It is sometimes called REAGIN: concentration in blood is low (20-500 ng/ml). The serum level is raised in worm infestation and is probably protective. Its main activi CELLS (or BASOPHTLS); ere IgE ity is mediated by MasT it is the principal mediator of atopic and anaphylactic disease. Plasma cell IgE .....attached by Fe to Second Degranulation Producing IgE ‘mast cell in tissues, exposure with release in response to leaving antigen- to specific of first exposure binding sites free antigen ....bound to a vt i 10 polywalent on surface mast cell retain ae antigen (histamine, etc.) ppropriate clone of plasma cells (so-called clonal selection). Scanned with CamScannerIMMUNE REACTIONS ANTIGEN-ANTIBODY INTERACTIONS an antibody (Ab) an Ag/Ab complex is formed. This (Ag) binds with m c ai Sony rying degrees and depends on the affinity of the antibody for an nd the avidity (strength when multiple epitopes on an antigen interact When ana reaction cs). with multiple binding s ‘The consequences of Ag/Ab interaction include: 1, PRECIPITATION A soluble antigen is rendered insoluble by aggregation of the Ag/Ab complexes into a lattice. Aggregation Pp Teads to cg odd we ty ge weit This reaction is the basis of immunoelectrophoresis, used e.g. to identify a monoclonal band PRECIPITATION Antigen in solution + Antibody in solution in myeloma. 2. AGGLUTINATION Particulate antigen, e.g. bacteria and red blood cells, are aggregated in the same way as in the precipitation reaction and the process is called AGGLUTINATION. Agglutination reactions are routinely performed to type red cells (ABO typing). 3. CROSS-REACTIVITY In some cases antibody elicited by one antigen can cross-react with an unrelated antigen usually because they share a similar epitope. e.g. Streptococcus pyogenes Cross reactivity with A 4 myocardial proteins \- Maantigen on ‘Antibodies to cell wall M antigen Rheumatic heart disease Scanned with CamScannerIMMUNE REACTIONS IMPLEMENT SYSTEM | Complement consists of nine main protein components present in inactive form a the | ' blood. There are 3 pathways of complement activation. Activation results in the formation of multi-molecular enzymes that activate further components in a cascade ultimately generating a membrane attack complex that is capable of causing cell lysis. ‘The mannose-binding lectin (MBL) and alternative pathways do not require antibody for activation and are therefore a component of the innate immune system. ADAPTIVE INNATE Classical { MeL pathway pathway Agia» complex | Bacteria \— Carbohydrate Pathogenic surface with binding (bacteria, endotoxin, >— surface protein fungal and yeast cell i etn wal FollgMorigc) | lectin (lectin) al) Activated C1-tke complex Bactericidal a tes Seana) Bactrim Go 56 €8 @7 ce co i venonave are ose csa 3 conte soaps = (doughnut tke ° Mediate ifiammation cab channel that \ yoni Chematas erupts cal rn membrane) Oa Opsonizatonot Red Hood cl pathogens and removal of immune . complexes Stoic Activation of C by A\ markers, this fix e/Ab complex is called fixxa ation can detect the presence o Eg. Test serum + antigen + C, If serum contains antibody, C is fixed, otherwise it cs. co , ; se it Add sensitised RBC (coated with Ab), ee ane free, Lysis of RBC = complement still free.» No lysis = C was fixed by Ab in test sa tion of complement. a Using red cel} f antigen or antibody in = serum, - Ro Ab in original serum, ‘Tum, : Scanned with CamScannerNN TOLERANCE Humoral and cell-mediated immunity are spe function. ic active immune responses with a protective In certain circumstances an antigen does not evoke these active responses. This is because the lymphocytes, although recognising the antigen, do not react ~ this is TOLERANCE. Natural ‘self’ tolerance (Central Tolerance) ‘The immune system recognises and tolerates its own tissues. This tolerance is developed in the fetal and carly neonatal periods, and prevents autoimmune diseases in normal individuals. Occurs in bone marrow and thymus. Acquired tolerance Son (Peripheral Tolerance) GEIANTIGEN After the neonatal period and BY throughout adult life, injections LYMPHOCYTES of soluble foreign antigens by selected routes (e.g. I.V., mucosal) may induce tolerance in the adult. This form of tolerance is the ABSENCE OF basis of desensitisation USUAL treatment in allergic disease IMMUNE and explains the absence of eg, RESPONSES food hypersensitivity in normal individuals. Occurs in mature lymphocytes. Daneray - Both 8 and T cots require 2 signals for activation, Lack ofthe second signal switches the cell of Dep Sang ©: Tea atom cD Artigen active | Boot — Beat — anergy NoTeet oso F cos CosoL, For T cas the signals are (MHC pepise and 2 costimulatory molecule 87.2 0n APC ‘A thir signal for T cas that provides rection has been proposed (2g for TM, I-12 and Yor M2, L-d) @eteon-Intetalite aT and 6 hmphecytes that cogs ‘sl age ae emirate by apoptots (@ona ignorance ~Atrescive mobos myn uractats because thy hava weak afin or the sa antigen. They hve ho patentee ached unr can cents and therefore pose a tvea othe host. @Peceptor editing -In ths process hr i secon rearangement len unolobin vaable region stesng receptor spectey and weir ctomany © o-Fest interactions -Fas-medted apoponl lay cra ein te removal of mate suoeacive Band yphoeyts. Fas-mededapoptos plays an mparart ln Wnone privileged sites (e.g brain, ee) Fes Fas FasL expressed ‘on APC, some spiel cls 08 ten ‘and activated @ apoptosis Tools. ‘Autoreactve Teal @egustor/supprestorT cols - A specand once 20d population fT cls tat suporess he esponses other Iympnosytes Tolerance is an important Protective mechanism. Sive rise to autoimmune disease (see p.107). Scanned with CamScanner When it breaks down, the serious effectsIMMUNOPATHOLOGY The complicated and delicately balanced immune mechanisms clearly have been developed to protect against antigens, particularly infections. When these immune reactions are upset, the protective mechanism can itself be a source of disease states. There are three main categories: 1. hypersensitivity states, 2. immune deficiency states and 3, autoimmune diseases. HYPERSENSITIVITY REACTIONS, These consist of an inappropriate response by an individual to an antigen, following a previous exposure. They differ from the protective immune response in that they are exaggerated, inappropriate or damaging to the host. Depending on the main type of immune response concerned, these are classified as follows: (a) Those associated with (b) Those associated with HUMORAL ANTIBODIES CELLULAR IMMUNITY immediate ~ types I, II, III. delayed (24~72 hours) ~ type IV. This classification is to some extent artificial. Hypersensitivity may start as an immediate humoral reaction but end in a mixed state with both humoral and cellular activities. In the 1960s, Coombs and Gell divided hypersensitivity reactions into four types that are still used today. ‘Type 1 Anaphylaxis, atopy, allergy This occurs within 20-60 minutes of exposure to antigen and is often referred to as ‘immediate type hypersensitivity’ All 3 terms have been used for this reaction. The basic mechanism is as follows. Fixation of IgE to MAST CELLS and basophils by Fc fragment mation First exposure Fo toAg of IgE (Y) Second exposure pesca aed to Ag (6) ‘Ag/Ab reaction on Release of mediators and surface of mast cell vasoactive substances = IMMEDIATE SYMPTOMS (within minutes) Antigens and ‘allergens’ ; / The most potent allergens are usually large molecules with molecular weights up to 40 000. Examples of common ‘allergens’ are pollen, house mite dust, cat fur and penicillin. Food allergy, e.g. to peanuts and milk, is uncommon. Antibod: This is Te. Plasma cells forming IgE are not normally found in the internal secretory surfaces of the body — tonsils, bronchi, gastrointestinal tract ~ but are present in large numbers in cases of allergy (and in defence against parasitic infections). Mast cells ; | ; These have a wide distribution but are prominent in the same areas'as the IgE-producing plasma cells, plus skin, bladder and synovial membranes. This explains the frequently used term ‘target organs’ when discussing hypersensitivity. Scanned with CamScannerHYPERSENSITIVITY STATES Clinical examples of Type I reaction ANAPHYLACTIC SHOCK 1st injection of antigen e.g. penicillin or a bee sting + General sensitisation 2nd injection of above > Acute collapse: bronchial | constriction; vomiting; | diarrhoea; perhaps a skin rash. May be fatal. Note that the antigens are injected - enter blood stream ~ basophils affected ~ widespread reaction | ASTHMA Ist contact with house mite dust or animal dander — Local sensitisation of bronchi HAY FEVER Ist contact with grass pollen + Local sensitisation of conjunctiva and nasal passages 2nd contact with above = Irritation or swelling of conjunctiva with nasal excessive watery secretion 2nd contact with above — Bronchial constriction and secretion of thick mucus cause dyspnoea (difficult breathing) | Chronic asthma may involve | cellular immunity with tissue | destruction. 1 common finding in the tissues of patients with allergies, attracted by factor released by mast cells, Allergic conditions are often familial s. Several candidate loci have been proposed including loci linked to gene for the IgE receptor on mast cells. inophils are eosinophil chemot with a genetic cytokine genes and Type Il - Cytotoxic type The antigen Ye is on the cell 7 — Specific antibody NK cells, macrophages, is & combination monocytes, neutrophils or DX. produces eosinophils bind Fe region Via specific receptors Complement activation, Increased phagocytic Antibods ty dependent cell via classical pathway activity (opsonic effect) mediated cytotoxicity DESTRUCTION OF CELL ‘This cytotoxic reaction causes some forms of haemolytic anaemia (e.g, autoimmune HA (p.392): Rhesus incompatibility (p.393)) and some blood transfusion reactions, Certain drugs (e.g. penicillins) can also cause autoimmune HA by acting as a hapten. This is a small molecule that only becomes immunogenic when combined with a host protein carrier In some auto-immune disorders antibodies of this type are directed against specialised cell surface receptors, e.g. Graves” disease or myasthenia gravis (see p.109), Type III - Immune complex (Arthus) type The reaction is due to the consequences of specific direct antigen/antibody combination - particularly complement activation (p.99) and platelet aggregation. The antibodies involved are IgG or IgM. Scanned with CamScannerHYPERSENSITIVITY STATES Vasoactive amines Le testa) ——» /ff- 9s) Effects on dee ‘Complement vessel wll je activation a Neutrophils. Ag/Ab (chemotaxis) ———> {immune complex) Thrombosis Platelet ———> (especially aggregation in venules) ‘Type III hypersensitivity may be systemic ot localised. Systemic Locatsed ‘a/R immu Comoe 06) Toema meseslson| | Tesue dopoaton tart, smal boas vets ‘Age enn Compl 10) ‘owa oeaby | Locatand inlarmatony a ae ae oe eae eee | | cee = Emase Eats ma stoke | en ies ma a cia saan 09, Seum sickness due to administration cf anttoun in fren serum. system Meus ‘rthematoeus due to antbowes 19 ONA {autommune| 6620) Type IV - (delayed) type This reaction is an antigen elicited cellular immune response which produces tissue injury independently of the presence of antibody. The reaction is usually delayed taking 24-72 hours to develop. Classic examples include the tubercle follicle, graft rejection and contact dermatitis. Normal skin First application Subsequent Epidermal oedema and ~ ‘of chemical application lymphocytic infiltration Antigen presented b Langerhans Perivascular cell is lymphocytes ht} in dermis Chemical + tissue protein = ‘foreign’ antigen ——> cellular immunity ——» inflammation Scanned with CamScannerIMMUNE DEFICIENCY STATES ‘The systems involved are: humoral 1. THE ADAPTIVE IMMUNE SYSTEM — cellular phagocytes HE INNATE IMMUNE SYSTEM complement in any one alters the immune response. The deficiencies may be of a primary nature, : genetic in origin, or secondary to some other disease or circumstance. Equally, 2. Failure common! the alteration in any system may be quantitative or qualitative. In many of these deficiencies there is a failure in more than one system. Primary (inherited) deficiencies of the specific system are rare. They include B cell, T cell and combined B and T cell deficits. B cell deficiency leads to infection by pyogenic bacteria. T cell deficits lead to infection by viruses, fungi and intracellular bacteria. Secondary deficiencies of the specific system are common. Usually T cell activity is affected, resulting in deficient cellular immunity and, later, B cell deficit occurs. ‘The acquired immunodeficiency syndrome (AIDS) is now a major world-wide public health problem. Other predisposing conditions and diseases include: Malnutrition - particularly with protein deficiency Iatrogenic effects ~ e.g. immunosuppressors: cytotoxics, corticosteroids Infections — (_—» IMPAIRED ———> INFECTION acute viral chronic bacterial IMMUNITY often OPPORTUNISTIC chronic protozoal, e.g. malaria Chronic debilitating disease - Gee p.84) eg renal failure: diabetes mellitus Malignant disease - eg advanced cancer: lymphoma, ion are Hodgkin’s disease Deficiencies of the innate immune system are rare. The disorders of neutrophil functi described on page 408. Scanned with CamScannerNn): ——ag TLL LL IMMUNE DEFICIENCY STATES - AIDS The acquired immune deficiency syndrome (AIDS) is a world-wide epidemic with large numbers of cases in sub-Saharan Africa and South East Asia. Globally, an estimated 40 million people are infected with the virus. ‘The virus (human immunodeficiency virus (HIV)) is of the retrovirus group: it infects and destroys CD4 T-lymphocytes (macrophages, monocytes and dendritic cells are also infected). ‘There are 2 strains of HIV: HIV1 which is more virulent and HIV2 which predominates in West Africa. 3 The disease is slowly progressive and untreated is usually ultimately fatal. Recently highly active antiretroviral therapy (HAART), usually a combination of drugs such as nucleoside analogues and proteases, has been shown to reduce viral load to undetectable levels and has decreased the incidence of opportunistic infections and the death rate in the USA. However these drugs are expensive and have significant side effects, AIDS CD4 < 200 x 10° Infections and tumours Infection CD4 > 500 x 108 Asymptomatic or a short febrile illness. Although the patient's cells contain HIV, tests for antibodies may be negative for up to several months. Latent period | D4 - 200-500x 108 | Virus present in \ lymphocytes: maybe | isti persistent lymph node | Infection << Opportunistic enlargement and fever. | | 1 Kaposi sarcoma Tumours << (2 \ ' ' \ { ' \ ' ' i ' lymphomas The whole range of opportunistic infection (see p.84), including disseminated virus infection (e.g, herpes simplex and cytomegalovirus), occurs. The diagram shows the more common AIDS-associated diseases and sites: Brain Tumours ~ especially lymphomas Infections ~ toxoplasmosis Inflammation - encephalitis Dementia Mouth, Trachea, Oesophagus Candidiasis Lungs Pneumocystis jiroveci (formerty carini) infection Other fungal infections, tuberculosis . Intestines Protozoal, salmonella infections Skin Kaposi's sarcoma, fungal infections, herpes zoster Blood Changes , ; Antibodies ~ Specific antibodies appear up to 6 months after infection and form the basis of the diagnostic test for HIV. The antibody titre may fall greatly late in the disease. Immunoglobulins are usually elevated in the early stages, CD4 lymphocytes may be severely reduced, producing a lymphopenia (see above). Scanned with CamScanner| IMMUNE DEFICIENCY STATES - AIDS EPIDEMIOLOGY AND TRANSMISSION Although the virus may be present in many body fluids and secretions, transmission is by the parenteral route, usually by 1. sexual contact, 2. infected blood or 3. from mother to infant. ‘Transmission does not occur with normal social contact and there is a very low risk to medical or nursing personnel using normal procedures. 1, Sexual contact: HIV is present in semen and vaginal fluid. Transmission may occur by homosexual intercourse. The risk of transmission is increased where there is genital ulceration or abrasion. 2. Infected blood: the risk from blood transfusion and blood products has now been virtually climinated by screening and sterilisation procedures (in the past many haemophiliacs were infected). The communal use of contaminated syringes and needles is important among drug addicts. 3. Mother to infant: around half a million infants become infected with HIV each year. sion of virus from HIV infected The majority of these infections result from transmi mothers during childbirth or by transfer of virus in milk during breastfeeding. Maternal antiretroviral therapy can reduce the incidence of transmission. Cellular mechanisms Note: Individuals with certain mutations in the CRS receptor are resistant to HIV. These mutations are more prevalent in Caucasian populations compared with African populations. [ste eer seg C8 @ intection of cts 2) Nuteocapsid containing viral genome enters cell 1) HIVgp 120 os attaches to CD4 and the chemotine receptor CCRS- 5) Translocation to ncleus and 2) Viral genome integration into released host DNA, 4) Reverse transcription yielding HIV dsDNA Effects 2) Syntheisis of viral proteins Pg on ribosomes 1) Transcription of A viral DNA to 3) Budding of genomic ssRNA membrane forming viral envelope 4) Virions that can infect other cells, Infected cells have a half-life of around 15 days Scanned with CamScannerAUTOIMMUNE DISEASES Autoimmune diseases result from, or are associated with, an immune response against the individual’s own cells, or in some cases cell products. Although both humoral and cellular immunity are involved, it is thought that changes in the latter are of primary importance. In autoimmunity, something occurs to destroy integrity of self tolerance. The aetiology of autoimmunity is not fully established. Potential causes include: 1. Genetic susceptibility ~ Genetic predisposition to autoimmune di in family members. eptibility to autoimmune disease may be linked to specific MHC alleles, c.g. ankylosing spondylitis HLA B27. 2. Environmental susceptiblity ~ Sequestered antigen — an antigen is exposed to the immune system following injury or infection, e.g. myocarditis after myocardial infarction. = Molecular mimicry ~ microbial antigens cross-react with self antigens. = Polyclonal activation — infectious agents can act as superantigens triggering many Band T cell clones. 3. Other triggers of autoimmunity — Hormones, e.g. SLE is more common in females and may be triggered by oestrogen. — Drugs ~ certain drugs may act as a hapten rendering a self antigen immunogenic. —T suppressor cells — loss of suppressor T cells can contribute to autoimmunity, e.g. individuals with inflammatory bowel disease and diabetes have reduced numbers of T suppressor cells. Scanned with CamScanner