Figure 1. Immune‐related diseases. Immune responses are necessary to eliminate pathogens. (1) These responses may, however, cause collateral damage to the host. (2) Defects in immunity can result in severe infections by agents that are not normally pathogenic; such immunodeficiency diseases can be primary genetic defects or secondary in cause (e.g. because human immunodeficiency virus (HIV) damages crucial components of immunite reactions). (3) Some individuals make responses against normally harmless substances (peanuts, pollen, fungal spores) resulting in allergies or other immune‐related sensitivitie. (4) Other individuals may make immune responses against self components leading to autoimmune diseases. (5) Immune responses can also cause transplant reactions including rejection. (6) If, however, immune responses are not able to reject abnormal tumour cells, a cancer may develop. (Autoinflammatory diseases that result from abnormalities of the innate immune system are not shown, Section 2.2.4.)
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Figure 2. Immune‐related therapies. Antigen‐based vaccines. A variety of agents ranging from DNA to attenuated living microbes can be used to induce a specific adaptive immune response that protects against subsequent infection. In the future it may be possible to vaccinate against cancers. Antigens can sometimes be used to reduce specific immune responses (e.g. desensitization in allergies). Therapeutic antibodies. Monoclonal antibodies that bind to and inhibit a molecule involved in a disease can be used to treat the disease. Such therapeutic antibodies are now used in some autoimmune diseases and cancers and in prevention of organ transplant rejection. Cell‐based therapies. In the treatment of cancer, antigen‐specific lymphocytes can be transferred or dendritic cells (DCs) used to induce specific responses. In the future it may be possible to use regulatory T cells (T reg) to suppress unwanted responses (e.g. in transplantation or autoimmune diseases).
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Figure 3. Mechanisms of immunopathology. Tissue damage caused by adaptive immune responses can be due to or independent of antibodies. IgE antibodies (IgE) cause allergy and anaphylaxis by acting through mast cells. IgG and IgM can modulate cell function directly, by killing the cell or by blocking or stimulating receptors. Immune complexes can cause acute inflammation locally or systemically. Cell‐mediated (antibody‐independent) immunopathology is usually due to T h1‐biased responses involving cytotoxic CD8 T cells and/or activated macrophages, but in some cases T h2‐biased responses are important such as in some forms of asthma.
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Figure 4. Immediate and delayed‐type hypersensitivity reactions. If an individual who has been sensitized to a particular antigen is challenged with the same antigen, an inflammatory response may occur very rapidly, within minutes to hours. This is called immediate hypersensitivity, and is seen in allergies and conditions such as Farmer's lung. Immediate hypersensitivity occurs, and can only occur, because there is pre‐formed antibody. Other responses take much longer (24–48 h) to occur. This is called delayed hypersensitivity, and is seen in the Mantoux test for immunity to tuberculosis and contact sensitivity to substances such as nickel. We call these responses delayed due to time taken to reactivate and expand memory cells, but the response in fact accelerated relative to the primary T cell response that occurs during sensitization.
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Figure 5. IgE in defence and disease (type I hypersensitivity reactions). IgE is thought to give some protection against parasitic helminth worms. However, some individuals exposed to antigens such as grass pollen or peanuts make adaptive responses in which B cells switch to IgE production. The secreted IgE binds to high‐affinity Fc receptors (FcRs) on mast cells. If the individual is re‐exposed to the antigen, it can cross‐link the IgE on mast cells. This induces the mast cells to release inflammatory mediators. Locally these cause acute inflammation but if they are released into the blood they may cause potentially fatal anaphylaxis. IgE responses are typically controlled by T h2 cells.
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Figure 6. IgM and IgG in defence and disease (type hypersensitivity reactions). Antibodies are crucial in defence against many bacterial and viral infections, largely by opsonizing the microbe, or by neutralization, preventing binding of toxins, viruses or bacteria to cells. Occasionally lysis of bacteria may occur. In disease, antibodies can act on cells to kill them (as in haemolytic anaemia) or modulate their functions. For example, in myasthenia gravis, autoantibodies to the acetylcholine receptor block binding of acetylcholine and cause muscle weakness. IgG responses can be controlled by either T h1 or T h2 responses.
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Figure 7. Immune complexes in defence and disease (type III hypersensitivity reactions). Immune complexes of soluble antigens and IgM or IgG antibodies bind complement and are normally cleared by macrophages after transport to liver and spleen by erythrocytes. Such complexes may also regulate immune responses following binding to DCs or B cells via FcRs or complement receptors. Large complexes cannot be cleared this way and are deposited locally in tissues or in small blood vessels in organs such as the kidney. Here, activated complement initiates acute inflammation and recruited neutrophils cause local tissue damage.
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Figure 8. T cell‐mediated immunity in defence and disease (type IV hypersensitivity reactions). T h1‐biased CD4 T cells are essential for protection against many microbes via the activation of CD8 T cells or macrophages. If, however, CD4 T cells have been sensitized against a self or harmless foreign antigen, they can stimulate tissue damage, again via CD8 T cells or macrophages. T h2‐biased T cells may be important in defence against some parasites, but are also responsible for the damage seen in conditions such as asthma.
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Figure 9. Lymphocyte development. The multi‐potential stem cell gives rise to the common lymphocyte precursor. This cell can develop into NK cells, B, T and NKT cells. NK cells and B cells complete their development in the marrow, while T and NKT cells complete theirs in the thymus. Conventional follicular B cells and αβ T cells undergo negative selection to reduce the chance of autoreactive cells being produced, although this process is incomplete (Figure 11). αβ T cells also undergo positive selection to ensure that their receptors are MHC‐restricted. The interested reader might wish to consider whether or not, and if so to what extent, positive and negative selection might apply to the other cell types shown.
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Figure 10. B cell and T cell epitopes. Conventional BCRs (surface Ig) and secreted antibodies recognize regions that are exposed on the surface of macromolecules as well as small molecules. The regions recognized are termed B cell epitopes or conformational epitopes. If an epitope is to be recognized it must have a relatively rigid three‐dimensional structure. Conventional T cells, in contrast, recognize MHC molecules with bound peptides that have been produced by degradation of proteins. These peptides (that can be bound by MHC molecules and recognized by TCRs) are called T cell epitopes or sequential epitopes since the peptide is a linear sequence from the intact protein. In contrast, conformational epitopes for B cells can be formed by amino acids that are widely separated in the primary sequence of a protein.
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Figure 11. Lymphocytes in health and disease. B and T cells as they develop express a pre‐formed, anticipatory repertoire of antigen receptors that can potentially recognize antigens from infectious agents. For both B and T cells, cells that express receptors for self antigens that are present in their environment during development may be eliminated before they enter the periphery, including secondary lymphoid organs. This process is inevitably incomplete and some potentially self‐reactive lymphocytes will enter the periphery where, under abnormal circumstances, they may induce autoimmune responses. Lymphocytes that express receptors for harmless self antigens such as pollen or food cannot be eliminated during development and unless peripheral mechanisms work to prevent their activation may induce immune‐related sensitivities. A high frequency of T cells can also react against molecules expressed by other (allogeneic) individuals and can be responsible for transplantation reactions (rejection and GVHD).
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Figure 12. CD4 T cell activation in immunopathology. Normally, DCs express intrinsic (self) or extrinsic (harmless foreign) peptides on their MHC molecules. If these DCs are not fully activated, when if they encounter a T cell specific for these peptide‐MHC complexes the T cell will not be activated and may undergo apoptosis. If, however, the same DC has been stimulated by PAMPs or possibly DAMPs in the periphery, it will increase expression of costimulatory molecules and may become be able to activate the T cell, which will then have the potential of mounting a damaging response against the self or harmless antigen.
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Figure 13. Damage‐associated molecular patterns. The initiation of adaptive immune responses to non‐microbial antigens (e.g. allograft rejection) may depend on the release of molecules from dead or damaged (e.g. hypoxic) cells that activate innate immune cells such as DCs. These molecules have been termed DAMPs. Some candidate DAMPs such as uric acid and ATP have been identified. Malignant tumours often possess areas of necrosis that could release DAMPs; however, such tumours have evolved multiple ways of preventing adaptive responses from rejecting the tumour.
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Figure 14. Epitope spreading. In established autoimmune disease, T cells may be found that respond to a variety of antigens from the cells or tissues affected. This does not, however, mean that these antigens were involved in the initiation of the disease. A single peptide could be responsible for the initiation of the response, but subsequent damage to the cells, perhaps with DAMP involvement, means that other peptides may then be presented in an immunostimulatory form to T cells. This is known as epitope spreading and may serve to increase the overall strength of an autoimmune response.
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Figure 15. Disease concordance in twins. The genetic contribution to a disease can be estimated by studying sets of identical (monozygotic) and non‐identical (dizygotic) twins where one twin has the disease. If the frequency of the disease in the other twin (concordance) is higher in identical than non‐identical twins this is strong evidence for a genetic contribution. In most autoimmune diseases concordance is less than 50% in identical twins.
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Figure 16. Mechanisms of allergy. Exposure to some antigens may lead to IgE synthesis, which binds to specific Fc receptors (FCRs) on mast cells. If the antigen cross‐links mast cell‐bound IgE, the mast cell degranulates, releasing pre‐formed mediators such as histamine and some cytokines. Other mediators such as the lipd metabolites (eicosanoids) leukotrienes and prostaglandins, are synthesized and secreted. by the mast cell. The result is local acute inflammation as in allergic rhinitis (runny nose) in hay fever.
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Figure 17. Peanut anaphylaxis. If inflammatory mediators are released in large amounts from sensitized mast cells they may enter the circulation and cause potentially fatal systemic effects. The most important effects are those on smooth muscle. These include broncho constriction, which may cause respiratory obstruction, and venous dilatation, which leads to the pooling of blood in veins, preventing it returning to the heart and leading to potentially fatal hypotension (low blood pressure).
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Figure 18. Asthma. Immune‐mediated asthma (there are other types) involves a T h2 response to inhaled antigens (allergens). In the presence of IL‐4, activated T cells switch responding B cells to make IgE. The acute, IgE‐dependent response to the antigen causes mediator release from mast cells that induce broncho‐constriction; this is responsible for the respiratory problems (wheezing). A T h2‐biased cell‐mediated chronic inflammatory response can also occur that is responsible for the structural changes in the airways known as tissue remodelling, which can become irreversible. In severe asthma, T h17 T cells may be involved.
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Figure 19. Guillain–Barré syndrome. Some infections, of which Campylobacter jejuni is the most common, may be followed by a progressive muscular paralysis. An antibody response is made to bacterial LPS, and the antibody cross‐reacts with a ganglioside, GM 1, expressed on the myelin sheath of peripheral nerves. Complement damages the nerve sheath, leading to impaired conduction and paralysis and neutrophils may also be involved. There may also be a T cell‐mediated response which results in lymphocytes and macrophages infiltrating the nerves. The disease is usually self‐limiting over a long period, but may be treated by plasmapheresis to remove damaging antibodies non‐specifically or by giving large amounts of non‐specific Ig intravenously (IVIG therapy).
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Figure 20. Thyroid autoimmune disease. Hyperthyroidism (Graves' disease) may be caused by agonist antibodies to the TSH receptor which induce long‐lasting stimulation of thyroid hormone secretion. Hypothyroidism involving decreased secretion of thyroid hormones, may be caused by blocking antibodies to the TSH receptor, but may also be due to antibody‐independent cell‐mediated immunity involving cytotoxic T cells and activated macrophages a type IV response, very different to the other two types shown.
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Figure 21. Drug‐induced haemolytic anaemia. Some drugs, such as methyldopa previously used as a treatment for hypertension, on rare occasions may induce a haemolytic anaemia. It is suggested that the drug modifies an erythrocyte (RBC) protein, possibly generating modified peptides that can activate CD4 T cells. B cell tolerance is less complete than T cell tolerance and an antibody response is induced that leads to RBC destruction by lysis or opsonization. Stopping the drug resolves the problem.
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Figure 22. Haemolytic disease of the new born. If a Rh‐negative mother has a Rh‐positive baby, during birth some foetal RBCs escape into the maternal circulation and the mother makes an IgG anti‐Rh response. If she has a second pregnancy with a Rh‐positive foetus, the anti‐Rh antibodies will cross the placenta and destroy the foetal RBCs. This can be prevented very effectively if, immediately after the first and subsequent births, the mother is given anti‐Rh antibodies; these this prevents her becoming sensitized and she does not make an active anti‐Rh response.
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Figure 23. Pathogenesis of systemic lupus erythematosus. SLE is an inflammatory condition resulting from the deposition of circulating immune complexes in small blood vessels such as those in the skin, joints and kidney. These complexes activate complement, which induces acute inflammation, including the recruitment of neutrophils and macrophages, at the site of deposition. In SLE the antibodies are specific for DNA or DNA‐associated proteins. Two suggestions for pathogenesis are that there may be inefficient removal of apoptotic cells, leading to the release of DNA and associated proteins, and/or that clearance of circulating immune complexes is inefficient.
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Figure 24. Farmer's lung. Some individuals who inhale fungal spores over time make an IgG response to spore antigens. The IgG diffuses into the lungs and, when spores are next inhaled, local immune complexes form. These activate complement and local acute inflammation follows. Symptoms appear a few hours after the spores are inhaled.
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Figure 25. Type I (insulin‐dependent) diabetes. For reasons that are largely unclear, some individuals make an adaptive immune response that destroys their insulin‐secreting β cells in their pancreatic Islets of Langerhans. It is suggested that an infection (possibly Coxsackie virus) activates CD4 T cells that cross‐react with a β cell peptide. This activates CD4 and CD8 T cells that invade the Islets and induce destruction of the β cells. Infiltrating macrophages are also present and may play a part in causing the damage.
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Figure 26. Multiple sclerosis. For reasons that are largely unclear, some individuals make adaptive responses to myelin proteins expressed in the CNS; often myelin basic protein is the major antigen. Activated CD4 and CD8 T cells migrate to the CNS and recruit macrophages into the area. Effector mechanisms generated by these cells result in damage to the myelin sheaths of nerves, resulting in apparently random patches of demyelination, which can cause a variety of different symptoms. Antibodies specific for myelin may also be present but their role in pathogenesis is unclear.
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Figure 27. Multiple sclerosis‐like disease in humanized mice. Mice that have no T or B cells (RAG –/–) can be made transgenic for human MHC class II molecules, human CD4 and T cells that express a TCR for a human myelin basic protein peptide (MBP). These mice are given human haematopoietic stem cells and develop human lymphocytes and DCs. The T cells will have been selected in the thymus on human MHC class II molecules. If the mice have been given MHC class II genes associated with susceptibility to multiple sclerosis, they may develop a multiple sclerosis‐like disease with clinical features very similar to those found in human patients expressing the same MHC alleles.
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Figure 28. Regulatory T cells in murine inflammatory bowel disease. T cell‐deficient mice can be reconstituted by giving them T cells from a normal animal. When CD4 T cells were separated into naïve (CD25 –) and effector/memory (CD25 +) populations using surface molecule expression, it was found that the transfer of naïve T cells induced an inflammatory disease in the large intestine (inflammatory bowel disease), somewhat similar to human Crohn's disease. If, however, the supposed effector/memory T cells were also transferred, the inflammatory bowel disease was suppressed. The effector/memory population was found to contain CD25‐expressing CD4 T cells that had this suppressive function, T reg. If, however, naïve T cells were transferred into germ‐free mice, no inflammatory bowel disease developed.
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Figure 29. Pathological mechanisms in rheumatoid arthritis. In rheumatoid arthritis, a chronic inflammatory response in the synovium of joints leads to destruction of cartilage and bone. Examination of the affected synovium shown an infiltration with cells which include T and B lymphocytes, plasma cells, activated macrophages and some neutrophils. It thus appears that all the possible effector mechanisms of adaptive immunity are present and determining which is or are the most important in the pathogenesis of the disease is proving difficult.
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Figure 30. Transplantation terminology. An autograft is a transplant made within the same individual. An isograft is a transplant between two genetically identical isogeneic or syngeneic individuals, such as identical twins or inbred strains of animals. An allograft is a transplant between genetically different, allogeneic members of the same species. A xenograft is from one species to another xenogeneic species.
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Figure 31. Hyperacute allograft rejection. If the recipient of a vascularized graft such as a kidney possesses preformed antibodies against antigens expressed on the kidney endothelium (e.g. MHC molecules or blood group antigens), the antibodies may bind and activate complement. This leads to endothelial damage (neutrophils may be involved in causing damage), which in turn induces platelet aggregation and fibrin deposition, leading to thrombus formation and occlusion of the kidney blood vessels. The kidney dies of anoxia.
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Figure 32. Sensitization to allografts. Direct pathway. DCs (passenger cells) in the transplant migrate from the graft to secondary lymphoid tissues where they stimulate alloreactive host T cells. Indirect pathway. Host DCs or their precursors migrate into the transplant from the blood and acquire donor antigens, including MHC antigens. The DCs then migrate from the graft to secondary lymphoid organs where they present peptides from the donor antigens, bound to host MHC molecules, to host T cells. The indirect pathway is the one used for the induction of responses to “normal” antigens, whereas the direct route is unique to the setting of transplants.
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Figure 33. Effector mechanisms in acute allograft rejection. When tissues or organs are transplanted between normal individuals of the same species, rejection takes place over days (organs) or 1–2 weeks (skin). The immune response activates all effector mechanisms of the immune system including CD8 and CD4 T cells, macrophages and antibodies. All of these may be present within the graft and it is not clear which is/are the most important. Antibodies are probably less important than cell‐mediated mechanisms, and the strength of the response is such that either cytotoxic T cells or activated macrophages may be sufficient to cause rejection.
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Figure 34. Chronic allograft rejection. Sometimes, an organ graft that has been performing efficiently for a considerable time – even years – can start to fail insidiously. This often represent chronic rejection. The main pathological change in chronic rejection is smooth muscle proliferation and fibrosis (collagen deposition) leading to thickening of the walls of small arteries, diminished blood flow (ischaemia) and organ failure. Both antibody‐ and cell‐mediated immune responses may play a role in pathogenesis, and chronic rejection may represent an excessive healing response. Secretion of growth factors for smooth muscle cells by macrophages and endothelial cells may play a role in the arteriole wall thickening.
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Figure 35. Graft versus host disease (GVHD). Transplanted allogeneic bone marrow contains donor‐derived mature T cells that are not rejected by the host. Some of these T cells are alloreactive and recognize and are activated by host MHC molecules. The activated T cells then migrate to tissues such as the skin, liver and intestines, where they induce T cell‐dependent tissue damage. Because they are in effect rejecting the host this phenomenon is called GVHD.
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Figure 36. Tumour antigens. Tumours may express antigens derived from at least three different sources. If the tumour is associated with viral infection, antigens from the virus may be expressed. All tumours require multiple mutations to develop their typical characteristics. These mutations may generate novel peptides that can be recognized by T cells. In some tumours, genes that are normally only active during early development of a tissue or organ may be re‐activated e.g. synthesizing “oncofoetal” antigens. (In other cases, there is dysregulation of normal cell antigens, e.g. leading to over‐expression; not shown.)
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Figure 37. Stages in tumour immunity. As tumours progress they can express tumour antigens that induce T cell and or NK cell responses for example. These may destroy tumour cells before a tumour is clinically apparent; this is sometimes called the elimination phase. The tumour cells will, however, continue to mutate. At a certain stage, it is possible that the immune system can kill mutated cells as they arise and an equilibrium phase is reached. However, any mutation that enables a mutant cell to evade or avoid an immune response that would kill the tumour cell will give the mutant cell a selective advantage, and the mutant clone will outgrow the other tumour cells, this is now the escape phase. Over time a tumour will have been selected by the immune response to become resistant to all effector mechanisms.
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Figure 38. Tumour immune escape mechanisms. Many mechanisms have been identified in tumours that assist their evasion of immune response. Tumours may decrease expression of MHC class I and other molecules involved in immune activation (e.g. adhesion and costimulatory molecules) and increase expression of negative costimulatory molecules. Tumours may secrete inhibitory cytokines and other molecules that inhibit DC functions, induce the formation of T reg and inhibit T cell activation.
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