Autoimmunity

immunology

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This module will help you

learn about immune responses to self tissues. understand how tolerance to self antigens is maintained. see how self tolerance might be broken. test your knowledge and immunology problem-solving skills.

Autoimmunity Tolerance Autoimmunity The ability to make immune responses is heavily regulated to ensure that when pathogens are eliminated, the immune response is shut down to avoid wasted resources and hypersensitivity. In spite of this regulation and mechanisms for clonal deletion of many self-reactive T and B cells, the immune system can occasionally attack self tissues and produce autoimmunity. At the other end of the immune spectrum, deficiencies in the ability to make an adequate immune response can result in life-threatening infections. Autoimmunity is caused by an adaptive immune response against "self" antigen. The random generation of many diverse TCR and BCR makes autoimmunity possible. Clonal deletion and anergy of self-specific lymphocytes greatly reduces but does not eliminate the possibility of low affinity self-specific responses. Transient autoimmune responses are common but usually cause no lasting damage. Because self antigens are continually present in the body, when autoimmune responses are prolonged the resulting tissue damage can be life-threatening. Risk factors for autoimmune disease include the presence of certain HLA alleles, sex hormone levels, infection, and other environmental factors. Autoimmune diseases can be caused by antibodies or T cells and may be organ-specific or systemic. The table below summarizes information about some human autoimmune diseases. Autoimmune diseases are initiated by activation of antigen-specific T cells. Th2 cells activate B cells to make autoantibodies, which (by activating complement) damage tissues directly or initiate prolonged inflammation. CTL and macrophages activated by Th1 cells are directly cytotoxic and also promote inflammation. The damage done by some autoimmune responses is limited to a single organ, while other diseases cause systemic damage. The events that initiate specific autoimmune diseases are not known. Risk factors for autoimmune diseases are genetically linked to the presence of specific Class I or Class II HLA alleles. Two possible models attempt to explain HLA linkage to autoimmunity. One scenario is that certain HLA alleles are better at presenting pathogen peptides which resemble self peptides to mature T cells. The HLA B27 (Class I) allele is associated with an 80-fold increased risk of alkylosing spondylitis, characterized by inflammation and damage to the spine. Recent research shows that B27 can bind peptides in the absence of tapasin. This is an advantage in certain virus infections, where the virus interferes with production of tapasin. However, the peptides bound in the absence of tapasin are different from those bound in the presence of tapasin, and might include some self peptides that could induce autoimmunity. Therefore, people with the B27 Class I MHC allele might be more likely to respond to virus infections by producing CTL that can recognize self peptides and kill uninfected cells.

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The other model for autoimmunity proposes that certain HLA alleles are less efficient at presenting self peptides to developing T cells in the thymus, so that negative selection fails. This scenario is illustrated by IDDM (Insulin-Dependent Diabetes Mellitus or Type I diabetes). IDDM is strongly linked to the presence of HLA DR3 and DR4 alleles. HLA DR2 is protective, meaning the people with DR2 who also have DR3 or DR4 rarely develop diabetes. The actual allele which is linked to susceptibility is now known to be an HLA DQ tightly linked to DR3 and DR4. HLA DQ chain normally has an aspartic acid at position 57, which forms a salt bridge with the chain. DQ chains with valine, serine, or alanine at position 57 do not form a salt bridge, making the Class II molecule less stable and affecting its peptide-binding affinity. It has been proposed that negative selection of pancreatic islet cell-specific T cells during thymus development is less efficient in people with the altered alleles, raising their risk of developing diabetes by 25 fold. Human Autoimmune Diseases Disease Autoantigen Symptoms Lysis of RBC by complement and FcR+ cells, anemia Abnormal bleeding Glomerulonephritis, pulmonary hemorrhage Thyroid over-activity Thyroid under-activity Low blood glucose High blood glucose, ketoacidosis Progressive weakness Skin blisters Anemia Arthritis, myocarditis, heart valve scars Infertility Damage to vertebrae Systemic vasculitis Arthritis Glomerulonephritis, vasculitis, rash Extent* Type II: antibodies to cell surface molecules Autoimmune hemolytic anemia Autoimmune thrombocytopenic purpura Goodpasture's syndrome Graves' disease Hashimoto's thyroiditis Hypoglycemia Insulin-resistant diabetes Myasthenia gravis Pemphigus vulgaris Pernicious anemia Rheumatic fever Spontaneous infertility Ankylosing spondylitis Mixed essential cryoglobulinemia Rheumatoid arthritis Systemic lupus erythematosus (SLE) Rh blood group antigens, I antigen Platelet integrin GpIIb:IIIa Basement membrane Type IV collagen Thyroid-stimulating hormone receptor Thyroglobulin, thyroid peroxidase Insulin receptor (agonist) Insulin receptor (antagonist) O O O O O O O O O O O O S S S S

chain of nicotinic acetylcholine

receptor Epidermal cadherin Intrinsic factor, gastric parietal cells Streptococcal cell wall antigens; antibodies cross-react with heart muscle Sperm antigens

Type III: Immune complex disease Immune complexes Rheumatoid factor IgG complexes Rheumatoid factor IgG complexes DNA, histones, ribosomes, snRNP, scRNP Myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein Thyroid antigen(s) Pancreatic cell antigen(s) Unknown synovial joint antigen

Type IV: T cell-mediated disease Experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) Hashimoto's thyroiditis Insulin-dependent (Type I) diabetes mellitus (IDDM) Rheumatoid arthritis *O = organ-specific, S = systemic Brain invasion by CD4 T cells, weakness Thyroid under-activity S O O S

cell destruction
Joint inflammation and destruction

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Studies of IDDM, rheumatoid arthritis, MS, and SLE in identical twins generally show a 20% in disease concordance, which means that in 20% of cases where one twin develops autoimmunity, the other will develop the same disease. In fraternal twins, concordance is 5%. This finding illustrates that genetic background is an important but not the only risk factor. Sex hormones are linked with the occurrence of some autoimmune disease: women are 10-20 times more likely than men to develop multiple sclerosis or SLE, while men are three times more likely than women to develop ankylosing spondylitis. Other autoimmune diseases such as IDDM, myasthenia gravis and Goodpasture's syndrome occur with equal incidence in both men and women. Whatever the original antigen that triggers an immune response, as cells are killed and their contents are released more antigens, many of which are not normally present outside of cells to induce clonal deletion or clonal anergy, become available to activate the immune system. This is called determinant spreading. Activation of an autoimmune T cells specific for one epitope can activate B cells specific for several different epitopes associated with the same multimolecular complex. An example is seen in Systemic Lupus Erythematosis (SLE), where a Th cell specific for histone H1 can activate B cells specific for H1 and also B cells specific for DNA. Both H1-specific and DNA-specific B cells bind nucleosomes and present H1 peptides to helper T cells. When autoimmune disease is caused by autoantibodies, the antigen can often be identified and the disease mechanism classified as Type II or Type III hypersensitivity. In autoimmune hemolytic anemia, antibodies to red blood cell antigens initiate complement lysis and phagocytosis of RBC in the spleen reticuloendothelial system (RES). Antibodies to platelets and neutrophils can also cause depletion of these cells in the RES, although leukocytes are more resistant to complement lysis than are erythrocytes. Treatment for autoimmune hemolytic anemia can involve removal of the spleen. Complement activation in levels too low to lyse cells results in damaging inflammation due to chemotaxis of neutrophils and macrophages and their activation and production of cytokines. ADCC can also result in tissue damage and cell death. An example of antibody-mediated autoimmunity is seen in Hashimoto's thyroiditis, where antibodies to thyroid enzymes or hormones result in damage to the thyroid. Antibodies to cell aurface receptors may stimulate or inhibit receptor function. Antibodies to TSH receptor in the thyroid stimulate thyroid hormone production and induce hyperthyroidism (overactive thyroid) in Grave's Disease. Antibodies to the receptor for acetylcholine, a neurotransmitter, block nervous system signals to muscle cells and leads to myasthenia gravis, a progressive muscle weakness. Antibodies to insulin receptor have been shown in some cases to mimic insulin function and cause low blood sugar and in other cases to block insulin function and cause high blood sugar. Antibodies to basement membrane Type IV collagen, present in the kidney, lungs, and inner ear, cause Type II hypersensitivity in Goodpasture's syndrome. Antigens must be accessible for antibody-mediated autoimmune disease to occur. Type IV collagen is exposed in the kidney, so Goodpasture's syndrome always results in kidney disease. In general, only smokers also get lung damage with Goodpasture's syndrome, because damage from smoking exposes collagen in the lung. Hearing is rarely lost even though Type IV collagen is also present in the inner ear because it is hidden from the immune system. In Systemic Lupus Erythematosis (SLE), IgG production to many self antigens results in tissue damage throughout the body (systemic or system-wide disease). Since these self-antigens are present in all cells, antibody can bind and form immune complexes that activate complement whenever cells are damaged. Phagocytes are attracted and damage more cells, resulting in Type III hypersensitivity. Genes associated with SLE include those for proteins involved in antigen clearance, tolerance induction, and organ-specific disease susceptibility. Persisting infection can also lead to Type III hypersensitivity, where continuing antibody production to a pathogen cause tissue damage at the site of infection. An example is Lyme arthritis seen in some people infected with Borrelia burgdorferi , the spirochete that causes Lyme disease. IgG autoantibodies may be transferred across the placenta and cause transient symptoms in the newborn infant. Damage is usually not permanent; removal of maternal antibodies can be accomplished with plasmapheresis. T cell-mediated damage results in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis (which also has some Type III characteristics), and insulin-dependent diabetes. It is more difficult to identify autoimmune T cells and the antigen to which they are responding than it is to identify antibodies and their antigens. Specificity of autoimmune T cells may be identifiable in animal models of disease, such as experimental autoimmune encephalitis (EAE), a model for multiple sclerosis where disease is induced by injection of myelin basic protein. Both CD8 and CD4 T cells have been implicated in IDDM pathology. Th1 cells are associated with both EAE and rheumatoid arthritis.
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Since autoimmune disease is mediated by normal immune mechanisms, controlling the disease without making the patient susceptible to infection is the greatest challenge. Immunosuppressive drugs and experimental therapies are discussed in the Transplantation module. Tolerance Natural tolerance, the inability to make an immune response to an antigen, can occur for a number of reasons. Clonal deletion of self-reactive T and B cells during development removes lymphocytes with high avidity receptors for ubiquitous self antigen present in the thymus and marrow. The particular HLA alleles available to present self-antigen to developing T cells will influence which self peptides are presented with high enough avidity to induce clonal deletion and which are presented with low avidity. Clonal anergy occurs in the periphery, when immature B cells encounter soluble antigen that cross-links BCR and T cells encounter unprocessed antigen or processed antigen in the absence of co-stimulatory signals. Clonal anergy maintains tolerance to some (but not all) self antigens that are not available for clonal deletion in the thymus and marrow. Specific autoimmune diseases like those described above are probably not due to general failure of clonal deletion or clonal anergy. Most self antigen is presented with insufficient avidity to induce either clonal deletion or lymphocyte activation. Immunological ignorance refers to the common occurrence of low numbers of low avidity self-specific T cells existing in the presence of low levels of presented self peptides without becoming activated to respond. Humans make at least 105 proteins (average size 300 amino acids) which can be processed to generate 3 x 107 distinct peptides for presentation to T cells. Each APC has a maximum of 105 MHC molecules per cell with which to present these peptides; T cells must bind at least 10-100 identical peptides on an APC to become activated. Most peptides presented on APC would therefore be below the threshold for T cell detection. The best chance of stimulating autoimmune T cells would be with tissue-specific antigens, which are less likely to induce clonal deletion. We have seen above that there are relatively few autoimmune diseases and all people with a given disease respond the the same antigen(s), supporting the notion that autoimmunity occurs only under rare circumstances. The level of antigen presentation depends on which MHC alleles are available, and certain MHC alleles are linked with certain autoimmune diseases. An animal model illustrating immunological ignorance is the mouse bearing a transgene for a TCR specific for myelin basic protein (MBP) presented on self Class II MHC. Although all T cells in the mouse express the autoreactive TCR, the mouse shows no autoimmune disease. MBP presentation is low in all tissues except the CNS, where T cells do not usually go. When these mice are immunized with MBP, T cells are activated and migrate into all tissues including the CNS. There they produce cytokines in response to MBP that cause EAE. Induction of autoimmunity also requires co-stimulation of self-specific T cells. T cells which bind antigen without co-stimulatory signals undergo anergy rather than activation. If self-specific T cells do receive co-stimulation in the secondary lymphoid organs (perhaps from IL-2 produced by a nearby Th1 cell), the effectors that go to the periphery can interact with only a limited number of targets lacking co-stimulatory molecules before they die. Tolerance is also maintained by regulatory (suppressor) T cells. Cells which can transfer tolerance are CD4+ CD25+ T cells. Depletion of cells with this phenotype from normal mice or from normal cells given to athymic mice results in development of autoimmune disease. This tolerance is dominant and can be transferred to another animal with T cells. For example, neonatal rats injected with bone marrow cells from allogeneic rats become tolerant to skin grafts of the same allotype but not other allogeneic skin grafts. T cells transferred from the tolerant rat to another rat make the recipient tolerant to the same MHC allotype as long as allogeneic cells are transferred with the suppressor T cells. Tolerance can be eliminated (broken) if cells are transferred from an animal immunized to the allogeneic cells; these cells probably kill the allogeneic cells. NOD (non-obese diabetic) mice spontaneously develop type I diabetes. Transfer of a particular clone of insulin-specific T cells blocks islet destruction in NOD mice. The insulin-specific T cells home to the islets and produce TGF, an immunosuppressive cytokine. Another model that demonstrates suppressor T cell function is EAE. In mice injected with MBP in adjuvant, spinal paralysis develops and T cells producing IFN are found in the brain. If mice are first fed MBP, injection of MBP with adjuvant does not cause paralysis and T cells in the brain of these mice produce TGF. Activation of specific suppressor T cells is being investigated as a possible immunotherapy for autoimmune disease. Another possible therapy being tested is immune deviation, switching a Th1 response to a Th2 response or vice versa (see Vaccines).
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The body contains immunologically privileged sites; allografts placed in these sites do not elicit immune rejection. Immunologically privileged sites include the brain, testis, eye, and uterus (the fetus can be considered an allograft). Cells and proteins do leave these sites and circulate in the body, although they do not travel in the lymphatics. Nave lymphocytes are excluded from these sites. Immunosuppressive factors, probably TGF, are produced in these sites and are released from them with the cells and proteins. Tissues in these sites also express FasL, allowing them to kill any effector (Fas+) T cells which enter the sites. Antigens in immunologically privileged sites can be targeted by the immune system. In sympathetic opthalmia, damage to one eye can on rare occasions result in an autoimmune response to eye proteins that can damage the uninjured eye. Self-specific B cells also exist in the body but are prevented from responding to self antigen by several mechanisms. B cells recognizing specific self antigen in the secondary lymphoid organs are trapped in the T cell areas; if no activated self-specific T cells are available to provide help, the B cells die. B cells which bind soluble self antigen undergo anergy; they downregulate membrane IgM expression and live for only a short time. An anergic B cell which does bind a Th2 cell expressing FasL undergoes apoptosis rather than activation. Finally B cells in germinal centers undergoing somatic hypermutation, that can produce self-specific B cells, undergo apoptosis when exposed to soluble self antigen. Development of autoimmunity has been linked to infection; for example, many people who develop IDDM have experienced recent infection with a Coxsackie virus (which generally causes only mild symptoms). Induction of EAE requires administration of complete Freund's adjuvant (CFA) containing killed Mycobacterium tuberculosis along with the MBP. Mice given MBP in adjuvant without the M. tuberculosis remain healthy, and T cells from these mice later transferred to another mouse and exposed to MBP in CFA do not develop EAE. It is believed that infection induces inflammation that stimulates APC to express B7 that can activate T cells to self antigens. Lack of APC B7 in the absence of inflammation leads to T cell anergy. Some infections induce autoimmunity through molecular mimicry, where a pathogen antigen induces a response cross-reacting with self. The classic example is rheumatic fever following infection with Streptococcus pyogenes. Antibodies to Streptococcal antigen bind host heart tissue and can damage it. The responses is usually transient, since the T cells are specific for the Streptococcal antigen and not for self. Other examples of autoimmunity following infection include reactive arthritis following infection with Shigella, Salmonella, Yersinia and Camplyobacter, as well as chronic Lyme arthritis. Human studies are currently underway to investigate a possible link between coronary artery disease and infection with Chlamydia pneumoniae. Infections may also protect from autoimmunity. NOD mice which are kept pathogen free spontaneously develop IDDM, while mice kept in environments where some pathogens occur develop less IDDM. SLE is rare in African women, but occurs in 1 of 500 African-American women living in the US where infections (especially by parasites) are less common. References The Lupus Foundation http://www.lupus.org/index.html The National Institute for Arthritis and Musculoskeletal and Skin Diseases http://www.nih.gov/niams The National Institute for Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/ Practice Quiz Pick the one BEST answer for each question by clicking on the letter of the correct choice. 1. All of the following probably contribute to the development of autoimmunity EXCEPT a. cross-reactivity of pathogen and self antigens. b. expression of self antigen in the thymus or bone marrow. c. low avidity presentation of some self peptides in the thymus. d. random generation of TCR and BCR specificities.

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e. tissue injury which releases normally hidden self antigens. 2. The elimination of self-reactive T cells during thymus education is called a. apoptosis. b. clonal selection. c. clonal anergy. d. negative selection. e. positive selection. 3. An autoimmune disease mediated by Type III hypersensitivity is a. autoimmune hemolytic anemia caused by anti-A blood group antigen. b. Grave's Disease caused by anti-TSH receptor antibodies. c. IDDM caused by CTL to islet antigens. d. Lyme arthritis caused by immune complexes resulting from a persistent infection with Borrelia burgdorferi. e. Myasthenia gravis, caused by antibodies to the acetylcholine receptor 4. Tolerance is induced by all of the following EXCEPT a. administration of antigen with adjuvant. b. clonal anergy of self-reactive mature T cells which bind antigen without co-stimulation. c. clonal deletion of self-reactive immature B cells whose BCR is extensively cross-linked by antigen. d. failure of particular MHC alleles to present certain peptides. e. regulatory T cells that suppress immune responses. 5. Autoimmune diseases which are Type II hypersensitivities include all of the following EXCEPT a. Goodpasture's syndrome cause by autoantibodies to Type IV collagen. b. insulin-resistant diabetes caused by autoantibodies to insulin receptor. c. multiple sclerosis caused by Th1 cells specific for proteins in the brain and spinal cord. d. pemphigus vulgaris caused by autoantibodies to epidermal cadherin. e. rheumatic fever caused by antibodies to streptococcal antigens that cross-react with heart tissue. 6. Induction of autoimmunity usually involves a. activation of antigen-specific T cells. b. anergy of antigen-specific B cells. c. development of autoimune disease in everyone with certain HLA alleles. d. occurrence of infection in the absence of inflammation. e. recruitment of antigen-specific dendritic cells to T cell areas of the lymph nodes. 7. The chances of developing a given autoimmune disease are linked to all of the following EXCEPT a. contracting an infectious disease. b. gender. c. having an identical twin with the disease. d. inheriting certain HLA alleles. e. total absence of thymus education. 8. Autoantibodies to a cell surface receptor a. bind the cell to mimic the action of the natural ligand for that receptor b. block cell activation via that receptor.
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c. cause the destruction of the cell by ADCC. d. cause the destruction of the cell via complement-mediated lysis. e. All of the above are possible consequences. 9. Organ-specific autoimune diseases include all of the following EXCEPT a. autoimmune hemolytic anemia. b. Hashimoto's thyroiditis. c. insulin-dependent diabetes mellitus (IDDM). d. myasthenia gravis. e. rheumatoid arthritis. 10. Increased risk of developing Type 1 diabetes (IDDM) associated with HLA DR3 and DR4 a. can be lowered by the presence of HLA DR2. b. has been discovered to be due to a genetic mutation in those alleles induced by closely linked DQ. c. means that everyone with those HLA alleles will develop diabetes during his or her lifetime. d. occurs because DR3 and DR4 cannot present self antigen in the thymus. e. protects individuals with IDDM from malaria. 11. Of the following, it is usually the easiest to identify specific a. antigens for which autoimmune T cells are specific. b. antigens to which autoantibodies are being produced. c. environmental factors which promoted development of autoimmunity. d. pathogen antigens which initiated the autoimmune response. e. All of the above are equally easy to determine. 12. Determinant spreading occurs when a. antigenic epitopes move from one cell to another. b. B cells specific for one epitope provide co-stimulation to Th2 cells specific for different epitopes. c. CTL killing leads to release of new antigens to which B cells can produce antibodies. d. Th2 cells specific for one epitope on an antigen complex activate B cells specific for several different epitopes on that same complex. e. Answers b, c and d are examples of how determinant spreading could occur. 13. Feeding of myelin basic protein (MBP) to mice prevents them from later developing experimental autoimmune encephalomyelitis when they are injected with MBP and adjuvant. The mechanism by which antigen feeding prevents EAE is though to be a. activation of regulatory T cells producing IFN. b. activation of regulatory T cells producing TGF. c. clonal anergy of all MBP-specific T cells. d. clonal deletion of all MBP-specific T cells. e. induction of an IgE response instead of an IgG response to MBP. 14. Immunological ignorance to an antigen occurs when a. all lymphocytes specific for that antigen have undergone clonal deletion or clonal anergy. b. the antigen is absent from the body (non-self). c. the antigen is presented on self MHC with such high avidity that specific T cells are activated to undergo apoptosis. d. the antigen is presented on self MHC at such low avidity that specific T cells are not activated. e. the antigen is sequestered in the cell cytoplasm.
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15. Self-specific B cells are not generally responsible for the induction of autoimmunity because they a. are not present in the body. b. can be activated by self antigens but not produce any self-specific antibodies. c. cannot be activated by binding cell surface antigen. d. require activation by self-specific T cells, whose activates are more tightly regulated than those of B cells. e. undergo somatic recombination, which eliminates self-specific B cells. 16. Immune deviation might alleviate autoimmune disease by a. activating cytotoxic T cells to become regulatory T cells. b. distracting the immune system to respond to a different, less harmful self antigen. c. substituting allogeneic T cells for autoimmune T cells via bone marrow transplantation. d. switching the autoimmune response from a Th1 response to a less damaging Th2 response. e. targeting the immune response to an immunologically privileged site. 17. The link between infection and autoimmunity is related to four of the following observations. Find the exception. a. Antigens on pathogens may induce the production of antibodies which bind self antigen. b. Infection stimulates the production of inflammatory cytokines which induce dendritic cells to express more B7. c. Infection stimulates the production of inflammatory cytokines which induce dendritic cells to express more MHC molecules. d. Molecular mimicry of self antigen by pathogens antigen results in clonal deletion of self-reactive T cells that might otherwise cause autoimmunity. e. People who suffer more parasite infections are less likely to develop SLE than people of similar genetic backgrounds who are not infected by those parasites. Problem Select one of the autoimmune diseases described in the table above under Type II and briefly describe the immune mechanism(s) of tissue damage. How could there be T cells specific for self antigen present after negative selection in the thymus? Has the autoantigen been identified in the disease you picked? Why is it often difficult to identify the autoantigen? Does the presence of antibody to an antigen indicate that that antigen triggered the autoimmunity? Do the same for a disease in the Type III and Type IV sections of the table. Why are some diseases listed in more than one section? Top

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http://microvet.arizona.edu/Courses/MIC419/Tutorials/autoimmunity.html Written by Janet M. Decker, PhD jdecker@u.arizona.edu Last modified August 26, 2003

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