Autoimmunity

Autoimmunity

1. AUTOIMMUNITY Presented by Moderator : Dr.Varughese George Dr. K Shanmughasamy

2. CONTENTS DEFINITION HISTORY TOLERANCE FACTORS INFLUENCING AUTOIMMUNITY AUTOIMMUNE DISEASES – CLASSIFICATION SYSTEMIC LUPUS ERYTHEMATOSUS HASHIMOTO’S THYROIDITIS GRAVE’S DISEASE RHEUMATOID ARTHRITIS SJOGERN SYNDROME PERNICIOUS ANEMIA AUTOIMMUNE HEMOLYTIC ANEMIA TYPE 1 DIABETES MELLITUS MYASTHENIA GRAVIS MULTIPLE SCLEROSIS SUMMARY

3. DEFINITION Auto immunity is breakdown of the immune system’s ability to discriminate between self and nonself . condition in which structural or functional damage is produced by action of immunologically competent cells or antibodies against the normal components of the body. 5-7 % of adults affected, 2/3rds involving women. > 40 human diseases, autoimmune in origin.

4. DEFINITION 3 requirements to call it Autoimmunity : The presence of an immune reaction specific for some self antigen or self tissue. Evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance. The absence of another well-defined cause of the disease.

5. HISTORY Serge Metalnikoff (1900) reported that some animals were able to form antibodies against their own spermatozoa. Paul Ehrlich (1901) rejected the concept that an organism's immune system could attack the organism's own tissue calling it "horror autotoxicus ". Julius Donath and Karl Landsteiner (1904)reported autoantibodies can cause disease by showing that autoantibodies (‘ hemolysins ’) caused paroxysmal cold hemoglobinuria .

6. HISTORY Ernst Witebsky and Noel Rose (1956) were able to induce an experimental autoimmune thyroiditis mediated by autoantibodies . Witebsky (1957)postulated in Witebsky postulates, modified later (1994) for placing a disorder under Autoimmune disease. There are three considerations : Direct evidence from transfer of pathogenic antibody or pathogenic T cells. Indirect evidence based on development of the autoimmune disease in experimental animals. Conditional evidence from clinical clues, from signs and symptoms of patient.

7. TOLERANCE Normal immune system must differentiate between self and non-self. Immunologic tolerance  unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that antigen. Failure of self tolerance  lack of responsiveness to an individual’s own antigens. underlies our ability to live in harmony with our cells and tissues. Autoimmunity results from the loss of self-tolerance. Types : Central Tolerance. Peripheral Tolerance.

8. TOLERANCE Central tolerance: Immature self-reactive lymphocytes that recognize self antigens in generative (“central”) lymphoid organs die by apoptosis; other fates . Peripheral tolerance: Mature self-reactive lymphocytes that recognize self antigens in peripheral tissues are inactivated ( anergy ), killed (deletion) or suppressed.

9. CENTRAL TOLERANCE Immature T cells that recognize self antigens in the central (generative) lymphoid organs, some are killed by apoptosis - Negative selection or deletion in Thymus. escape killing and differentiate into regulatory T cells. In the B-cell lineage, some are killed by apoptosis. some of the self-reactive lymphocytes switch to new antigen receptors that are not self-reactive - Receptor editing in Bone Marrow.

10. Deletion of self-reactive T cells in the thymus: how are self antigens expressed in the thymus? Many self antigens are processed and presented by thymic APCs in association with self MHC. Any immature T cell that encounters a self antigen undergoes deletion/negative selection and the T cells that complete their maturation are thereby depleted of self-reactive cells AIRE (autoimmune regulator) is a regulator of gene transcription that stimulates thymic expression of many self antigens which are largely restricted to peripheral tissues . Mutations in AIRE gene gives rise to Autoimmune Polyendocrine Syndrome in which T cells specific for multiple self antigens escape deletion and attack tissues expressing the self antigens.

11. PERIPHERAL TOLERANCE Self-reactive T cells that escape negative selection in the thymus can potentially wreak havoc unless they are deleted or effectively muzzled. Several mechanisms in the peripheral tissues that silence such potentially autoreactive T cells : Anergy - functionally inactive . or Suppression by regulatory T-lymphocytes. or Deletion by activation induced cell death by Activation of pro-apoptotic member of Bcl family called BIM. Fas-Fas ligand system.

12. PERIPHERAL TOLERANCE Anergy - functional inactivation of lymphocytes induced by encounter with antigens. Activation of T cells requires two signals: Signal 1 : recognition of peptide antigen in association with self MHC molecules on APCs. Signal 2 : costimulatory signals (e.g., through B7 molecules) provided by the APCs. If Signal 2 is not delivered due to weak expression of costimulatory molecules The T cell becomes anergic and cannot respond to the antigen.

13. PERIPHERAL TOLERANCE Suppression by regulatory T cells - The responses of T cells to self antigens may be actively suppressed by regulatory T cells. Regulatory T cells are CD4+ cells that express high levels of CD25 (IL-2 receptor a chain) Generated by self antigen recognition in the thymus or peripheral tissues Generation requires a transcription factor called Foxp3 Mutations in FoxP3 gene are the cause of a severe autoimmune disease IPEX in humans. associated with deficiency of regulatory T cells.

14. PERIPHERAL TOLERANCE Activation-induced cell death - apoptosis of mature lymphocytes as a result of self-antigen recognition. Stimulation of T cells by self antigen triggers apoptosis by Engagement of death receptor Fas engaged by its ligand coexpressed on the same or neighboring cells - Death receptor pathway. Mutations in the Fas gene are responsible for an autoimmune disease - ALPS. or Imbalanced expression of pro-apoptotic proteins - member of Bcl family called BIM ( Bcl-2-like protein 11) Mitochondrial pathway

15. The factors that lead to a failure of self-tolerance and the development of autoimmunity include : inheritance of susceptibility - genes that may disrupt different tolerance pathways. infections and tissue alterations that may expose self-antigens and activate APCs and lymphocytes in the tissues.

16. FACTORS INFLUENCING AUTOIMMUNITY

17. Genetic Factors There is increased expression of Class II HLA antigens on tissues involved in autoimmunity. There is increased familial incidence of some forms of the autoimmune disorders. There is higher incidence of autoimmune diseases in twins (monozygotic > dizygotic ) favouring genetic basis. Most human autoimmune diseases are associated with multiple genes. Genome wide association studies are revealing genetic polymorphisms associated with autoimmune diseases.

18. Immunological factors Polyclonal activation of B cells by stimuli such as infection with microorganisms & their products bypasses T cell tolerance. Generation of self-reacting B cell clones bypasses T cell tolerance. Decreased T suppressor and increased T helper cell activity lead to high levels of autoantibody production by B cells contributing to autoimmunity. Fluctuation of anti- idiotype network control may cause failure of mechanisms of immune tolerance. Sequestered ‘Self-antigens’ may act as ‘foreign-antigens’ if introduced into the circulation later.

19. Sequestered antigens C ertain self anigens are present in closed systems and are not accessible to immune apparatus. These are known as sequestered antigens ( HIDDEN ANTIGENS )

20. Ag related from hidden location Many self Ag are found in hidden location eg . CNS , Testes , Eye (CORNEA) Organ damage Hidden Ag released Reaches blood stream Encounter Ag sensitive cells Stimulate autoimmunity

21. Examples of Sequestered Antigens Myelin basic protein (MBP), associated with MS. Sperm-associated antigens in some individuals following vasectomy. Lens and corneal proteins of the eye following infection or trauma . Heart muscle antigens following myocardial infarction.

22. Enviromental factors Ultraviolet (UV) radiation causes cell death and maylead to the exposure of nuclear antigens, which elicit pathologic immune responses in lupus. Smoking is a risk factor for rheumatoid arthritis, perhaps because it leads to chemical modification of self antigens. Strong gender bias, with many of these diseases being more common in women > men owing to hormones and other mechanisms.

23. Role of Infections and Tissue Injury Molecular mimicry : Viruses and other microbes may share cross-reacting epitopes with self antigens, such that responses may be induced by the microbe but may attack self tissues. e.g. Rheumatic heart disease. Microbial infections with resultant tissue necrosis and inflammation can cause upregulation of costimulatory molecules on APCs in the tissue favoring breakdown of T cell anergy and subsequent T cell activation.

24. Autoimmune Diseases

25. Criteria for diagnosis of autoimmune diseases. LABORATORY EVIDENCE 1. Presence and documentation of relevant autoantibodies in the serum 2. Demonstration of T cell reactivity to self antigen 3. Lymphocytic infiltrate in the pathologic lesion 4. Production of cytokines by helper T cells e.g. interferon,IL4 5. Evidence to support production of pathologic lesions in the tissue by transplacental transmission 6. Transfer of an autoimmune disease to an experimental animal by administration of autoantibodies .

26. Criteria for diagnosis of autoimmune diseases. CLINICAL EVIDENCE 1. Association of other autoimmune disease. 2. Improved therapeutic response to immunosuppressive agents. 3. Family history of autoimmune disease.

27. Systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of protean manifestations and variable clinical behavior. Clinically, it is an unpredictable, remitting and relapsing disease of acute or insidious onset that may involve virtually any organ in the body. It affects principally the skin, kidneys, serosal membranes, joints, and heart. Immunologically, the disease is associated with an enormous array of autoantibodies , classically including antinuclear antibodies (ANAs). The clinical presentation of SLE is so variable, with so many overlapping features with those of other autoimmune diseases (RA, polymyositis , and others),

28. PATHOGENESIS of SLE The fundamental defect in SLE is a failure to maintain self tolerance, leading to the production of a large number of autoantibodies that can damage tissues either directly or in the form of immune complex deposits. The pathogenesis of SLE involves a combination of genetic and environmental factors. Genetic susceptibility and exposure result in failure of self-tolerance and persistence of nuclear antigens. Autoantibodies serve to internalize nuclear components, which engage TLRs and stimulate IFN production. IFN may stimulate B and T cell responses to the nuclear antigens.

29. PATHOGENESIS of SLE Genetic Factors Familial association Family members have an increased risk for the development of SLE. Up to 20% of clinically unaffected first-degree relatives may have autoantibodies . Monozygotic twins (25%) > Dizygotic twins (1-3%) HLA association. The odds ratio (relative risk) for persons with HLA-DR2 or HLA-DR3 is 2 to 3, and if both haplotypes are present, the risk is about 5. Other genes. Genetic deficiencies of classical pathway complement proteins, especially C1q, C2, or C4, are seen in about 10% of patients with SLE.

30. PATHOGENESIS of SLE Environmental Factors. Ultraviolet (UV) radiation (sun exposure) exacerbates the lesions of SLE --> causes apoptosis of host cells,leading to an increased burden of nuclear fragments and inflammatory responses to the products of dead cells. Cigarette smoking has been shown to be associated with the development of SLE. Sex hormones had been thought to exert an important influence on the development of disease. Drugs such as procainamide and hydralazine can induce an SLE-like disease, by cause demethylation of DNA.

31. Immunologic Abnormalities in SLE. Type I interferons . Blood cells show a striking molecular signature that indicates exposure to interferon-α (IFN-α), a type I interferon that is produced mainly by plasmacytoid DCs. TLR signals. Studies in animal models have shown that TLRs that recognize DNA and RNA, notably the DNA recognizing TLR9 and the RNA-recognizing TLR7, produce signals that activate B cells specific for self nuclear antigens. Failure of B cell tolerance. Studies with B cells from patients with SLE suggest the presence of defects in both central and peripheral tolerance, resulting in a higher frequency of autoreactive B cells than that typical for healthy people.

32. Spectrum of Autoantibodies in SLE

33. LE CELL PHENOMENON First diagnostic laboratory test described for SLE. Principle :ANAs cannot penetrate the intact cells and thus cell nuclei should be exposed to bind them with the ANAs resulting in homogeneous mass of nuclear chromatin material. LE cell is a phagocytic leucocyte , commonly poly morphonuclear neutrophil , and sometimes a monocyte , which engulfs the homogeneous nuclear material of the injured cell. Two LE cells having rounded masses of amorphous nuclear material (LE body) which has displaced the lobes of neutrophil to the rim of the cell.

34. Morphology of major lesions in SLE Blood Vessels. An acute necrotizing vasculitis affecting small arteries and arterioles may be present in any tissue. Kidneys. Diffuse lupus nephritis (class IV) is the most serious form of renal lesions in SLE and is also the most commonly encountered in renal biopsies, occurring in 35% to 60% of patients. Skin Lesions A characteristic erythematous or maculopapular eruption over the malar eminences and bridge of the nose (“butterfly pattern”) is observed in approximately half of the cases. Exposure to sunlight (UV light) exacerbates the erythema (so-called photosensitivity), and a similar rash may be present elsewhere on the extremities and trunk.

35. Lupus nephritis Lupus nephritis showing a glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes (periodic acid Schiff stain) Deposition of IgG antibody in a granular pattern, detected by immunofluorescence .

36. Histopathology of skin lesions in SLE An H&E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema at the dermoepidermal junction. An immunofluorescence micrograph stained for IgG reveals deposits of immunoglobulin along the dermoepidermal junction.

37. Hashimoto’s Thyroiditis Immune destruction of thyroid cells An association of cytotoxic lymphocyte-associated antigen 4 (CTLA4), a T cell regulatory gene, with autoimmune phenomenon in Hashimoto’s disease has been reported. There is initial activation of CD4+ T helper cells, which then induce infiltration of CD8+ T cytotoxic cells in the thyroid parenchyma. In the process, B cells are also activated to form autoantibodies , which bring about immune destruction of thyroid parenchyma.

38. Hashimoto’s Thyroiditis The following autoantibodies against different thyroid cell antigens are detectable in the sera of most patients with Hashimoto’s thyroiditis : Thyroid microsomal autoantibodies (against the microsomes of the follicular cells). Thyroglobulin autoantibodies . TSH receptor autoantibodies . Less constantly found are thyroid autoantibodies against follicular cell membranes, thyroid hormones themselves and colloid component other than thyroglobulin .

39. Hashimoto’s Thyroiditis There is lymphoid cell infiltration with formation of lymphoid follicles having germinalcentres ; small, atrophic and colloid-deficient follicles; presence of Hurthle cells which have granular oxyphil cytoplasm and large irregular nuclei; andslight fibrous thickening of lobular septa.

40. Grave’s Disease Genetic factors. A familial occurrence has been observed. Susceptibility to develop Graves’ disease has been found associated with HLA-DR3(Hashimoto’s thyroiditis has both HLA-DR3 and HLA-DR5 association, CTLA-4 and PTPN22 (a T-cell regulatory gene). Autoimmune disease association Graves’ disease and Hashimoto’s thyroiditis are frequently present in the same families and the two diseases may coexist in the same patient.

41. Production of thyroid hormones is regulated by thyroid-stimulating hormones (TSH) The binding of TSH to a receptor on thyroid cells activates adenylate cyclase and stimulates the synthesis of two thyroid hormones: thyroxine and triiodothyronine A person with Grave’s Disease makes auto-antibodies to the receptor for TSH. The binding of these auto-antibodies to the receptor mimics the normal action of TSH, without the regulation, leading to overstimulation of the thyroid The auto-antibodies are called long- acting thyroid stimulating hormones Grave’s Disease

42. Grave’s Disease Autoantibodies TSH-receptor autoantigen is the main antigen against which autoantibodies are directed. These are as under: Thyroid-stimulating immunoglobulin (TSI): It binds to TSH receptor and stimulates increased release of thyroid hormone. ii) Thyroid growth-stimulating immunoglobulins (TGI): It stimulates proliferation of follicular epithelium. iii) TSH-binding inhibitor immunoglobulins (TBII): It is inhibitory to binding of TSH to its own receptor. Depending upon its action as inhibitory or stimulatory to follicular epithelium, it may result in alternate episodes of hypo- and hyperthyroidism.

43. Grave’s Disease The follicles are small and are lined by tall columnar epithelium, which is piled up at places forming papillary infoldings . Colloid is nearly absent and appears lightly staining, watery and finely vacuolated.

44. Rheumatoid Arthritis Rheumatoid arthritis (RA) is a systemic, chronic inflammatory autoimmune disease affecting many tissues but principally attacking the joints. It causes a nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis. The pathologic changes are caused mainly by cytokine-mediated inflammation, with CD4+ T cells being the principal source of the cytokines. Many patients also produce antibodies against cyclic citrullinated peptides (CCPs)

45. Pathogenesis of Rheumatoid Arthritis

46. Rheumatoid Arthritis Immunologic derangements Detection of circulating autoantibody called rheumatoid factor (RF) against Fc portion of autologous IgG in about 80% cases of RA. The presence of antigen-antibody complexes ( IgG -RF complexes) in the circulation as well as in the synovial fluid. The presence of other autoantibodies such as antinuclear factor (ANF) , antibodies to collagen type II, and antibodies to cytoskeleton. Antigenicity of proteoglycans of human articular cartilage. The presence of g-globulin, particularly IgG and IgM , in the synovial fluid. Association of RA with amyloidosis . Activation of cell-mediated immunity as observed by presence of numerous inflammatory cells in the synovium , chiefly CD4+ T lymphocytes and some macrophages.

47. RA involves first the small joints of hands and feet and then symmetrically affects the joints of wrists, elbows, ankles and knees. The proximal interphalangeal and metacarpophalangeal joints are affected most severely. Frequently cervical spine is involved,but lumbar spine is spared.

48. The characteristic histologic features are villous hypertrophy of the synovium and marked mononuclear inflammatory cell infiltrate in synovial membrane with formation of lymphoid follicles at places.

49. Sjogern Syndrome Sjögren syndrome is a clinicopathologic entity characterized by dry eyes ( keratoconjunctivitis sicca ) and dry mouth ( xerostomia ), resulting from immune-mediated destruction of the lacrimal and salivary glands . Occurs as an isolated disorder (primary form), also known as the sicca syndrome, or more often in association with another autoimmune disease (secondary form).

50. Pathogenesis of Sjogern Syndrome Autoimmune disease caused by CD4+ T cell reactions against unknown antigens in the ductal epithelial cells of the exocrine glands. Systemic B cell hyperactivity, as evidenced by the presence of ANAs and rheumatoid factor (RF) (even in the absence of associated RA). Most patients with primary Sjögren syndrome have autoantibodies to the ribonucleoprotein (RNP) antigens SS-A (Ro) and SS-B (La) - not specific. Genetic variables like inheritance of certain class II MHC alleles.

51. Histopathology in Sjogern Syndrome Histopathologic findings include intense lymphocytic and plasma cell infiltration with ductal epithelial hyperplasia.

52. PERNICIOUS ANAEMIA Chronic disorder of middle-aged and elderly individual of either sex in which intrinsic factor (IF) secretion ceases owing to atrophy of the gastric mucosa. The most characteristic pathologic finding in PA is gastric atrophy affecting the acid and pepsin-secreting portion of the stomach and sparing the antrum . Gastric epithelium may show cellular atypia . About 2-3% cases of PA develop carcinoma of the stomach.

53. PERNICIOUS ANAEMIA The incidence is high in patients with other autoimmune diseases such as Graves’ disease, myxoedema , thyroiditis , vitiligo , diabetes and idiopathic adrenocortical insufficiency. Patients have anti-parietal cell antibody (90% cases) and antiintrinsic factor antibody (50% cases). Relatives of patients with PA have an increased incidence of the disease or increased presence of autoantibodies . Corticosteroids have been reported to be beneficial in curing the disease both pathologically and clinically. PA is more common in patients with agammaglobulinaemia supporting the role of cellular immune system in destruction of parietal cells. Certain HLA types have been reported to be associated with PA.

54. PERNICIOUS ANAEMIA Chronic atrophic gastritis (right) There is marked gastric atrophy with disappearance of gastric glands and appearance of goblet cells (intestinal metaplasia ) Chronic atrophic gastritis with intestinal metaplasia .

55. Autoimmune Haemolytic Anaemia (AIHA) Autoimmune haemolytic anaemia (AIHA) characterised by formation of autoantibodies against patient’s own red cells. Depending upon the reactivity of autoantibody, AIHA is further divided into 2 types: ‘Warm’ antibody AIHA in which the autoantibodies are reactive at body temperature (37°C). ‘Cold’ antibody AIHA in which the autoantibodies react better with patient’s own red cells at 4°C.

56. Autoimmune Haemolytic Anaemia (AIHA) ‘WARM’ ANTIBODY AIHA Warm antibodies reactive at body temperature and coating the red cells are generally IgG class antibodies and occasionally IgA . Human red cells coated with IgG antibodies are bound to the surface of RE cells, especially splenic macrophages . Red cells coated with IgG along with C3 on the surface further promote this red cell- leucocyte interaction, accounting for more severe haemolysis . The spleen traps and destroys these red cells coated with IgG antibodies. Positive direct Coombs’ ( antiglobulin ) test for presence of warm antibodies on the red cell, best detected at 37°C. A positive indirect Coombs’ ( antiglobulin ) test at 37°C may indicate presence of large quantities of warm antibodies in the serum.

57. Autoimmune Haemolytic Anaemia (AIHA) ‘COLD’ ANTIBODY AIHA The antibodies are IgM type which bind to the red cells best at 4°C. These cold antibodies are usually directed against the I antigen on the red cell surface. Agglutination of red blood cells by IgM cold agglutinins is most profound at very low temperature . Haemolytic effect is mediated through fixation of C3 to the red blood cell surface and not by agglutination alone. It is seen in the course of certain infections (e.g. Mycoplasma Pneumonia , infectious mononucleosis) and in lymphomas. Positive direct Coombs’ test for detection of C3 on the red cell surface but IgM responsible for C3 coating on red cells is not found.

58. TYPE 1 DIABETES MELLITUS Type 1 diabetes is an autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting against endogenous beta cell antigens. The fundamental immune abnormality in type 1 diabetes is a failure of self-tolerance in T cells. The principal susceptibility locus for type 1 diabetes resides in the chromosomal region that encodes the class II MHC molecules on 6p21 (HLA-D). Environmental factors, especially infections caused by certain viruses (mumps, rubella, and coxsackie B viruses, in particular) may be an initiating trigger, perhaps because some viral antigens are antigenically similar to beta cell antigens (molecular mimicry)

59. Pathogenesis of Type 1 Diabetes Mellitus Autoimmune attack directed against specialized insulin-producing cells (beta cells) that are located in spherical clusters, called the islets of Langerhans,scattered throughout the pancreas. Activated CTLs migrate into an islet and begin to attack the insulin producing cells, causing insulitis . This is is followed by cytokine (IFN- γ , TNF-  α and IL-1) release and the presence of auto-antibodies, which leads to a cell-mediated DTH response. The subsequent beta-cell destruction is thought to be mediated by cytokines released during the DTH response and by lytic enzymes released from the activated macrophages.

60. islet of Langerhans (a) in pancreas from a normal mouse (b) one in pancreas from a mouse with a disease resembling insulin-dependent diabetes mellitus

61. MYASTHENIA GRAVIS Neuromuscular disorder of autoimmune origin in which the acetylcholine receptors ( AChR ) in the motor end-plates of the muscles are damaged. Presents clinically with muscular weakness and fatiguability , initially in the ocular musculature but later spreads to involve the trunk and limbs. 10% mortality due to severe generalised disease and involvement of respiratory muscles. Other autoimmune diseases have been found associated with MG such as autoimmune thyroiditis , rheumatoid arthritis, SLE, pernicious anaemia and collagen-vascular diseases.

62. MYASTHENIA GRAVIS The basic defect is reduction in the number of available AChRs at the postsynaptic muscle membrane. These changes result in decreased neuromuscular transmission leading to failure to trigger muscle action potentials and consequent weakened muscle contraction. About 85-90% patients have anti- AChR -antibodies in their sera which reduce the number of available AChRs by blocking the active sites of the receptors . or damaging the post-synaptic muscle membrane in collaboration with complement. Majority of patients may have either thymoma or thymic hyperplasia. The thymus possibly sensitises B cells to produce anti- AChR antibodies.

63. MYASTHENIA GRAVIS Light microscopy a few clumps of lymphocytes may be found around small blood vessels. Degenerating muscle fibres are present in half the cases. Electron microscopy Reduction in synaptic area of the motor axons due to flattening or simplification of postsynaptic folds. The number of AChRs is greatly reduced. It is possible to demonstrate the complex of IgG and complement at the neuromuscular junctions by combination with immunocytochemistry

64. MULTIPLE SCLEROSIS An autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space. Women are affected twice as often as men. Caused by a combination of environmental and genetic factors that result in a loss of tolerance to myelin antigen. A significant fraction of the genetic risk for MS is attributable to HLA-DR variants, the DR2 allele being the one that most significantly increases the risk for developing MS. A central role for CD4+ T cells has been suggested, with an increase in TH17 and TH1 CD4+ cells thought to be a critical component of the injury to myelin.

65. MULTIPLE SCLEROSIS Affected areas shows multiple, well-circumscribed, slightly depressed, glassy-appearing, gray-tan, irregularly shaped lesions termed plaques. In an active plaque there is evidence of ongoing myelin breakdown with abundant macrophages containing myelin debris. Active plaques fall into four classes: Type I, which has macrophage infiltrates with sharp margins Type II, which is type I + complement deposition. Type III, with less well-defined borders and oligodendrocyte apoptosis. Type IV, with nonapoptotic oligodendrocyte loss. In inactive plaques, the inflammation mostly disappears, leaving behind little to no myelin.

66. Section of fresh brain showing a plaque around occipital horn of the lateral ventricle. Unstained regions of demyelination (MS plaques) around the fourth ventricle. Luxol fast blue–periodic acid–Schiff stain for myelin

67. MULTIPLE SCLEROSIS The CSF in patients with MS shows a mildly elevated protein level with an increased proportion of immunoglobulin and moderate pleocytosis . When the immunoglobulin is examined further, oligoclonal bands usually are identified. Although B cells are clearly involved in the pathogenesis, the contribution of these characteristic antibodies to the disease process is unknown.

68. SUMMARY Autoimmunity - Breakdown in self-tolerance. Muliple causes - genetic, environmental, nutrition, infections, etc Organ specific or Systemic. Majority are caused by autoAb production Treatment: Immunosuppressive drugs, Abs against TCR, cytokines, adhesion molecules, etc.

69. References Robbins and Cotran Pathologic Basis of Disease 9 th edition. Harsh Mohan Textbook of Pathology, 7 th edition. Kuby Immunology 5th edition. Yamamoto K Mechanisms of Autoimmunity, the Journal of the Japan Medical Association Vol . 129, No. 7, 2003, pages 895–898

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