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Autoimmune diseases

Autoimmune diseases. Overview. Immune reactions against self antigens—autoimmunity—are an important cause of certain diseases in humans, estimated to affect at least 1% to 2% individuals the mere presence of autoantibodies does not indicate an autoimmune disease exists.

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Autoimmune diseases

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  1. Autoimmune diseases

  2. Overview • Immune reactions against self antigens—autoimmunity—are an important cause of certain diseases in humans, estimated to affect at least 1% to 2% individuals • the mere presence of autoantibodies does not indicate an autoimmune disease exists

  3. Pathologic autoimmunity Three requirements 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 isof primary pathogenic significance; the absence of another well-defined cause of the disease.

  4. Autoimmune diseases

  5. Clinical manifestations • Organ disease • example: diabetes mellitus • Generalised disease • example: lupus erythematous

  6. Tolerance • Immunologic tolerance is the phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen. • Lymphocytes with receptors capable of recognizing self antigens are generated constantly, and these cells have to be eliminated or inactivated as soon as they recognize self antigens, to prevent them from causing harm

  7. Mechanisms of tolerance

  8. Central tolerance • immature self-reactive T and B lymphocyte clones that recognize self antigens during their maturation in the central (or generative) lymphoid organs (the thymus for T cells and the bone marrow for B cells) are killed or rendered harmless • Negative selection of self-reactive T cells in thymus: When immature lymphocytes encounter the antigens in the thymus, many of the cells die by apoptosis • A wide variety of autologous protein antigens, including antigens thought to be restricted to peripheral tissues, are processed and presented by thymic antigen-presenting cells in association with self MHC molecules and can, therefore, be recognized by potentially self-reactive T cells • Receptor editing of developing B in bone marrow: B cells that recognize self antigens in the bone marrow reactivate the machinery of antigen receptor gene rearrangement and begin to express new antigen receptors, not specific for self antigens. • If receptor editing does not occur, the self-reactive cells undergo apoptosis, thus purging potentially dangerous lymphocytes from the mature pool.

  9. Mechanisms of central tolerance: AIRE

  10. Mechanisms of peripheral tolerance • Anergy. • activation of antigen-specific T cells requires two signals: recognition of peptide antigen in association with self MHC molecules on the surface of APCs and a set of costimulatory signals (“second signals”) from APCs such as CD28 on T cells that bind to their ligands (the costimulators B7-1 and B7-2) on APCs. • If the antigen is presented to T cells without adequate levels of costimulators, the cells become anergic. Because costimulatory molecules are not expressed or are weakly expressed on resting dendritic cells in normal tissues, the encounter between autoreactive T cells and their specific self antigens displayed by these dendritic cells may lead to anergy. • Several mechanisms of T-cell anergy have been demonstrated in various experimental systems. One of these, which has clinical implications, is that T cells that recognize self antigens receive an inhibitory signal from receptors that are structurally homologous to CD28 but serve the opposite functions. Two of these inhibitory receptors are CTLA-4, which (like CD28) binds to B7 molecules, and PD-1, which binds to two ligands that are expressed on a wide variety of cells. • mice in which the gene encoding CTLA-4 or PD-1 is knocked out develop autoimmune diseases. Furthermore, polymorphisms in the CTLA4 gene are associated with some autoimmune endocrine diseases in humans. • Anergy also affects mature B cells in peripheral tissues. It is believed that if B cells encounter self antigen in peripheral tissues, especially in the absence of specific helper T cells, the B cells become unable to respond to subsequent antigenic stimulation and may be excluded from lymphoid follicles, resulting in their death.

  11. T-cellanergy

  12. Mechanisms of peripheral tolerance • Suppression by regulatory T cells • A population of T cells called regulatory T cells functions to prevent immune reactions against self antigens. • Regulatory T cells develop mainly in the thymus, as a result of recognition of self antigens • The best-defined regulatory T cells are CD4+ cells that express high levels of CD25, the α chain of the IL-2 receptor, and a transcription factor of the forkhead family, called FOXP3. • Both IL-2 and FOXP3 are required for the development and maintenance of functional CD4+ regulatory T cells. Mutations in FOXP3 result in severe autoimmunity in humans and mice; in humans these mutations are the cause of a systemic autoimmune disease called IPEX (an acronym for immune dysregulation, polyendocrinopathy, enteropathy, X-linked). In mice knockout of the gene encoding IL-2 or the IL-2 receptor α or β chain also results in severe multi-organ autoimmunity, because IL-2 is essential for the maintenance of regulatory T cells. • The mechanisms by which regulatory T cells suppress immune responses are not fully defined, but their inhibitory activity may be mediated in part by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, which inhibit lymphocyte activation and effector functions. • Regulatory T cells also express CTLA-4, which may bind to B7 molecules on APCs and reduce their ability to activate T cells via CD28.

  13. Tregsuppressoryactivity Regulatory T (TReg) cells might mediate their effects by modifying the functions of other T cells, both CD4+ and CD8+ populations, either directly through T-cell–T-cell interactions or indirectly through antigen-presenting cells (APCs). The outcome of TReg-cell activity is inhibition of the function of effector T cells. 

  14. Mechanisms of peripheral tolerance • Deletion by apoptosis. • if T cells recognize self antigens, they may express a pro-apoptotic member of the Bcl family, called Bim, without antiapoptotic members of the family like Bcl-2 and Bcl-x (whose induction requires the full set of signals for lymphocyte activation). • A second mechanism of activation-induced death of CD4+ T cells and B cells involves the Fas-Fasligand system. if self antigens engage antigen receptors of self-reactive T cells, Fas and FasL are co-expressed, leading to elimination of the cells via Fas-mediated apoptosis. Self-reactive B cells may also be deleted by FasL on T cells engaging Fas on the B cells. • The importance of this mechanism in the peripheral deletion of autoreactive lymphocytes is highlighted by two mice that are natural mutants of Fas or FasL. These mice develop an autoimmune disease somewhat resembling human SLE, associated with generalized lymphoproliferation. In humans a similar disease is caused by mutations in the FAS gene; it is called the autoimmune lymphoproliferative syndrome (ALPS).

  15. Immune-privileged sites • Some antigens are hidden (sequestered) from the immune system, because the tissues in which these antigens are located (eye, testis, brain) do not communicate with the blood and lymph. • As a result, self antigens in these tissues fail to elicit immune responses and are essentially ignored by the immune system. • If the antigens of these tissues are released, for example, as a consequence of trauma or infection, the result may be an immune response that leads to prolonged tissue inflammation and injury. This is the postulated mechanism for post-traumatic orchitis and uveitis.

  16. Mechanisms of autoimmunity • Autoimmunity arises from a combination of • the inheritance of susceptibility genes • environmental triggers, such as infections and tissue damage

  17. Mechanisms of autoimmunity • Defective tolerance or regulation. • Despite the advances in understanding mechanisms of immune tolerance and regulation, it is not known why these may become defective in the majority of common autoimmune diseases. • Abnormal display of self antigens. • Abnormalities may include increased expression and persistence of self antigens that are normally cleared, or structural changes in these antigens resulting from enzymatic modifications or from cellular stress or injury • Inflammation or an initial innate immune response. • Microbes or cell injury may elicit local inflammatory reactions resembling innate immune responses, and these may be critical inducers of the autoimmune disease.

  18. Susceptibility genes • Autoimmunity has a genetic component. • The incidence of many autoimmune diseases is greater in twins of affected individuals than in the general population, and greater in monozygotic than in dizygotic twins, proof that genetics contributes to the development of these disorders. • Greatest contribution: HLA genes • Example: HLA-B27 and ankylosing spondylitis and HLA-B27; individuals who inherit this class I HLA allele have a 100-200 fold greater chance (odds ratio, or relative risk) of developing the disease compared with those who do not carry HLA-B27 • Note that the majority of individuals with this allele will not develop the disease anyway • Not clear why: not necessarily due to a better ability of some HLA molecules to display self-antigens

  19. Role of infections

  20. Role of infections • infections may upregulate the expression of costimulators on APCs. If these cells are presenting self antigens, the result may be a breakdown of anergy and activation of T cells specific for the self antigens. • some microbes may express antigens that have the same amino acid sequences as self antigens. Immune responses against the microbial antigens may result in the activation of self-reactive lymphocytes. This phenomenon is called molecular mimicry. • A clear example of such mimicry is rheumatic heart disease, in which antibodies against streptococcal proteins cross-react with myocardial proteins and cause myocarditis. • Some viruses, such as Epstein-Barr virus (EBV) and HIV, cause polyclonal B-cell activation, which may result in production of autoantibodies.

  21. General features of autoimmune diseases • Autoimmune diseases tend to be chronic, sometimes with relapses and remissions, and the damage is often progressive. • When the response is inappropriately directed against self tissues, physiological amplification mechanisms exacerbate and prolong the injury. Another reason for the persistence and progression of autoimmune disease is the phenomenon of epitope spreading, in which an immune response against one self antigen causes tissue damage, releasing other antigens, and resulting in the activation of lymphocytes by these newly encountered epitopes • The clinical and pathologic manifestations of an autoimmune disease are determined by the nature of the underlying immune response. Some of these diseases are caused by autoantibodies, whose formation may be associated with dysregulated germinal center reactions. Most chronic inflammatory diseases are caused by abnormal and excessive TH1 and TH17 responses; examples of these diseases include psoriasis, multiple sclerosis, and some types of inflammatory bowel disease. CD8+ CTLs contribute to killing of cells, such as islet β cells in type 1 diabetes. In some autoimmune diseases, such as rheumatoid arthritis, both antibodies and T cell–mediated inflammation may be involved.

  22. SLE (systemic lupus erythematosus) • SLE is an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs) • injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues. • The disease may be acute or insidious in its onset, and is typically a chronic, remitting and relapsing, often febrile, illness. Injury to the skin, joints, kidney, and serosal membranes is prominent. Virtually every other organ in the body, however, may also be affected. • SLE is a fairly common disease, with a prevalence that may be as high as 1 in 2500 in certain populations. • SLE predominantly affects women, with a frequency of 1 in 700 among women of childbearing age and a female-to-male ratio of 9 : 1 during the reproductive age group of 17 through 55 years

  23. Autoantibodies in SLE • Antinuclear antibodies (ANAs). The most widely used method for detecting ANAs is indirect immunofluorescence, which can identify antibodies that bind to a variety of nuclear antigens, including DNA, RNA, and proteins (collectively called generic ANAs). The pattern of nuclear fluorescence suggests the type of antibody present in the patient’s serum. Many basic patterns are recognized: • diffuse nuclear staining usually reflects antibodies to chromatin, histones, and, occasionally, double-stranded DNA. • Rim or peripheral staining patterns are most often indicative of antibodies to double-stranded DNA and sometimes to nuclear envelope proteins. • Speckled pattern refers to the presence of uniform or variable-sized speckles. This is one of the most commonly observed patterns of fluorescence and therefore the least specific. It reflects the presence of antibodies to non-DNA nuclear constituents such as Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens. • Nucleolar pattern refers to the presence of a few discrete spots of fluorescence within the nucleus and represents antibodies to RNA. This pattern is reported most often in patients with systemic sclerosis. • Centromeric pattern. Patients with systemic sclerosis often contain antibodies specific for centromeres, which give rise to this pattern. • Though the pattern and sensitivity of the ANAs is controversial, the test remains in use. • Other autoantibodies: • Directed against blood cells, such as red cells, platelets, and lymphocytes; • Antiphospholipid antibodies are present in 30% to 40% of lupus patients. They are actually directed against epitopes of plasma proteins that are revealed when the proteins are in complex with phospholipids. Some of these antibodies interfere with in vitro clotting tests, such as partial thromboplastin time. Therefore, these antibodies are sometimes referred to as lupus anticoagulant. Despite the observed clotting delays in vitro, however, patients with antiphospholipid antibodies have complications related to excessive clotting (a hypercoagulable state), such as thrombosis.

  24. Patterns of ANAs Diffuse Rim Speckled Centromeric

  25. Pathogenesis of SLE The fundamental defect in SLE is a failure of the mechanisms that maintain self-tolerance.

  26. Genetic factors • Family members of patients have an increased risk of developing SLE. As many as 20% of clinically unaffected first-degree relatives of SLE patients reveal autoantibodies and other immunoregulatory abnormalities. • There is a higher rate of concordance (>20%) in monozygotic twins when compared with dizygotic twins (1% to 3%). • Studies of HLA associations support the concept that MHC genes regulate production of particular autoantibodies. Specific alleles of the HLA-DQ locus have been linked to the production of anti–nuclear, and antiphospholipid antibodies, although the relative risk is small.

  27. Environmental factors • Exposure to ultraviolet (UV) light exacerbates the disease in many individuals. UV irradiation may induce apoptosis in cells and may alter the DNA in such a way that it becomes immunogenic, perhaps because of enhanced recognition by TLRs. In addition, UV light may modulate the immune response, for example, by stimulating keratinocytes to produce IL-1, a cytokine known to promote inflammation.

  28. A Model for the Pathogenesis of SLE. • Immunologic abnormalities in SLE—both documented and postulated—are varied and complex. • Potential model: • UV irradiation and other environmental insults lead to the apoptosis of cells. • Inadequate clearance of the nuclei of these cells results in a large burden of nuclear antigens. • Underlying abnormalities in B and T lymphocytes are responsible for defective tolerance, because of which self-reactive lymphocytes survive and remain functional. These lymphocytes are stimulated by nuclear self antigens, and antibodies are produced against the antigens. • Complexes of the antigens and antibodies bind to Fc receptors on B cells and dendritic cells, and may be internalized. • The nucleic acid components engage TLRs and stimulate B cells to produce more autoantibodies. TLR stimuli also activate dendritic cells to produce interferons and other cytokines, which further enhance the immune response and cause more apoptosis. • The net result is a cycle of antigen release and immune activation resulting in the production of high-affinity autoantibodies.

  29. Model for the pathogenesis of systemic lupus erythematosus. In this hypothetical model, susceptibility genes interfere with the maintenance of self-tolerance and external triggers lead to persistence of nuclear antigens. The result is an antibody response against self nuclear antigens, which is amplified by the action of nucleic acids on dendritic cells (DCs) and B cells, and the production of type 1 interferons. TLRs, Toll-like receptors.

  30. Lupus nephritis. A, Focal proliferative glomerulonephritis, with two focal necrotizing lesions at the 11 O’clock and 2 O’clock positions (H&E stain). Extracapillary proliferation is not prominent in this case. B, Diffuse proliferative glomerulonephritis. Note the marked increase in cellularity throughout the glomerulus (H&E stain). C, Lupus nephritis showing a glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes (periodic acid-Schiff stain). D, Electron micrograph of a renal glomerular capillary loop from a patient with SLE nephritis. Subendothelial dense deposits (arrowheads) correspond to “wire loops” seen by light microscopy. B (with arrow) refers to the basement membrane. E, Deposition of IgG antibody in a granular pattern, detected by immunofluorescence. B, Basement membrane; End, endothelium; Ep, epithelial cell with foot processes; Mes, mesangium; RBC, red blood cell in capillary lumen; US, urinary space.

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