Autoimmunity PDF

Type III hypersensitivity reactions (Immune complex-induced hypersensitivity reactions) Type III HSR results from formation of antigen-antibody complexes and activation of complement system. Normally, circulating immune complexes generated in acute, or chronic infections are cleared by the phagocyt...

Type III hypersensitivity reactions (Immune complex-induced hypersensitivity reactions) Type III HSR results from formation of antigen-antibody complexes and activation of complement system. Normally, circulating immune complexes generated in acute, or chronic infections are cleared by the phagocytic system in the liver and spleen. However, in some cases, when immune complexes are produced in excessive amounts or are not efficiently cleared for example: 1. If the size of immune complexes is small, macrophages cannot remove them efficiently 2. Complement deficiency 3. There are intrinsic defects in macrophages cleaning function. Therefore, immune complexes will deposit in tissues (locally or systemically). These immune complexes activate the complement system. C3a and C5a fragments are anaphylatoxins that cause degranulation of local mast cells. C3a and C5a also attract neutrophils, which can accumulate in large numbers at the site of immune-complexes deposition, figure 13. Because the immune complexes bind avidly to components of the basement membranes, phagocytes cannot engulf them and they release their granule contents causing tissue damage. Tissue injury causes platelets aggregation leading to microthrombi formation, vascular occlusion, and tissue necrosis. Type III hypersensitivity reactions may be localized or generalized. Examples of localized type III HSRs a- Arthus reaction: In this case, immune complexes deposited locally. Example penicillin injection. First injection sensitizes the person’s immune system to produce IgG antibodies. Second injection resulting in formation of immune complexes and triggering of type III HSRs. Symptoms of local type III HSRs occur within 3-6 hours. b- Generalized hypersensitivity reactions type III (serum sickness) Systemic immune complexes form in the circulatory system and deposit in tissues particularly glomeruli, joints, pleura, and pericardium. Symptoms appear 6-15 days. Serum sickness is an acute self-limited allergic disease. Type IV HSRs (Delayed or cell-mediated HSR) This type of hypersensitivity reactions is due to the activation of pre-sensitized T lymphocytes rather than antigen-antibody reaction. Major cells participate in type IV HSR are CD4+T cells (mainly Th1), CD8+ T cells, and macrophages. Type IV hypersensitivity reactions peaks at 24-72 hours after exposure to the antigen. There are two types of type IV HSRs: T cell-mediated cytolysis and cytokine-mediated inflammation I- T cell mediated cytolysis It is mediated by CD8+ CTL. Chemical substances act as haptens. They cross lipid membrane, bound to intracellular proteins and are presented to CD8+ T cells in association with MHC class-I molecules. CD8+ T cells recognize the complex, activated and differentiated into CTL (effector killer cells). CTL destroy cells bearing peptide-MHC complex via either releasing of perforin and granzymes or Fas/FasL interaction. Example is contact dermatitis in which the blister is formed due to killing of keratinocytes by CTLs at the site of contact with the chemical allergen. II- Cytokine-mediated inflammation It is mediated by CD4+ T cells. It is commonly due to pathogenic antigens (especially intracellular microbes) but it can happen with haptens. Inflammation is mediated by secretion of cytokines produced mainly by Th1 cells. Antigenic peptides are presented to resting T helper cells in association with MHC class II molecules on DCs (or macrophages). DCs produce IL-12 which stimulates naïve T helper cells to differentiate into Th1 subset. Th1 cells secrete IFN-γ and IL-2. IFN-γ is the most potent macrophage- activating cytokine known. Activated macrophages have increased phagocytic and microbicidal activity Examples of this type of reaction are contact dermatitis, and granuloma formation. Diagnosis of contact dermatitis Patch test It tests a panel of antigens to which the patient may probable sensitized. The tested antigens are around 40 standard chemical substances such as nickel, neomycin, rubber, fragrances, etc. They are fixed on a tape which is stacked on the back of patient. The tape is then left for 2-4 days. Then the patient is examined for any allergic reaction. Immunologic Tolerance Immunologic tolerance is the unresponsiveness to self-antigen (tolerogens) but normally responses to non-self antigens (immunogens). Mechanisms of tolerance Two types of tolerance are known: central tolerance and peripheral tolerance. 1- Central tolerance (figure 16) It occurs in the generative lymphoid organs. Principal mechanisms of central tolerance include a- Clonal deletion (negative clonal selection): strongly autoreactive lymphocytes will be killed at thymus and bone marrow. b- Receptor editing: change lymphocyte specificity (for B cell only) c- Development of T regulatory cells (diversion): Recognition of self-antigens by T cells may lead to the development of Treg cells for these antigens. 2- B- Peripheral tolerance It occurs in the secondary lymphoid organs (e.g. spleen, lymph nodes) and in non-lymphoid tissues. Peripheral tolerance is important to inhibit autoreactive lymphocytes that escape central tolerance. The principal mechanisms of peripheral tolerance include: 1- Anergy (functional unresponsiveness): It is due to Activation by signal 1 in absence of costimulatory signal (signal 2) Engagement of inhibitory receptors: CTLA-4 (or programmed death 1 PD1) binds to B7 (or PD1-L) instead of CD28. 2- Ignorance Some of self-antigens may be sequestered from the immune system by anatomic barriers, such as in brain, eyes and testes, and thus cannot engage antigen receptors. 3- Suppression T regulatory cells produce transforming growth factor beta (TGF-β) and IL-10. These cytokines suppress immune responses by Th1 cells, Th2 cells and macrophages. 4- Deletion (cell death): normal T cells express Fas but not FasL. Repeated stimulation of T cells results in the coexpression of the death receptor Fas and its ligand FasL. FasL binds to Fas on the same cell or on neighboring cell and triggers apoptosis by activation of caspase. 5- Helplessness Many B cells and CD8+ T cells must have help from CD4+ T cells in order to make a response. Therefore, making CD4+ T cells tolerant will make the previous cells without help. Autoimmunity It is the breakdown of self-tolerance and mounting immune response against self- antigens. Autoimmune diseases are more common among females than males. Symptoms usually appear in the middle age (over 30 years). Causes of autoimmunity The exact etiology of most autoimmune diseases is unknown but could be due to: 1. Defects in the negative clonal selection 2- Defects in number or function of Treg cells 3- Polyclonal activation Some microbes (e.g. EBV) stimulate activation of many lymphocyte clones 4- Defects in Fas or FasL 5. Release of sequestered antigens due to tissue injury e.g. eye lens protein after trauma. 6. Molecular mimicry (cross-reaction) Viruses and bacteria may have epitopes that are similar to those of normal host cells. For example: Rheumatic heart disease results from molecular mimicry between Streptococcal M proteins and heart antigens. 7- Th17 cells over activity They produce large amounts of IL-17 which stimulates cell-mediated immunity. 8- Alteration of self-antigens 9- Genetic predisposition HLA-DQ2 and HLA-DQ8 genes are associated with celiac disease. HLA-B27 is associated with ankylosing spondylitis. 10- Sex hormones Estrogen hormone promotes humoral immunity by enhancement of B lymphocytes activity.