Microbiology – Autoimmunity – Flashcards
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| autoimmunity definition |
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| reflects loss of immunologic tolerance to self tissues and cellular antigens "immune cells attack self tissues!" "forbidden" or self-reactive lymphocytes were physically eliminated during ontogeny autoreactive lymphocytes are generally of no pathological consequence because they are rendered ANERGIC (incactive) by maturation of lymphocytes processes if the maturation process fails to render these self-reactive cells ANERGIC or doesn't eliminate them through apoptosis, the potential of an autoimmune disease developing is highly likely |
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| central tolerance of T cells |
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| physical deletion of autoreative lymphocytes clones Negative selection - primary mechanism thymic T cells that react against self peptides presented by Class I or Class II MHC molecules are triggered into apoptosis (receive signal 1 in absence of signal 2) |
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| the effectiveness of negative selection is dependent upon what? |
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| negative selection, like regular foreign antigen immune defenses, depends on the immune systems ability to present the self peptides in MHC molecules correctly (as in having the correct antigen peptide anchor residues in relation to polymorphic contact residues in MHC molecules) |
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| what are the two things that go wrong in central tolerance |
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| certain self-peptides may not be available in thymus for negative selection MHC may not present certain peptides effectively for negative selection |
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| relative risk |
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| numerical value the risk for getting certain autoimmune diseases increases when individuals carry particular MHC alleles (different alleles are related to different diseases) |
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| cryptic epitopes |
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| epitope - region on antigen peptide that invokes an immune response cryptic epitopes arise when APCs do not efficiently process antigens and present "cryptic" epitopes that are WEAKLY immunogenic as an antigen is processed ,cryptic epitopes are revealed that don't initially activate T cells, but become prominent later in the response (epitope spreading) |
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| what are the 4 mechanisms of peripheral tolerance of T cells (peripheral tolerance - regulates self-reactive T cells that escape the thymus |
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| autoimmune T cell responses are limited by... 1. hiding self antigens in IMMUNOLOGICALLY PRIVILEGED SITES (CNS) 2. CD4+ cells are limited by restricted tissue/cell distribution of MHC class II 3. CTL responses limited by the restricted tissue/cell distribution of costimulatory molecules such as B7 (CD80/86) - inappropriate expression of co-stimulatory molecules will increase the prob of autoimmune T cell responsiveness 4. Treg cells (regulatory T cells) provide balance of cytokines (stop runaway cytokine responses and can result in anergy of autoimmune lymphocytes) |
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| how do immunologically privileged sites contribute to peripheral tolerance |
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| autoimmune T cell responses are hindered by KEEPING SELF ANTIGENS that can potentially make an autoimmune response AWAY FROM these potentially autoreactive T cells CNS is an example of an area that contains antigens that aren't screened against in thymus, thus, they must be kept away |
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| how are TH1, TH2 and TH17 (CD4+) cells kept from invoking autoimmune response after they have left the thymus (peripheral tolerance)? |
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| these cells can only react to antigen presented on MHC class II molecules thus, they are restricted to tissues and cell areas that contain these types of antigen presenters |
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| how are autoimmune CTL responses avoided after these CD8+ cells have left the thymus (peripheral tolerance) |
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| CTLs are also limited by the restricted tissue/cell distribution of co-stimulatory molecules (such as B7 which contains CD80/86) T cells given signal 1 in absence of signal 2 will undergo apoptosis/anergy |
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| how do Treg cells help prevent autoimmunity (peripheral tolerance) |
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| they provide a delicate balance of cytokines that can steer autoimmune responses away from potentially harmful effector activities this can result in anergy of autoimmune lymphocytes |
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| explain central tolerance of B cells |
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| must delete immature (IgM-only) B cells via negative selection occurs in bone marrow 3 things can go wrong 1. limited exposure to self-antigens results in incomplete deletion of B cells 2. mutation of B cells activated against foreign antigen could result in a new B cell that is reactive to self-antigens 3. B cells made against a foreign antigen could closely resemble a self antigen and thus allow for IMMUNE CROSS REACTIVITY |
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| what are the 3 things that can go wrong in central tolerance for B cells? |
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| 1. limited exposure to self-antigens results in incomplete deletion of B cells 2. mutation of B cells activated against foreign antigen could result in a new B cell that is reactive to self-antigens 3. B cells made against a foreign antigen could closely resemble a self antigen and thus allow for IMMUNE CROSS REACTIVITY |
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| antigen mimicry |
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| antigen has structural similarity to self peptides results in immune cross reactivity (antibodies attack both antigen and the self-peptide that is similar) |
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| give some examples of antigen mimicry in common pathogens |
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| streptococcal M protein ---> heart valve tissue (causes rheumatic fever) measles virus P3 antigen -> myelin basic protein Polio virus VP2 antigen -> acetylcholine receptor Cytomegalo virus IE2 antigen -> HLA-DR antigen Papilloma virus E2 antigen --> insulin receptor |
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| in antigen mimicry, what does the streptococcal M protein mimic? |
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| heart valve tissue causes rheumatic fever |
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| in antigen mimicry, what does the measles virus P3 antigen mimic? |
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| myelin basic protein |
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| in antigen mimicry, what does the polio virus VP2 antigen mimic? |
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| acetylcholine receptor |
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| explain peripheral tolerance in B cells |
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| it is composed of two branches, ANTIGEN SEQUESTRATION and SPLIT TOLERANCE antigen sequestration involves hiding potentially autoreactive antigens in immunologically privileged sites (CNS, interior of eye lens) split tolerance happens when a B cell is autoreactive and has escaped negative selection, however, it is unable to be activated because it's helper T cell (TH2) has successfully been destroyed/anergized through T cell central/peripheral tolerance (CAVEAT - anergic T cells can be activated or B cells can bypass activation with helper T cells) |
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| split tolerance |
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| split tolerance happens when a B cell is autoreactive and has escaped negative selection, however, it is unable to be activated because it's helper T cell (TH2) has successfully been destroyed/anergized through T cell central/peripheral tolerance CAVEAT - anergic T cells can be activated or B cells can bypass activation with helper T cells (T Cell Bypass mechanisms) |
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| explain the 2 main T cell bypass mechanisms |
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| 1. nonspecific, T inducer-INDEPENDENT MITOGENS and ADJUVANTS; these products can activate B cells w/o inducer T cells; e.g. Staph protein A, Epstein-Barr virus 2. nonspecific, T inducer-DEPENDENT in this scenario, a foreign antigen physically links to a self antigen, causing antibodies to be formed against the self antigen; B cells activated by TH2 cells; ALSO, TH cells may come in contact with PARTIALLY DEGRADED SELF-ANTIGENS that seem foreign, its activated B cells will attack these self antigens |
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| explain the different ways self-reactive antibodies cause autoimmune disease |
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| 1. they increase or decrease tissue activities due to BINDING OF ANTIBODY TO BIOLOGICALLY IMPORTANT RECEPTOR MOLECULES (e.g. myasthenia gravis) 2. antibody-mediated COMPLEMENT LYSIS (thrombocytopenia) 3. IMMUNE-COMPLEX DISEASE - antigen-antibody complexes my nonspecifically activate complement cascade causing bystander tissue damage 4. Antibody-dependent cell-mediated cytotoxicity (ADCC) - Fc RECEPTOR-bearing killer cells (CTL/NK cells) can demonstrate cytotoxicity against cells bound by specific antibody; effector cells themselves express no specificity for antigen, just Fc portion of antibody 5. Antibody-mediated attack by FcR-bearing and Complement Receptor-bearing phagocytes 6. danger to prenatal infants |
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| list the examples of autoimmune diseases of unknown etiology |
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| grave's disease (agonist for Thyroid SH receptor = hyperthyroidism) myasthenia gravis (antagonist for ACh receptors) insulin-dependent diabetes mellitus (insulin receptor) multiple sclerosis (demyelinating disease of CNS; antibody thought to target myelin itself or oligodendrocytes) rheumatoid arthritis (type IV HS with TH17 cells; IgG produced by synovial B cells attacked by anti-IgG antibody) goodpasture's syndrome systemic lupus erythematosus |
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| LE cells |
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| phagocytes that try to dispose of immune complexes... unsuccessfully |
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| Anti-receptor diseases (antibody attacks receptor) |
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| Graves Disease - TSH receptor agonist (hyperthyroidism) Myasthenia Gravis - AChReceptor antagonist Insulin-dependent Diabetes Mellitus - pancreatic islet cells antagonist |
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| multiple sclerosis |
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| demyelinating disease of the CNS inductive event unknown mixed and complex immune effectors; antibody and cell-mediated responses probably involving type II and type IV HS type II and type IV HS remitting-relapsing progression; activating vs. suppressing regulation antigenic target unclear; myelin producing cells (oligodendrocytes) vs. myelin itself |
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| rheumatoid arthritis |
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| type III and type IV HS prominent immune complex disease in joints abnormal IgG is produced in the synovium of certain individuals an Ab response is generated against the abnormal IgG the anti-IgG antibody is referred to as Rheumatoid Factor (RF) with time, large quantities of insoluble antigen/antibody complexes trigger complement cascade result is progressive tissue damage in the joint |
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| systemic lupus erythematosus |
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| systemic; multiple tissues specificities; prominent ANA+(anti nucleic acid)/DNA-reative antibodies and hematopoietic/lymphopoietic cell antibodies inducing event unknown; likely regulatory dysfunction with sex hormone influences (note greater incidence in women during child-bearing years) prominent immune complex disease causing characteristic rash, serum complement depletion, kidney disease, and LE cells |
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| immunopathologic consequences in SLE |
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| antibody reactivities ---pathologic consequences erythrocytes ---------------hemolytic anemia platelets ------------------thrombocytopenia coagulants ----------------clotting problems lymphocytes --lymphopenia, immune deficiencies neutrophils--neutropenia, phagocyte deficiencies neuron---------------------CNS dysfunction above antibody reactivities plus-----------SICD DNA, Nucleoproteins, IgG--------Renal disease |
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| goodpasture's syndrome |
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| type II HS autoantibodies against type IV collagen of the basement membrane primarily react with renal that of renal glomeruli, but can also react with pulmonary alveoli |
