hypersensitivity II & III – Flashcards
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| what are type II hypersensitivity disorders mediated by? |
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| antibodies directed against antigens present in the cell surfaces or extracellular matrix |
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| are type II hypersensitivity disorders intrinsic or extrinsic? |
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| they can be intrinsic to the cell membrane/matrix or they may be an exogenous antigen (such as a drug or metabolite) that is absorbed onto the cell or matrix |
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| is the antigen soluble in type II hypersensitivity disorders? |
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| no the antigen has to be attached to something, (if soluble, then it would be type III) |
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| what are the three mechanisms of type II hypersensitivity disorders? can they happen together? |
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| opsonization and complement followed by Fc receptor mediated phagocytosis, complement and Fc receptor mediated inflammation, and antibody mediated cellular dysfunction (antibody targets some surface structure on the cell that somehow alters the biologic function of the cell). these processes often happen together. |
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| how does opsonization and complement followed by Fc receptor mediated phagocytosis cause type II hypersensitivity disorders? (2 ways) |
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| antibodies IgG or IgM are deposited on the surface of cells and activate classical complement, generating C3b/C4b. phagocytes have receptors for both IgG (via Fc epsilon receptor) and for C3b/C4b. if either is bound, the opsonized cell is phagocytized. complement activation also leads to the formation of the membrane attack complex, which disrupts the membrane integrity by drilling holes in the lipid bilayer, causing osmotic lysis |
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| what is antibody-dependent cellular cytotoxicity? what cells can cause it? |
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| some cells can be killed by effector cells if they are coated with low levels of IgG. monocytes, neutrophils, eosinophils, and (especially) NK cells all bind via the Fc epsilon receptor and cell lysis proceeds without phagocytosis |
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| how does drug-induced cytotoxicity cause type II hypersensitivity disorders? what drugs do this? |
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| PCN, quinidine, methyldopa can all bind to the cell surface, creating a new epitope and generate an antibody. (PCN likes to bind to erythrocytes in type II -> but in type I, PCN has IgE created for it in allergic response) |
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| how does drug induced cytotoxicity occur with PCN to cause a type II hypersensitivity disorder? |
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| PCN sticks to RBCs during an infection it was administered to treat. complement binds normally to the infected PCN-coated RBCs, which stimulates macrophages to phagocytize and process them, who present antigen including PCN to T cells who become TH2 and present it to B cells, who produce antibodies for other PCN-coated RBCs. these antibodies then cause other PCN-RBCs to either be lysed via complement or phagocytosed by macrophages/neutrophils (via FcR) |
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| what is the end result of PCN-induced RBC cytotoxicity in a type II hypersensitivity disorder? |
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| anemia |
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| how does complement and Fc-receptor mediated inflammation cause a type II hypersensitivity disorders? |
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| when antibodies deposit in extracellular tissues such as basement membrane and matrix, cell injury in the form of inflammation occurs (not phagocytosis or lysis). these deposited antibodies can activate complement, particularly C5a (&C3a/C4a) that recruit neutrophils and monocytes that bind to the antibody Fc and release enzymes and ROS that cause tissue dammage |
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| how can antibody mediated cellular dysfunction cause a type II hypersensitivity disorder? what kinds of diseases are caused by this? |
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| myasthenia gravis and graves disease are examples of when antibodies bind to receptors and change the cellular process of the cells they bind |
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| how does antibody mediated cellular disfunction cause myasthenia gravis? what kind of disorder is this? |
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| antibody binds to the Ach receptor and acting as an antagonist, it blocks Ach binding at motor end plates of skeletal muscle, causing progressive muscle weakness. it is an autoimmune disorder caused by a type II hypersensitivity disorder. |
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| what is pemphigus vulgaris? |
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| when antibodies are made against desmosomes, disrupting intracellular junctions in the epidermis -> creating large vesicles |
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| how does antibody mediated cellular disfunction cause graves disease? |
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| antibodies are made against the thyroid stimulating hormone receptor on thyroid epithelial cells, and stimulate the cell (agonist action), causing hyperthyroidism |
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| what is goodpasture s syndrome? |
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| a type II hypersensitivity disorder where antibodies bind to non-collagenous protein in basement membranes of kidney glomeruli and lung alveoli and through complement/Fc receptor mediated inflammation nephritis and lung hemmorrhages occur |
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| what is acute rheumatic fever? |
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| a type II hypersensitivity disorder where antibodies bind myocardial antigen (often mitral valve through cross-rxn strep cell wall antigen) and myocarditis/arthritis occur due to inflammation and macrophage activation |
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| what are type III hypersensitivity disorders caused by? how do they cause damage? |
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| soluble antigen that form antigen-antibody complexes (immune complex) which mainly cause damage by eliciting immune responses wherever they get stuck |
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| can immune-complex mediated disease be systemic? |
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| yes, but drugs that caused this are less common (people used to be treated with horse sera. however, systemic lupus erythematosus is an example of an imune-complex mediated disease (auto immune disorder) |
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| what are the four mechanisms by which an immune complex causes tissue damage? |
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| 1)Fc receptor engagement: neutrophils/monocytes recruited, activated, lysosomes released=necrosis 2)complement (C5a/C3a) is activated: recruit phagocytes (see #1) and function as anaphylatoxins=vasoactive amines cause vasodilation+edema 3)platelets aggregate, form microthrombi=ischemia 4)hageman factor is activated which activates kinins=cause vasodilation+edema |
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| what are the net effects of immune complexes? |
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| necrosis, vasodilation and edema |
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| why does hyperacute graft rejection appear like as a type III hypersensitivity reaction? |
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| b/c it happens in the vasculature |
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| what are the 3 phases of systemic immune complex disease? |
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| introduction of the antigen/formation of immune complexes, deposition of immune complexes, and initiation of acute inflammatory reaction |
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| how can systemic type III hypersensitivity reactions become localized? |
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| the immmune complexes in the vasculature call in inflammatory cells that secrete TNF, which causes the endothelial cells to pull apart from each other, creating cracks where the immune complexes can get stuck -> can lead to fibrinoid necrosis |
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| where do antigens come from that usually kick off immune complexes? |
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| foreign antigen (usually a protein) that interacts with B/T cells leading to their antibodies being formed and secreted = immune complexes |
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| when do large immune complexes form? what happens to them? |
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| when there is an excess of antibody (rapidly removed by phagocytosis) |
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| when do small immune complexes form? what happens to them? |
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| when antigen is in excess, which usually leads to deposition of the immune complex. deposition can also be favored if phagocytes are overloaded/defective |
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| where are favored sites for complex deposition? |
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| kidneys (glomerulonephritis), joints (arthritis), skin, heart, serosal surfaces, small vessels (vasculitis), all pathologies associated with systemic lupus erythematosus (SLE) |
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| what has to happen for immune complexes to leave circulation? how does this happen? |
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| there has to be a change in vascular permeability. immune complexes can bind inflammatory cells via FcR/C3bR and trigger release of vasoactive amines or cytokines |
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| what are clinical signs that immune complexes have been deposited into tissue? |
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| fever, urticaria, arthralgias, lymphadenopathy, and proteinuria |
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| what are the mechanisms of tissue damage due to immune complex deposition? |
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| the complement cascade is activated and/or neutrophils and macrophages are activated via FcR |
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| when immune complexes are deposited how is tissue damage caused via the complement cascade? |
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| C5a directs the migration of PMNs and macrophages. C3a/C5a also function as anaphylatoxins |
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| what do macrophages release at sites of immune complex deposition? |
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| prostaglandins, vasodilators, chemotactic factors, lysosomal enzymes and ROSes |
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| what do immune complexes activate in terms of clotting? |
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| hageman factor and platelets are activated, leading to platelet aggregation -> both lead to formation of microthrombi, causing vasculitis, glomerulonephritis, and arthritis |
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| what is the antigen involved with systemic lupus erythematosus (a type II hypersensitivity disorder)? what are clinicopathologic manifestations? |
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| antigen: DNA, nucleotides, etc. clinicopathologic manifestations: nephritis, arthritis, vasculitis |
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| what is the antigen involved with polarteritis nodosa (a type II hypersensitivity disorder)? what are clinicopathologic manifestations? is it an autoimmune disorder? |
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| antigen: hep B virus surface antigen clinicopathologic manifestations: vasculitis. it is not an autoimmune disorder |
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| what is the antigen involved with poststreptococcal glomerulonephritis (a type II hypersensitivity disorder)? what are clinicopathologic manifestations? |
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| antigen: strep cell wall antigens that may be "planted" in glomerular basement membrane. clinicopathologic manifestation: nephritis |
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| what is the antigen involved with serum sickness (a type II hypersensitivity disorder)? what are clinicopathologic manifestations? |
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| antigen: various proteins clinicopathologic manifestations: arthritis, vasculitis, nephritis |
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| how will vasculature in kidneys affected by SLE and goodpasture's be different? |
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| in goodpastures, the antibodies deposit smoothly b/c they have specificity for the non-collagen protein in the basement membrane, but with SLE, the deposition of immune complexes is "lumpy-bumpy" and irregularly spaced/sized |
