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333 Cards in this Set
- Front
- Back
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disorders arising form excessive or inappropriate activity of immune system
disorders due to absence or hypofunction of some elements of immune system or tissues. |
two basic mechanisms for immunologically related diseases to occur
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-anaphalactic or "atopic reactions" (type I)
-cytotoxic, anti-tissue Ab reactions (type II) -immune complex deposition reactions (type III) |
type of reactions mediated by antibodies
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-delayed type hypersensitivity (DTH)
-granulomatous diseases |
lymphocyte mediated immune responses (type IV)
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type I, mediated by antibodies
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anaphalactic or "atopic" reactions
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type II, mediated by antibodies
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cytotoxic, anti-tissue antibody reactions
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type III, mediated by antibodies
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immune complex desposition reactions
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type IV
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lymphocyte mediated immune responses
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mediated by antibodies
lymphocyte mediated immune responses mixed Ab and lymphocyte disorders |
disorders arising form excessive or inappropriate activity of immune system
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endogenous/genetic
acquired--iatrogenic, infectious |
disorders due to absense or hypofuncion of some element of immune system or tissues.
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type I hypersensitivity reaction
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mediated by IgE and products of mast cells, eosinophils, and/or basophils
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type II hypersensitivity reaction
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mediated by direct antibody binding to cells or tissue components
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type III hypersensitivity reaction
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mediated by deposition of antigen-antibody complexes and activation of complement and neutrophils
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type IV hypersensitivity reaction
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mediated by T-lymphocytes and macrophages.
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type I immune reactions
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mast cells stimulated (typically via IgE bound to surface receptors) to release vasoactive and spasmogenic substances that act on endothelial cells and smooth muscle cells locally or systemically.
reactions can easily prove lethal |
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localized anaphalactic/atopic reactions
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asthma, hay fever, insect bites (mosquito, flea, etc.)
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systemic anaphalactic/atopic reaction
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insect stings (esp. Hymenoptera species)
drug allergies hives some food allergies anaphalaxsis (the syndrome) |
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IgE and Mast Cells
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Type I reactions mediated by these
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antigen
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dendritic cell processing
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dendritic cell
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Th2 cell stimulated
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T cell "help"
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B-cell plus antigen
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B cell
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plasma cell making IgE
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IgE
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FcRe on Mast cells
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IgE armed mast cell + antigen
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degranulation
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C3a and C5a
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anapylotoxins
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events occurring on respiratory mucosa after inhaled antigen encounter
hay fever, asthma |
Pollen-->antigen/allergen-->dendritic cell-->T cell receptor on TH2 cell-->IL-4-->IgE B cell-->IgE antibody-->IgE Fc receptor on Mast cell-->Antigen crosslinking-->release of primary and secondary mediators-->smooth muscle spasm, edema, leukocyte infiltration, mucus secretion, epithelial damage.
Mast Cell or TH2 cell-->Il-3, IL-5, GM-CSF-->eosinophil recruitment/activation-->release of granules and mediators. |
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mast cells
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can be triggered to degranule by many mechanisms, but IgE-mediated mechanism most common
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immediate
delayed |
two stages of Type I (anaphylactic) reactions
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immediate stage of Type I anaphylactic reactions, within one hour after allergen exposure
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IgE on mast cell surface binds its specific antigen, mast cell degranulates releasing preformed mediators into area
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delayed stage of type I anaphylactic reactions, 4-20 hours after allergen exposure
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once triggered, mast cell begins synthesis of other soluble mediators
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tissue events in type I reactions
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mast cell degranulation
edema vascular congestion |
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same
different |
mediators of both primary and secondary response are initiated at ___ time(s), but released in ___phase(s)
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events in mast cell degranulation
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Ag, IgE, IgE Fc receptor, signals for activation of PLA2/cytokine gene activation/degranulation, secreted cytokines/membrane phospholipids/granule contents
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initial response in type I hypersensitivity reaction
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5 min to 1 hr
vasodilation, vascular leakage, smooth muscle contraction, glandular secretion |
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secondary response in type I hypersensitivity reaction
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2 hours to days
tissue infiltration by eosinophils, basophils, neutrophils and some T cells; tissue injury, mucosal damage and remodeling |
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primary mediators, type I hypersensitivity reactions
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biogenic amines
chemotactic mediators enzymes proteoglycans |
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secondary mediators, type I hypersensitivity reactions
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leukotrienes
prostaglandins (D2) platelet activating factor (PAF) cytokines |
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major basic protein from eosinophil
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causes mast cell degranulation
epithelial desquamation |
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eosinophil
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major basic protein
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severe urticaria
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puffiness, matter of minutes
cold/heat induced, not IgE, have for rest of adult life, not in kids. localized type I reaction |
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localized type I reaction
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atopic keratoconjunctivitis
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asthma
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abnormal repair response to epithelial injury
smooth muscles around bronchiole hypertrophy so can contract more, airway reduced |
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structural changes of airways in chronic asthma
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epithelial shedding
gland hyperplasia matrix remodeling basement membrane pseudothickening inflammatory infiltrate muscle hyperplasia |
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systemic anaphylaxis
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bee stings, drug-reactions, etc
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type II immune reactions
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cytotoxic, lytic or anti-tissue antibody attacks
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type II immune reactions
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by binding antigen, antibody causes cell or tissue damage
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type II immune reactions
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humoral antibodies participate directly in injuring cells, rendering them susceptible to lysis or phagocytosis, making tissue elements susceptible to complement damage, or by altering the function of specific cell surface molecules/receptors
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cytotoxic or anti-tissue antibody reactions (type II)
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antibodies that fix complement
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cytotoxic or anti-tissue antibody reactions (type II)
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circulating antibodies that localize to its antigen on cell surface or on some other tissue constituent
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cytotoxic or anti-tissue antibody reactions (type II)
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site of damage defined by location at which antibody binds
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cytotoxic or anti-tissue antibody reactions (type II)
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often causes severe disease and tissue injury
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hemolysis
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antibodies coat erythrocytes making them susceptible to phagocytosis in spleen or liver or fixing complement to generate MACs
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hemolysis
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erythrocyte-->Ab binding-->opsonization and phagocytosis OR lysis
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acute hemolysis
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preexistent Ab high titer-->rapid intravascular hemolysis
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delayed hemolysis
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1-2 weeks
low/rising titer Ab-->slow extravascular hemolysis |
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cell activation
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inflammation
phagocytosis IC processing immunoregulation |
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cell lysis after antibody binding and complement activation
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Anti-B antibody (IgM) binds to B antigen on type B RBC
ABO incompatibility-->immune complex formation-->activation of complement-->C5-9 MAC-->membrane lesion/cell lysis |
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erythroblastosis fetalis
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Rh disease
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erythroblastosis fetalis
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RBC precursors seen in liver, spleen, muscle, wherever can put RBC
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Goodpasture's disease
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anti-collagen type IV
anti-GBM antibody (glomerular basement membrane) |
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Goodpasture's disease
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hemorrhage into lungs, kidney. renal failure due to hemorrhage.
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type II hypersensitivity reactions
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induction of anti-self antibodies
binding of Ab to self-constituents complement fixation/activation tissue lysis/opsonization/phagocytosis/cell-mediated cytotoxicity |
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type II hypersensitivity reactions
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direct attack on cells/tissues by antibodies
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type I hypersensitivity reaction
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mast cell/basophil mediated
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type III hypersensitivity reaction
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damage secondary to deposition of immune complexes (IgG-Ag)
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type IV hypersensitivity reaction
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T-cell/macrophage mediated-DTH (delayed-type hypersensitivity)
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classical type II hypersensitivity disease
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rheumatic fever
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rheumatic fever
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cross-reacting antibodies in streptococcal infections
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rheumatic fever
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vegetations on mitral valve leaflets
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rheumatic fever
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thickening, shortening and fusion of chordae tendineae
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rheumatic fever
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"fish-mouth" deformity of aortic valve
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type II mechanism
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antibodies can cause "autoimmune" overstimulation or receptor blockade
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Graves' disease, type II
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antibody has natural ligand activity
TSH can't bind b/c there's Ab to TSH receptor Ab binding stimulates excess production of thyroid hormone |
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Myasthenia gravis, type II
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antibody blocks natural ligand activity
tissue binding Ab, not destructive ACh from nerve ending can't bind to receptor on motor end plate of muscle b/c of Ab |
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type I hypersensitivity reactions
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asthma, hives, allergic rhinitis (hayfever)
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type I hypersensitivity reactions
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hives
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type I hypersensitivity reactions
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allergic rhinitis (hayfever)
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type I hypersensitivity reactions
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inudction of IgE response--antigen exposure--TH2 cells
"arming" mast cell mast cell degranulation parimary, secondary recruitment of cells-eosinophils eosinophil mediators |
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type II hypersensitivity reactions
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hemolytic anemia
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type II hypersensitivity reactions
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erythroblastosis fetalis
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type II hypersensitivity reactions
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Goodpasture syndrome
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type II hypersensitivity reactions
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myasthenia gravis
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type II hypersensitivity reactions
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rheumatic fever
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type II hypersensitivity reactions
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Graves' disease
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type II hypersensitivity reactions
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induction of anti-self antibodies
binding of antibodies to self-constituents complement fixation/activation tissue lysis/opsonization/phagocytosis/cell-mediated cytotoxicity |
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type III hypersensitivity reactions
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glomerulonephritis
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type III hypersensitivity reactions, systemic
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serum sickness
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type III hypersensitivity reactions
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polyarteritis nodosa
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type III hypersensitivity reactions, localized
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Arthus reaction
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type III hypersensitivity reactions
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induction of Ab
formation of Ab-Ag complexes complex deposition in tissue or on cells complement activation--production of complement factors complement damage to tissue neutrophil attraction and degranulation tissue destruction |
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type IV hypersensitivity reactions
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tuberculin reaction
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type IV hypersensitivity reactions
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granuloma formation
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type IV hypersensitivity reactions
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contact dermatitis (nickel allergy)
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type IV hypersensitivity reactions
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sensitization of T cells
Ag processing and presentation rechallenge or chronic Ag challenge cytokine/chemokine production attraction of other cells, esp activated macrophages giant cell formation cytotoxic T cells (CD8+) structure of granuloma |
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graft or transplant rejection
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importance of HLA/MHC matching
renal allograft rejection as prototype for teaching |
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hypersensitivity types II-IV but not type I
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rejection from combination of these hypersensitivity types
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antibody mediated
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hyperacute rejection; thrombosis, vessel attack
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acute rejection
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host become sensitized to donor tissue
cellular and Ab mediated attack on vessels (vasulitis), parenchymal attack and damage |
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chronic rejection
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mixed mcehanism, many macrophages, T- and plasma cells
extensive and longstanding damage and fibrosis to graft |
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graft vs. Host disease (GvHD)
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acute and chronic
transplanted tissue (i.e. T-cells) attack host skin, liver, GI track most affected |
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rheumatic fever
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excrescences fuse into fishmouth valve
aschoff bodies |
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type III immune reactions
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disease due to deposition of Ag-Ab complexes, can be localized or systemic
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type III immune reactions
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sensitization of immune system-->Ab produced
continuous or repeated Ag exposure Ag-Ab complexes formed and deposited in tissue complement cascade activated (C3a, C3b, C5 frags, MAC) attraction and activation of neutrophils and macrophages focal acute inflammation causes tissue destruction |
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type III immune reactions
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type and location of tissue damage determined by where and how complexes deposited
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type III hypersensitivity reactions, systemic
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SLE
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type III hypersensitivity reactions, systemic
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drug reactions
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type III hypersensitivity reactions, localized
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vasculitis
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type III hypersensitivity reactions, localized
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glomerulonephritisq
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type III hypersensitivity reactions, localized
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arthritis
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type III hypersensitivity reactions, localized
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pneumonitis
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sequence of events in tissue damage caused by deposition of immune complexes
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Ag-Ab complexes-->vessels, glomeruli, etc.-->C42-->
C3b phagocytosis C3a+C5a increased vascular permeability C3,C5 fragments, C567 chemotaxis C5-C9 Lysis -->vasculitis, glomerulonephritis, arthritis, endocarditis |
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pathogenesis of type III hypersensitivity reaction
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Ag/Ab immune complexes-->
Fc receptor engagement, complement activation, platelet aggregation, activation of Hageman factor -->neutrophil/monocyte recruitment, vasodilation/edema -->necrosis |
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type III hypersensitivity reactions
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involve neutrophils that do most of actual damage to tissue
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constituents of granules of neutrophils
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microbicial enzymes
neutral serine proteases metalloproetinases acid hydrolases cationic microbicidal peptides membrane receptors |
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localized type III reaction
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post-streptococcal glomerulonephritis
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post-streptococcal glomerulonephritis, type III
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neutrophils in glomerulus, Ag/Ab complexes
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vasculitis
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immune complex formation, deposition, inflammation
Ag in circulation, B cell-->plasma cell-->Ab Ag/Ab copmlex deposition, inflammatory cell-->cytokines complement onto Ab, neutrophils, platelet aggregation -->fibrinoid necrosis, neutrophil lysosomal enzymes |
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drug-induced
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small vessel vasculitis (type III reaction) often induced by this
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systemic type III hypersensitivity reaction
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serum sickness (true classic example)
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one-shot serum sickness
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day 12: heart, joint, kidney lesions; low complement level, Low Ag level, Low Ag/Ab complex level, free Ab rises right after
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type IV immune reactions, DTH
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diseases of this type result form cell or tissue injury caused by attack of Ag-specific, sensitized T-cells accompanied by macrophages
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cell-mediated hypersensitivity
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DTH, T cell mediated cytotoxicity, rejection of transplanted organ
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delayed-type hypersensitivity (DTH)
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CD4+ cell and macrophage mediated, e.g. Tuberculin Reaction
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delayed-type hypersensitivity (DTH)
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Granulomatous reactions, distince type of this reaction
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T-cell mediated cytotoxicity
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largely CD8+ cell mediated
e.g. response to tumors, viruses and allogenic cells |
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rejection of transplanted organ
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both CD4+ and CD8+ cells participate
B-cells/Ab may also be involved |
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detrimental macrophage-monocyte-microglial cell products
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TNFa/B
IL-1 superoxides nitric oxide hydroxyl radicals neuron toxins |
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beneficial (possibly) macrophage-monocyte-microglial cell products
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TGF-B
Growth & Trophic factors GM-CSF |
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chromosome 6
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human MHC gene locus
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type IV, DTH
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T-lymphocytes, Ag presenting cells and macrophages absolutely essential for this type of immune reaction
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type IV hypersensitivity reaction (DTH)
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APC presenting tissue antigen to CD4+ T cell which releases cytokines causing inflammation
Normal tissue presenting antigen to CD8+ T cell which releases cytokines causing inflammation or tissue injury |
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type IV hypersensitivity reaction (DTH)
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1 hr: injection of Ag
5 hr: rxn of sensitized lymphocytes with Ag 12 hr: release of lymphocyte mediators 24-48 hr: attraction and retention of unsensitized cells 72+ hr: destruction of Ag by activated cells and resolution |
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endothelial cell changes with inflammation
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leaky junctions,
activated like HEV's!! VCAM-1, MECA-352, CD49, MadCAM, E-Selectin, P-Selectin, transferrin Receptor |
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granuloma formation
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type IV hypersensitivity reaction that persists and causes tissue damage and scarring
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granuloma formation
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APC presents Ag to CD4+ TH1 cell, which releases TNF, IL-2, IFN-y, monocytes.
fibroblasts, giant cells, lymphocytes, macrophage, epithelioid cell make up ___ |
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allograft rejection
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aka Transplant Rejection
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allograft rejection
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both CD4+ and CD8+ cell participate; B-cells/Antibodies may also be involved
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ransplantation rejection reactions
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based on timing, mechnism and morphology
hyperacute, acute, chronic |
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hyperacute rejection
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moments to 48 hours
involves preformed Ab Ag-Ab reaction at endothelium results in rapid thrombosis of vessels |
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acute rejection
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weeks to months
___cellular ___humoral |
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acute cellular rejection
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involves sensitized CD4 and CD8 cells, lymphocyte/macrophage infiltrates
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acute humoral rejection
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involves anti-graft Ab
vasculitis, thrombosis, endothelial prolif. |
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chronic rejection
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months to years
vasculitis, intimal fibrosis, obliteration of lumen, organ ischemia, interstitial mononuclear cell infiltrates, organ atrophy |
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chronic rejection
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graft arteriosclerosis, tubular atrophy, interstitial fibrosis
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graft vs. host disease
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when you are the tissue being rejected
post bone marrow transplantation |
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acute graft versus host disease
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onset: up to day 100
organs: limited-skin, liver, GIT primary pathology: destruction of epithelium inflammatory responses: mild |
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chronic graft versus host disease
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onset after day 100
organs: widspread primary pathology: mixed epithelial and mesenchymal lesions inflammatory response: often marked |
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acute cellular rejection
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lymphocytes in renal parenchyma
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acute rejection
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T cells in this kind of rejection
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direct pathway of T cell rejection
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donor class I and class II antigens on APC in graft (along with B7 molecules, not shown) are recognized by CD8+ cytotoxic T cells an CD4+ helper T cells, respectively, of the host. CD4+ cells proliferate and produce cytokines that induce tissue damage by a local delayed hypersensitivity reaction and stimulate B cells and CD8+ T cells. CD8+ T cells responding to graft antigens differentiate into cytotoxic T lymphocytes that kill graft cells
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indirect pathway of T cell attack
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graft antigens are displayed by host APC’s and activate CD4+ T cels, which damage the graft y a local delayed hypersensitivty reactions.
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autoimmunity
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results from multiple factors, including susceptibility genes that may interfere with self-tolerance and environmental triggers (inflammation, other inflammatory stimuli, particularly infections) that promote lymphocyte entry into tissues, activation of lymphocytes and tissue injury. Self-reactive lymphocytes.
HLA genes are best defined genes known to be associated with it |
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organ-specific autoimmunity
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thyroid: Hashimoto's thyroiditis, primary myxedema, thyrotoxicosis
stomach: prenicious anemia adrenal: Addison's disease pancreas: insulin-dependent diabetes mellitus |
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non-organ-specific autoimmunity
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ermatomyositis: skin, muscle (7 vasculitis)
systemic lupus erythematous: skin, kidney, joints |
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autoimmunity
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predominantly type II or III
predominantly type IV mixed T cell and B cell |
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type II hypersensitivity reaction in autoimmune disease
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autoimmune hemolytic anemias, neutropenias, lymphopenias, throbocytopenias
Good pasture disease antireceptor Ab diseases myasthenia gravis Graves disease anti-insulin Ab bullous skin diseases pemphigus pemphigoid |
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type III hypersensitivity reaction involved in autoimmune disease
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systemic lupus erhthematosus
rheumatoid arthritis Sjogren syndrome scleroderma polymyositis-dematomyositis |
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SLE
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hematologic, arthritis, skin, fever, fatigue, weight loss, renal, CNS, pleurisy, myalgia, pericarditis, GI, raynaud phenomenon, ocular, peripheral neuropathy
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SLE
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acute malar rash is a sign of this disease
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SLE
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Libman-Sack's vegetations in this disease
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SLE
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membranous lupus nephritis
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SLE
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membranoproliferative glomerulonephritis type I in this disease
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SLE
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diffuse proliferative glomerulonephritis in this disease
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SLE
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arterial occlusion in patient with this disease who has retinal vasculitis
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systemic rheumatoid arthritis
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constitutional signs and symptoms of this disease:
fatigue, weight loss, myalgias, excessive sweating, low-grade fevers, morning stiffness, lymphadenopathy |
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process of synovial inflammation in rheumatoid arthritis
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antigen processing
antigen presentation by RF-specific B cells to T cells angiogenesis collagenase activation, lysosomal enzymes, metalloproteinases, serine proteases, cathepsins, tissue destruction |
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early rheumatoid arthritis
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symmetric synovitis, atlantoaxial subluxation with basilar invagination, and deformities in this disease
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RA
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invasive synovial pannus in this disease
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RA
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reactive lymphadenopathies, amyloidosis, muscle wasting, peripheral NS, neuropathy, mononeuritis, multiplex, scleritis, keratoconjunctivitis, pleural effusions, lung fibrosis/nodules/effusions, pericardial effusions, splenomegaly, amyloidosis of gut, anemia, thrombocytosis, skin thinning/ulceration
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RA
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bursitis and nodulosis
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RA
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intersitital pneumonitis in this disease
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primary amyloidosis, RA
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hypertrophic, shoulder pad sign in this disease
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amoyloid, RA
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nodule occlusion of auditory canal in this disease
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amyloidosis, RA
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not all of these are created equal
not all pink and waxy materials are this |
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parimary amyloidosis
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classifcation of amyloidosis with multiple myeloma, K or lambda light chains
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secondary amyloidosis
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classification of amyloidosis with protein A
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familial amyloidosis
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classification of amyloidosis with transthyretin mutant, protein A
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serile systemic amyloidosis
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serile cardiac classification of amyloidosis with transthyretin normal
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dialysis amyloidosis
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systemic amyloidosis from B2-microglobulin deposition
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forms of amyloidosis
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primary>localized>secondary=familial>senile
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acute phase reaction
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fibrobalsts and epithelial cells to macrophage to liver, acute-phase reaction proteins then serum amyloid protein for opsonization of pathogens and modulation of inflammation
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21
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amyloid precursor protein (APP) coded for by gene on this chromosome. APP protein clipped to produce AB amyloid that's deposited in brains of individuals with Alzheimer's disease
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diabetes mellitus
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1-3% of American population
autoimmune disease caused by immunological destruction of B-cells of islet |
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diabetes mellitus
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exceptionally strong genetic influence/predisosition
probably T cell mediated not currently preventable antigen unknown but must be B-cell speciic |
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loci associated with type I diabetes
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MHC locus - chromosome 6
insulin/IFG-2 - chromosome 11possible association of 18 other loci |
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systemic sclerosis and scleroderma
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disease pathogenesis involves T and B cells, endothelial cells, fibroblasts and myofibroblasts
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systemic sclerosis and scleroderma
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disease involves autoimmunity, vasculo pathy (raynaud's, nailfold capillaries), ECM abnormalities and fibrosis, skin disease, pulmonary fibrosis, pulmonary HT, renal crisis
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systemic sclerosis and scleroderma
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in this disease, risk of internal organ involvement strongly linked to extent and progression of skin theckening
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Sjogren's syndrome
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parotid enlargement in this disease
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graft rejection
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multiple mechanisms acting simultaneously in this disease
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DNA
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antigen in SLE
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immunological tolerance
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how immune system learns to distinguish self form foreign
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central tolerance
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mechanism of tolerance that involves clonal deletion, negative selection
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peripheral tolerance
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mechanism of tolerance that involves activation-induced apoptosis, anergy induction, suppression
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failure of immunological tolerance leading to autoimmunity
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mechanism:
breakdown of T cell anergy, failure of activation induced cell death, failure of suppression, molecular mimicry, polyclonal lymphocyte activation, release of sequestered antigens, exposure of cryptic angens, epitope spreading |
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SLE
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multisystem disease-many organs affected
more women than men |
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SLE
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in this disease, there are antibodies against DNA, histones, proteins bound to RNA, nucleolar antigens, "anti-nuclear antigens" (ANAs)
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SLE
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in this disease, there are 4 basic staining patterns of patient's serum antibodies on nuclei in tissue
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SLE
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in this disease, gneetic factors are important; however it is multigenic, no one bad gene
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SLE
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possible pathogenesis:
genetic susceptibility->environmental trigger->T cell and subsequent B cell stimulation->antibody production->various forms of antibody induced tissue damage |
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SLE
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end-organ damage in this disease: many tissues damaged but kidneys most frequently and severely damaged organ. renal failure is common endpoint, but skin, heart, blood vessels, brain and CT are also involved in various combinations in a variety of ways
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RA
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disease of synovial joints, but multiple tissues are damaged
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RA
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chronic, systemic inflammatory disease
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rheumatoid factor
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found in most RA patients. predominantly IgM directed against Fc component of IgG Ab
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RA
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in joints, this disease induces reactive, non-supperative (non-pus forming) inflammation fo synovium with T cell, plasma cells and macrophage infiltration. synovium proliferates and destroys articular cartilage of joint.
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RA
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"pannus" forms in this disease
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RA
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possible pathogenesis:
genetic susceptibility->environmental trigger (?virus/bacterium?)->T cell and subsequent B cell stimulation->antibody (rheumatoid factor) production->various forms T cell and possibly antibody induced tissue damage |
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amyloidosis
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not all forms of this disease are the same chemically. this is not of itself an inflammatory disease.
deposition is byproduct of chronic inflammatory activity against a spectrum of stimuli occurring in diverse tissues |
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amyloid
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this term refers to a pale-pink, amorphous material seen deposited in a wide range of tissues, materials that constitute it are highly heterogeneous
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amyloid
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recognized by its birefringent (acting like a lens) properties when congo red stained tissue is viewed thru microscope under polarized light. glows bright apple-green
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congo red
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this dye binds to unique molecular conformation assumed by all forms of amyloid, beta-pleated sheet configuration
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amyloid
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causes damaging effects in most organs by filling up interstitium of tissue until it blocks, crowds-out, or causes atrophy of adjacent normal structures
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AB amyloid
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this type of amyloid in Alzheimer's may actually act like irritating stimulus inducing chronic activation of macrophage-like cells (microglia) in the vicinity
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AL amyloid form
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disease association of this amyloid form is myeloma/B cell tumors
source protein: Ig light chains |
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AA amyloid form
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disease association of this amyloid form is reactive/chronic inflammatory conditions
source protein: SAA |
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Ab2M amyloid form
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disease association of this amyloid form is chronic renal failure
source protein: B2-microglobulin |
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AB
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disease association of this amyloid form is Alzheimer's Disease
source protein: amy. precursor prot. encoded on Chr 21 |
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primary immunodeficiencies
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global, selective, cytokine or cytokin receptor mutations, adhesion molecule mutations, complement component abnormalities, mutations of regulators of complement
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secondary immunodeficiencies
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naturally occurring, infectious, iatrogenic
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primary: global immunodeficiencies
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all components affected in this type of immunodeficiency
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primary: selective immunodeficiency
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only B or T cells affected in this type of immunodeficiency
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primary: selective: restrictive immunodeficiencies
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subsets of T cells or isolated antibody types abnormal/missing
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secondary: naturally occurring immunodeficiencies
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type of immunodeficiency
tumors: lymphoma, myeloma, leukemia, etc. malnutrition pregnancy |
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primary immunodeficiencies
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X-linked agammaglobulinemia, common variable immunodeficiency, hyper IgM syndrome, DiGeorge Syndrome, severe combined immunodeficiency diseases (SCID), complement or complement regulatory problems
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secondary immunodeficiencies
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type of immunodeficiency due to certain neoplasms that displace immune system
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secondary immunodeficiencies
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type of immunodeficiency due to iatrogenic (physician caused) from anti-neoplastic Rx
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HIV-1 infection resulting in AIDS
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single most important acquired immunodeficiency of our era
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X-linked agammaglobulinemia
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failure of B cells to develop in this disease
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X-linked agammaglobulinemia
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btk (b-cell tyrosine kinase) mutations in this disease
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X-linked agammaglobulinemia
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X-linked disease, thus almost exclusively in males
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X-linked agammaglobulinemia
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in this disease: problems in early childhood: viral infections, Girardia, arthritis
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Common Variable Immunodeficiency
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heterogeneous group of disorders - various causes
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Common Variable Immunodeficiency
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all antibody classes usually involved in these types of disorders
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Common Variable Immunodeficiency
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B cell developmental defects in this group of disorders
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Common Variable Immunodeficiency
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URIs, pulmonary, herpetic, and Giardia infections in this group of disorders
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Common Variable Immunodeficiency
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this group of disorders afflicts both sexes, onset in later childhood, adolescence
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Common Variable Immunodeficiency
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in this group of disorders, high frequency (20%) of autoimmune disease development
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hyper IgM syndrome
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T-cell disorder
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hyper IgM syndrome
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isotype switching from IgM to IgG or IgA is impaired in this disease
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hyper IgM syndrome
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CD40/CD154 interactions abnormal in this disorder
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hyper IgM syndrome
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has both X-linked an dautosomal forms
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hyper IgM syndrome
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in this disorder, recurrent pyogenic infections and Pneumocystis pneumonitis
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DiGeorge Syndrome
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ambryonic malformation of pharyngeal pouches 3 & 4
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DiGeorge Syndrome
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thums and parathyroids fail to develop in this disease
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DiGeorge Syndrome
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severe T cell deficiencies in this disease
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DiGeorge Syndrome
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Tetany due to Ca++ dysregulation in this disease
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DiGeorge Syndrome
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disease due to unidentified gene on chromosome 22
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DiGeorge Syndrome
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partial form of this disease exists, is self-correcting
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Severe Combined Immunodeficiency Diseases (SCID)
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both B and T cell limbs of the immune system absent in this disease
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Severe Combined Immunodeficiency Diseases (SCID)
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immunological problems from birth (Candida infections, GvHD) in this disease
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Severe Combined Immunodeficiency Diseases (SCID)
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most common (50-60%) form is X-linked, thus more in males
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Severe Combined Immunodeficiency Diseases (SCID)
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mutation causing disease is in a common chain shared by numerous cytokine receptors
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Severe Combined Immunodeficiency Diseases (SCID)
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autosomal mutations in this disease
adenosine deaminase (ADA) deficiency |
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Complement or Complement Regulator Problems
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hereditary angioedema in this disorder
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hereditoary angioedema
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C1 inhibitor deficiency
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retroviruses
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double-stranded RNA virus
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pathogenesis of AIDS
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how cells get infected (CD4, CXCR4, CCR5)
replication steps cell-cell spread macrophage transport transformation from asymptomatic infection to AIDS |
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AIDS syndromes
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opportunistic infections
Kaposi's sarcoma CNS lymphoma CNS is the second target organ beyond the immune system |
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SCID
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disease affecting stem cell to lymph
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Bruton's
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disease affecting lymph to B cell
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Common Variable
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disease affecting B cell to plasma cell
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DiGeorge
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disease affecting T cells
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AIDS
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disease affecting Th cells
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Chediak-Higachi, Kostmann's
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disease affecting myeloid cells
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Reticular dysgenesis
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disease affecting bone marrow to stem cell
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CGD
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disease affecting neutrophils, monocytes, eosinophils
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X chromosome associated diseases
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Chronic granulomatous disease (21)
Wiskott-Aldrich syndrome (11) severe combinded immunodeficiency (13) agammaglobulinaemia (XLA) (22-23) X-linked lymphoproliferative syndrome (XLPS) (24-27) |
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B cell deficiencies
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selective IgA deficiency
X-linked agammaglobulinemia of Bruton, common variable immunodeficiency what type of immunodeficiency? |
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T cell deficiencies
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DiGeorge Syndrome, what type of immunodeficiency?
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combined B & T cell deficiencies
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SCID, what type of immunodeficiency?
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acquired or naturally occurring "secondary" immunodeficiency illnesses
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lymphoma, Hodgkin's disease, iatrogenic (chemo)
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selective IgA deficiency
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maturation defect in IgA producing cells
common: 1 in 700 people most asymptomatic some with recurrent infections HIGH incidence of autoimmune diseases |
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X-linked agammaglobulinemia of Bruton
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disease with block in production of Ab light chains--heavy chains made
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X-linked agammaglobulinemia of Bruton
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disease in which low or absent IgG in serum
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X-linked agammaglobulinemia of Bruton
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frequent and severe bacterial infections
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X-linked agammaglobulinemia of Bruton
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increased risk of autoimmune disease
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X-linked agammaglobulinemia of Bruton
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high risk of developing poliomyelitis from vaccination
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X-linked agammaglobulinemia of Bruton
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get chronic encephalitis in this disease
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type I
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typ eof Common Variable immunodeficiency with predominant B-cell defect
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type 2
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typ eof Common Variable immunodeficiency with predominant immunoregulatory T-cell defect (inbalance)
decreased Th increase T suppressor |
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type 3
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typ eof Common Variable immunodeficiency with autoantibodies to T- or B-cells
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common variable immunodeficiency
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low or high numbers of B-cells
hypogammaglobulinemia bacterial infections high incidence of autoimmune diseases |
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common variable immunodeficiency
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everything turns white
auto-immune attack on melanocytes in hair follicle and base of skin not immunodeficiency problem, getting into auto-immune rxn |
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common variable immunodeficiency
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verruca vulgaris in this disease
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common variable immunodeficiency
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aphthous ulcers in this disease
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common variable immunodeficiency
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lung disease, lymphoid interstitial penumonitis (not infection)
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DiGeorge syndrome
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congenital malformation causes this disease
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DiGeorge syndrome
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T cells absent or very low and T cell responses markedly abnormal in this disease
B cells normal |
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DiGeorge syndrome
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with this disease, high susceptibility to viruses and fungi
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DiGeorge syndrome
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cardiac malformations very common in this disease--principal cause of death
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Candida infection, DiGeorge
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causes oral thrush
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DiGeorge syndrome
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in this disease, subcortical thymus dependent region shows marked depletion of lymphocytes
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SCID
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lymphopenia, hypogammaglobulinemia, high risk of viral, bacterial and fungal infections
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lymphopenia, SCID
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low or absent T cells
frequently low/absent B cells |
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SCID
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X-linked
mostly due to defect in cytokyne receptors (IL-7 receptor) leading to poor lymphoid tissue formation |
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SCID
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in this disease, get herpes simplex virus infection
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SCID
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in this disease, get varicella superinfected with bacteria
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SCID
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in this disease, get pneumocystis carinii pneumonia
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C2 deficiency
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most common complement deficiency
more common in Europeans, Caucasians |
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C2 deficiency
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50% homozygotes develop SLE-like disease
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C1-C4 deficiency
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this type of primary complement deficiency disorder has
clinical features: infectious and autoimmune disorders lab findings: decreased complement activity, absent specific component pathogens: encapsulated bacteria, strep pneumoniae, H. influenze |
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C5-C9 deficiency
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this type of primary complement deficiency disorder has
clinical features: severe Neisseria infections lab findings: absent specific components; decreased complement activity pathogens: N meningitidis, disseminated gonococcal infection |
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Properdin
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this type of primary complement deficiency disorder has:
clinical features: meningococcal meningitis lab findings: abnormal alternative pathway pathogen: N. meningitidis |
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C1 inhibitor deficiency, hereditary angioedema
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in this complement deficiency, complement cascade proceeds unchecked
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C1 inhibitor deficiency, hereditary angioedema
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in this complement deficiency, mast cells degranulate-vessels leak=edema
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C1 inhibitor
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this blocks enzymes responsible for activating various systems
blocks Hagemann Factor (F-XII), a coagulation factor blocks Kallikrein, acute response, inflammation factor blocks plasmin that's used to make fibrinogen one factor: multiple different functions |
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Hereditary angioedema, C1 Inhibitor Deficiency
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Minor trauma, maybe even just cold weather or minor scratch, something trivial, coagulation pathway and other pathways get activated, activate Hageman factor, start coagulation and complement pathways, get C3a and C5a causing mast cells to degranulate
minor trauma, infection, tissue damage--> activated Hageman factor--> plasminogen to plasmin--> activated C1--> complement cascade (anaphylotoxins) |
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hereditary angioneurotic edema, C1 inhibitor deficiency
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little scratch causes hand to puff up
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hereditary angioneurotic edema, C1 inhibitor deficiency
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swollen face, eyes swollen shut. if trauma back of throat, around larynx, in trachea, will swell right up, people die of asphyxiation
most of the time will subside, not quickly, over hours and day or 2, not permanent |
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chronic inflammatory diseases that induce specific T-cell defect
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TB, leprosy, sarcoidosis, measles
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naturally occurring secondary immunodeficiencies: humoral immunity affected
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type of immunodeficiency that involves B cell neoplasms, B cell lymphomas and plasmacytoma, Waldenstrom's macroglobulinemia
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naturally occurring secondary immunodeficiencies: cellular immunity affected
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type of immunodeficiency that involves Hodgkin's disease, thymoma and other T cell tumors, TB, sarcoidosis, leprosy, measles
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naturally occurring secondary immunodeficiency: combined cellular and humoral immunity affected
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type of immunodeficiency associated with AIDS aging
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naturally occuring secondary immunodeficiency
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type of immunodeficiency associated with AIDS
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lymphoma
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replaces normal lymphoid elements
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pre-chemotherapy
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lot of myeloid elements, dark cells, lot of progenitor cells
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post-chemotherapy
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can't see any hematopoietic elements, even at higher power. few residual red cell elements hanging around. no immune system for weeks/months
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HIV
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virus that has highest mutation rate normally of any element
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HIV
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Long terminal repeat makes virus so insidious
When turn it on? When start making virus? If T-cell sees antigen in right context, signal tells virus to start replication. When need elements of immune system and call them up, that’s what turns virus on and causes it to replicate NFKB, etc. bind to LTR, start making virus. |
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Long Terminal Repeat (LTR)
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contains control regions that bind host transcription factors (NF-KB, NFAT, Sp1, TBP)
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Long Terminal Repeat (LTR)
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required for initiation of transcription
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Long Terminal Repeat (LTR)
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contains RNA trans-acting response element (TAR) that binds Tat
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HIV insidiousness
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protein that promotes virus assembly at cell surface, RNA binding protein, virion binding, overcomes inhibitory effect of unidentified host factor promoting cell-free viral transmission, promotes CD4 degradation and influences virion release, chemokine receptor binding, fusion, downregulation of surface CD4 and MHC I expression, blocks apoptosis, virion infectivity enhanced, enhances RNA Pol II-mediated elongation of integrated viral DNA, promotes nuclear export of incompletely spliced viral RNAs, G2 cycle arrest, HIV infection of macrophages, viral enzymes encoded
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viremia in HIV
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causes headache, swollen lymph nodes, people think it's just bad cold
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AIDS
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primary infection in blood, mucosa
infects CD4+ T cell and dendritic cell drainage to lymph nodes, spleen infection established in lymphoid tissue, eg lymph node acute HIV syndrome, spread of infection thruout body, viremia immune response, anti-HIV Ab, HIV-specific CTLs partial control of viral replication clinical latency, latent infection/provirus, low-level infection other microbial infections: cytokines (TNF) extensive viral replication and CD4+ cell lysis destruction of lymphoid tissue: depletion of CD4+ T cells |
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HIV
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gp120 on virus binding to CD4 on cell, conformational change, gp120/CD4 bind CCR-5(chemokine receptor), gp41 on virus penetrates cell membrane, membrane fusion, HIV RNA genome into cell, RT-mediated synthesis of proviral DNA, integration of provirus into host cell genome, HIV RNA transcript, synthesis of HIV proteins, assembly of virion core structure, budding and release of mature virion
cytokine activation of cell/transcription of HIV genome/transport of viral RNAs to cytoplasm |
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cytopathic effect of HIV
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chronic T cell activation-->viral replication in infected CD4+ T cells--> death of infected cells
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apoptosis by HIV
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chronic T cell activation-->activation of uninfected CD4+ T cells-->activation-induced cell death
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killing of infected cells by virus-specific CTLs by HIV
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chronic T cell activation-->Expression of HIV peptides on infected CD3+ T cells-->CTL
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HIV infection to AIDS
|
possible acute HIV syndrome, wide dissemination fo virus, seeding of lymphoid organs-->clinical latency-->constitutional symptoms-->opportunistic diseases-->death
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HIV infection to AIDS
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viral particles in plasma, then CTLs specific for HIV peptides, then anti-envelope Ab then anti-p24 Ab
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AIDS
|
activation of cell-mediated immunity after Mycobacterium tuberculosis infection GONE IN THIS DISEASE
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diseases secondary to AIDS
|
mycobacterium avium intracellulare (MIA), carinii, toxoplasmosis, Karposi's sarcoma
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Karposi's
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not everyone with HHV8 has this, but everyone with this disease has HHV8
synergy HHV8 and HIV, spindle cells (HIV infected), synergize and cause massive lesions |
