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76 Cards in this Set
- Front
- Back
5 cardinal signs of inflammation?
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Rubor (red), dolor (pain), calor (hot), tumor (swelling), functio laesa (loss of fn)
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3 families of adhesion molecules involved in acute inflammation?
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Selectins, immunoglobulin-family adhesion proteins, integrins
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What are the steps in neutrophil margination and adhesion during inflammatory response?
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1) Margination 2) Rolling3) Activation4) Adhesion5) Transmigration
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What occurs during "margination"?
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neutrophils line vessel walls due to increased blood viscosity due to fluid extravasation
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What occurs during "rolling"?
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E- and P-selectins on endothelial cells bind weakly to neutrophils
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What occurs during neutrophil "activation" and "adhesion"?
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neutrophils are stimulated by chemokines to express their integrins, which firmly adhere to immunoglobulin-family adhesion proteins on endothelial cells (ICAMs)
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What occurs during neutrophil "transmigration"?
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leukocytes move between endothelial cells, and migrate through basement memb towards inflammatory stim (chemotaxis)
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What is chemotaxis?
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when leukocytes are attracted to and move toward an injury, moves along a chemical gradient
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Chemotactic factors?
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Chemokines (IL-8), C5a, finbrinopeptides, leukotriene B4 (LTB4), formyl methyl peptides
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Hemodynamic changes in acute inflammatory response?
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1. Transient initial vasoconstriction, followed by massive vasodilation2. Increased vascular permeability (due to endothel cell contraction or injury) -> leakage of proteinaceous fluid -> edema3. Blood stasis due to increased viscosity -> facilitates neutrophil margination
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Causes of NEUTROPHILIA?
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BACTERIAL infections, and other causes of ACUTE INFLAMMATION, such as infarction (usu w/in 1st 24hrs); EARLY RELEASE from bone marrow reserve pool
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Causes of MONOCYTOSIS?
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TB, brucellosis, typhus, salmonella (seen w/CHRONIC INFLAMMATION)Replace neutrophils after 2-3 days, are longer lived, can divide/proliferate in tissue
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Causes of LYMPHOCYTOSIS?
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VIRAL infections (influenza, mumps, rubella, infectious mononucleosis)BACTERIAL infections (whooping cough and TB)**prominent in CHRONIC INFLAMMATION
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Causes of EOSINOPHILIA?
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ALLERGIC reactions and PARASITIC infections, also in polyarteritis nodosa and Hodgkin lymphoma
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Causes of BASOPHILIA?
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chronic myelogenous leukemia and other myeloproliferative diseases (mast cells and basophils are source of histamine)
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Key steps in phagocytosis?
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1. engulfment of opsonized particle by macrophage or neutrophil, forming phagosome2. fusion with lysosome to make phagolysosome3. digestion
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What are the most important opsonins in phagocytosis?
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IgG subtypes and C3b
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Types of intracellular microbial killing in phagocytosis?
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Oxygen dependent:1. NADPH oxidase-dependent2. myeloperoxidase-dependentOxygen independent:1. lysosome-dependent
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Basic mechanism of killing in oxygen-dependent microbial killing during phagocytosis?
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H2O2 (and other free radicals) are produced/activated, and disrupt cell walls
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Endogenous mediators of acute inflammation?
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1. Vasoactive amines2. Arachidonic acid metabolites3. Cytokines4. Kinin system5. Complement system6. Nitric oxide
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Effects of HISTAMINE?
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vasodilation and increased vascular permeability
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Where is histamine released from?
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Basophils, mast cells, platelets
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What triggers release of histamine from PLATELETS?
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is liberated by platelet aggregation and release reaction, which is triggered by 1)endothelial injury and thrombosis, or 2)platelet activation factor (PAF)
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What triggers the release of histamine from MAST CELLS or BASOPHILS?
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1. antigen binds to IgE on mast cell/basophil2. C3a or C5a (ANAPHYLATOXINS) bind to receptors on mast cell/basophil3. physical stimuli (heat/cold)4. IL-1 (cytokines)
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What substances does PAF release, and what other effects does it have?
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1. releases histamine and 5HT from platelets2. vasoactive and bronchospastic effects3. activates arachidonic acid
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What does VASOACTIVE mean?
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causing constriction or dilation of blood vessels
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What is a VASOACTIVE AMINE?
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acts on blood vessels to alter permeability or to cause vasodilatione.g. histamine and 5HT
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What are the 2 ARACHIDONIC ACID PATHWAYS?
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1. cyclooxygenase pathway2. lipooxygenase pathway
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What are the general effects of arachidonic acid metabolites?
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short range hormones that rapidly decay, they mainly affect inflammation and hemostatis via vasodilation/vasoconstriction, platelet aggregation, etc
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What 2 enzymes catalyze the cyclooxygenase pathway?, and which one is expressed in gastric mucosa?
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COX-1 (in gastric mucosa) and COX-2
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What substances inhibit the catalysts of the cyclooxygenase pathway, and via what mechanism?
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aspirin and other NSAIDs inhibit prostaglandin synthesis (prostaglandin is the intermediate between arachidonic acid and TXA2,PGI2,PGD2,PGE2,PGF2)
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What might be the benefit of selective COX-2 inhibitors?
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actions of COX-1 in gastric mucosa are preserved, thus avoiding anti-inflammatory effects in gastric mucosa, and preventing gastric ulceration
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What are the three classes of products of the cyclooxygenase pathway?
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1. (Platelet) Thromboxane A2 (TXA2)2. (Endothelial) Prostacyclin (PGI2)3. PGD2, PGE2, PGF2
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What are the opposing functions of TXA2 and PGI2?
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TXA2: IN PLATELETS, promotes platelet aggregation and vasoconstrictionPGI2: IN ENDOTHELIUM, inhibits platelet aggregation and causes vasodilation
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What are the functions of PGD2, PGE2, and PGF2?
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vasodilation (plus pain for PGE2)
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Products of lipooxygenase pathways?
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leukotriene B4 (LTB4), LTC4, LTD4, LTE4
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What is the function of LTB4?
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neutrophil chemotaxis
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What is the function of LTC4, LTD4, LTE4?
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vasoconstriction, bronchospasm, increased permeability"slow-reacting substance of anaphylaxis" (SRS-A)
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Common cytokines involved in inflammation?
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IFN-gamma (activates monocytes), IL-1 & TNF (s/c by monocytes)
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Main cytokine effects on inflammation?
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1. Systemic effects (fever, leukocytosis)2. Hepatic synthesis of acute phase proteins3. Synthesis of adhesion molecules4. Neutrophil degranulation5. Promote thrombosis
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What is the important peptide product of the kinin system that plays a role in inflammation?
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bradykinin
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What are the 2 cascade reactions necesesary to create bradykinin?
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1. Hageman factor (factor XII) converts prekallikrein -> kallikrein2. Kallikrein converts high molecular weight kininogen (HMWK) -> bradykinin
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What are the effects of BRADYKININ?
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increase vascular permeability, pain, vasodilation, bronchoconstriction
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Which complement proteins participate in inflammatory response?
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C3a & C5a, C3b, C5b-C9
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What is an ANAPHYLATOXIN?
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mediate degranulation of basophils and mast cells w/release of histamine (e.g. C3a and C5a)
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What are the 4 functions of C5a?
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1. anaphylatoxic effect2. chemotactic effect on neutrophils3. induces expression of leukocyte adhesion molecules4. activates lipooxygenase pathway of arachidonic acid metabolism
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What is the function of C3b?
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opsonization of invader for phagocytosis by neutrophil/macrophage
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What is the function of C5b-C9?
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Forms membrane attack complex (MAC) = lytic agent for bacteria and other cells
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What are the 3 main functions of the complement cascade?
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1. opsonization of pathogens (C3b)2. recruitment of inflammatory cells (C3a, C5a)3. killing of pathogens (C5b-C9)
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What are the effects of NITRIC OXIDE during the inflammatory process?
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produced by endothelial cells; smooth muscle relaxation (controls vasc tone), inhibits platelet aggregation, increased vascular permeabilityaka endothelium-derived relaxing factor
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What triggers the ALTERNATIVE PATHWAY of complement activation?
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bacterial surface
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What triggers the CLASSICAL PATHWAY of complement activation?
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antigen-antibody complex (IgG or IgM)
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What molecules are unique to the alternative pathway?
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C3, factors B and D -> C3 converatse
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What molecules are unique to the classical pathway?
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C1, C2, C4 -> C3 convertase
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3 potential outcomes of acute inflammation?
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1. restoration of tissue and function2. tissue destruction and persistent acute inflammation3. conversion to chronic inflammation
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4 ways that tissue destruction from acute inflammation can manifest itself?
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1. abscess 2. ulcer3. fistula4. scar
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What are the characteristics of an ABSCESS?
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filled w/pus (neutrophils, monocytes, liquefied cellular debris), walled off by fibrous tissue, results from tissue destruction by lysosomal products, usu caused by bacterial infections
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What is the "final result" of tissue destruction?
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Scar, w/resultant distortion of structure, and sometimes altered function
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What histological changes occur when acute inflammation becomes chronic?
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replacement of neutrophils and monocytes w/lymphocytes, plasma cells, and macrophages; proliferation of fibroblasts and new vessels, w/scarring and architectural distortion
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What are the 3 major diseases caused by defects of neutrophils?
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1. Chronic granulomatous disease (CGD)2. Chediak-Higashi syndrome3. Leukocyte adhesion deficiency (LAD)
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Molecular defect in CHRONIC GRANULOMATOUS DISEASE (CGD)?
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deficiency of NADPH OXIDASE, thus failure to generate superoxide anion and other O2 radicals -> oxygen-dependent microbial killing cannot proceed
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Histologic marker of CGD?
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phagocytes that ingest but do not kill certain microorganisms
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Symptoms of CGD?
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recurrent infections w/catalase-positive bacteria and fungi
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Why is a person w/CGD still protected from catalase-negative organisms?
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catalase-negative organisms produce sufficient H2O2 to permit oxygen-dependent microbicidal mechanisms to proceed (catalase negative organisms destroy H2O2)
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Molecular defect in CHEDIAK-HIGASHI SYNDROME?
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granule structural defect
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Markers for CHEDIAK-HIGASHI SYNDROME?
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abnormal white blood cells:-chemotactic defects-degranulation defects-large cytoplasmic granules caused by impaired fusion of lysosomes
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Symptoms of CHEDIAK-HIGASHI SYNDROME?
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absent NK activity, partial albinism, cranial/peripheral neuropathy, repeated infections
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Molecular defect of LEUKOCYTE ADHESION DEFICIENCY (LAD)?
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absence of CD18--common beta chain of leukocyte integrins; interferes with neutrophil adhesion and transmigration
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Symptoms of LEUKOCYTE ADHESION DEFICIENCY (LAD)?
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recurrent chronic infections, failure to form pus, does not reject umbilical cord stump
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2 major patterns of CHRONIC INFLAMMATION?
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Chronic nonspecific inflammation, granulomatous inflammation
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Chronic inflammation commonly arises in what 3 settings?
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1. persistent infections2. autoimmune diseases3. prolonged exposure to toxic agents
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3 common histologic markers of chronic inflammation?
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1. collection of chronic inflammatory cells (macrophages, lymphocytes, plasma cells)2. tissue destruction3. repair involving angiogenesis and fibrosis
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Who activates what in CHRONIC NONSPECIFIC INFLAMMATION?
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-MONOCYTES recruited by chemotactic factors-MONCYTES/MACROPHAGES secrete cytokines, which activate LYMPHOCYTES-LYMPHOCYTES then secrete additional cytokines that activate MONOCYTES/MACROPHAGES-MACROPHAGE presents antigen to activate B LYMPHOCYTE, which forms antibody-producing PLASMA CELLS
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What is a GRANULOMA?
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collection of activated macrophages that have an enlarged, squamous cell-like (EPITHELIOD) appearance
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What disease is characterized by CASEATING GRANULOMAS?
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TB
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What disease is characterized by NONCASEATING GRANULOMAS?
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sarcoidosis
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