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complement cascade

4 Pages

Course Code
BLG 307
Clare Chua

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IMMUNOLOGY COMPLEMENT SYSTEM I. Overview -proteins necessary for humoral and cellular immjunity in a highly regulated cascade of proteolytic events -activated directly by exposure to foreign cell surfaces -indierectly through interactions with Ab -split products mediate cell migration, activation/adhesion- interact with CR on other cells (leuk/plat/endo/SM/epi) -terminal proteins (C5b-C9) = pore forming structure that can activate or lyse cells Complement initiates 1. Attracting/Activating granulocytes and macs 2. Opsonizing bacteria/cells to target for phag 3. Pore Formation in c ell membranesrupture 4. Activation of antigen-specific B and T cells Complement Actiavation (All converge in the activation of C3) A. Classical Pathway 1. C1 binds Fc portion of ANTIBODY via Q domain (C1Q) -C1 is a multiprotein complex: C1Q has six ubunits with collagen like tails and globular head -Ab can be with antigen or on cell surface -must bind MULTIPLE antibodies Fc’s for protease activity -(IgM bound to antigen for steric change 2 IgG’s aggregagte by binding antigenic surace) -C1q critical physical link between the Ab and complement arms of immunity 2. C1S (ser protease) cleaves C4 into A and B  C4B (thioester group) attaches to bacterial surface. attracts C2 -note C4B stron nucleophile and will be deactivated by water -C1S cleafves many C4s 3. C1S cleaves C2 into A and B  C4B + C2A = CLASSICAL C3 CONVERTASE (C3-directed protease) B. MBL (mannose-binding lectin) Pathway -lectin and alternative pathway are key in immediate defense and natural immunity -don’t have memory but can differentiate self (evolved before classical pathway) 1. same process except MBL substitutes C1 complex (by passes Ab) binds mannose via its lectin heads MBL MASPS cleaves C4 and C2 to make Classical C3 Convertase (C4B + C2A) **no antibody recognition necessary; bacteria is directly recognized** C. Alternative Pathway -simplest, most primitive way (relies on C3 tickover) NO SPECIFICITY binds any nucleophile -amplification pathway b/c always making C3b which could form anathor C3 convertase (1) C3 binds bacterial surface spontaneously Microenvironment of binding determine activation of factor b or inactivation of C3b by H (2) Binds FACTOR B which is cleaved by FACTOR D into a and b Bb stays behind Ba floats away PROPERDIN stabilizes C3Bb  ALTERNATIVE C3 CONVERTASE (C3b +B + P) Classical AND alternative pathways converge here **both convertases have same function: CLEAVE C3 into C3a and C3b** both also have sim. structure (C4b:C3b::C2a:Bb) AMPLIFICATION – presence of one C3b leads to activation of 250+ others some bind bacteria covalently (thioester); most are hydrolyzed by water PHAGOCYTOSIS – phagocytic cells have several receptors FcR, C1qR, CR1 (for C3b), CR3 (for I-C3b) -Antigens coated with C3b fragments and antibody opsonized Activate Phagocytic and killing mechanisms through simultaneous activation of FcR and CR1 receptor Summary C3  soluble C3a (inflammation) + bound C3b (opsoniztion) PORE FORMING PATHWAY C3 cleaved into a and b C3b binds to C4b2a or C3Bb C4b2a3b[classical] or C3BbC3b [alternative] (C5 convertases) C5 convertase s cleaves C5 into a and b C5b, C6, 7, 8, 9 = MAC  form PO
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