k7 - the complement system3
TRANSCRIPT
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The complement The complement systemsystem
Evy Sulistyoningrum
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Outlines Components of complement
systemComplement system activationEffector mechanism of
complement systemRegulation of complement
system activityComplement abnormality-related
disease
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Introduction Introduction Jules Bordet
◦Heat labile protein → inactive at 56°C for 30 min◦Augments opsonization and bacterial
killing by antibody→ complement
Definition:A group of protein which possess enzymatic property, they interact with one to another attending specific and non-specific immune reponse.
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Complement proteinComplement proteinProduced by:
◦ Hepatocytes◦ Monocyte/Macrophage◦ Fibroblasts◦ Endothelial◦ Reproductive◦ Adipocytes◦ Astrocytes
Stored in inactive form (proenzyme)2 form:
◦ Soluble: C1q, C1r, C1s, C2-C9, Factor B, D, H◦ Membrane bound: CR1, C3aR, DAF, MCP
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Components of complement Components of complement systemsystemIntrinsic components: main component in
complement cascadeEx: C1-C9, MBL, MASP, Factor B, Factor D
Regulatory proteinsEx: C1 inhibitor, C4-binding protein, Factor H, DAF (Decay-accelerating factor), MCP (Membrane cofactor protein), etc
Complements receptorsEx: CR1, CR2, C3aR, etc
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How the complements How the complements work?work?Enzymatic cascadeActivation:
◦Classical pathway◦Lectin pathway◦Alternative pathway
Effector phase:◦Recruitment of inflammatory and
immunocompetent cells◦Opsonization◦Pathogen killing
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How the complements How the complements work?work?
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Complement activationComplement activationClassical pathways: antigen-
antibody complexMBL pathway: interaction of
microbial carbohydrates with mannose binding lectin (MBL) in the plasma and tissue fluids.
Alternative pathway: spontaneously cleavage C3 → C3b binding to microbial surfaces and to antibody molecules
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Complement activationComplement activation
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CCLLAASSSSIICCAALL
PPAATTHHWWAAYY
Trigerring substance: Ag-Ab complexComponents: C1 (C1q, C1r, C1s), C2-C9
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Classical pathway: Classical pathway: processprocess
◦Recognition step Binding of C1q to Ag-Ab complexes Autocatalysis of C1r → altered C1r cleaves
C1s→ active C1s capable of cleaving both C4 and C2 (C4-C2 convertase)
◦Activation step Activated C1s cleaves C4 into C4a and
C4b C4b bind to C2 Activated C1s cleaves C2 into C2a and
C2b forming C4b2a complex (C3 convertase)
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Classical pathway: Classical pathway: activationactivation
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Classical pathway: Classical pathway: activationactivation
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Classical pathway: Classical pathway: activationactivation
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Classical pathway: Classical pathway: activationactivation
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MMBBLL
PPAATTHHWWAAYY
Triggering substance : interaction of microbial carbohydrates with mannose binding lectin (MBL) in the plasma and tissue fluids
Components: MBL, MASP1, MASP2, C2-C9
Process:◦ Recognition step
Mannan-binding lectin (MBL) binds mannose of bacteria and interacts with serine protease resulting in MBL-associated serine protease (MASP)
MASP2 is analogous to C1r and C1s and leads to cleaving of C4 and C2.
◦ Activation step ≈ Classical pathway
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AAL L TTEERRNNAATTIIVVEE
PPAATTHHWWAAYY
Trigerring substance: LPS, endotoxin, etcComponents: C3,C5~C9, factor B, factor D,
factor P
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Cont’d…Cont’d…Process:
◦ Spontaneous activation of C3 C3 is hydrolyzed producing C3(H2O) C3b bind to factor B Factor B is cleaved by Factor D to
produce C3bBb complex (C3 convertase)
◦ Stabilization of C3 convertase C3b or C3bBb need a suitable stabilizing
membrane or molecule (C3 activator) Bacteria or their products (LPS, etc),
factor P (properdin)
AAL L TTEERRNNAATTIIVVEE
PPAATTHHWWAAYY
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Alternative pathway: Alternative pathway: activationactivation
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Alternative pathway: Alternative pathway: activationactivation
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Cont’d…Cont’d…
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Cont’d…Cont’d…
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Cont’d…Cont’d…
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Cont’d…Cont’d…
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Cont’d…Cont’d…
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Cont’d…Cont’d…
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Complement activationComplement activation
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Late events on complement Late events on complement cascadecascadeForming C5 convertase:Forming C5 convertase:
C3 convertase cleaves C3 into C3a and C3bClassical& MBL pathwaysC3b binds to the C4b2a complex →
C4b2a3b complex (C5 convertase)
Alternative pathways C3b binds to C3bBb complex → C3b2Bb
complex (C5 convertase)C5 convertase will cleave C5 into C5a and C5b
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Forming C5 convertaseForming C5 convertaseC4b2a
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Cont’d…Cont’d…Lytic terminal sequence: MAC
C5 convertase cleaves C5 into C5a and C5bC5b binds the membrane and C6 and C7→
C5b67 complex which attaches quickly to the cell membrane.
C8 binds to this complex form C5b678 and inserts to the plasma membrane
C9 binds to C5b678 molecules and polymerizeC5b6789 complex = MAC (Membrane
attack complex) → formation of a hole in the membrane → cell lysis
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Lytic terminal sequence: Lytic terminal sequence: MACMAC
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Membrane attack complexMembrane attack complex
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Complement-Mediated Lysis of E. coliAlive Killed
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Complement’s movie movie
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Complement components on Complement components on late eventslate events
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Effector activity of Effector activity of complementscomplements
Cell lysis◦ MAC mediates lysis of target cell
Opsonization◦ C3b and C5a attach to CR on phagocytic cells and
promote phagocytosisMediating inflammation response
◦ Anaphylatoxins (C4a, C3a,C5a) : basophil/mast cell degranulation → dilatation of blood vessels, contraction of smooth muscles
◦ Chemotactic factors : attract neutrophils and phagocytes
◦ Induce cytokine release, adhesion molecule and acute phase protein expression
◦
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OOPPSSOONNIIZ Z AATT IIOONN
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Small complement fragments (C3a, C4a and C5a) induce local inflammatory response
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IINNFFLLAAMMM M AATTOORRYY
EEFFFFEECCTT
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Complement ReceptorsComplement Receptors
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Figure 2-19Figure 2-19
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Self regulation◦Spontaneous decay of complement
components C3b, C4b, C5b; C3 convertase, C5 convertase
◦Limited half-life for the convertases
Effect of regulative factors
COMPLEMENT COMPLEMENT REGULATIONREGULATION
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Effect of regulative Effect of regulative factorsfactors
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Effect of regulative Effect of regulative factorsfactors
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Effect of regulative Effect of regulative factorsfactors
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Effect of regulative Effect of regulative factorsfactors
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Complement deficienciesComplement deficienciesActivation components
◦Classical pathway : C2 & C4 deficiencies : defects in clearing
immune complex, ex: SLE C3 deficiencies: frequent pyogenic
bacterial◦Alternative pathway
Properdin & factor D : increase susceptibility to pyogenic bacterial
◦MBL Some immunodeficiency patients
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Terminal complement componentsC5, C6, C7, C8, C9: recurrent bacterial
infections (N. Meningitidis, N. Gonorrhoea)Regulatory Components
◦ C1-Inhibitor deficiency: Hereditary Angioneurotic Edema
◦ DAF, CD59: Paroxysmal Nocturnal Haemoglobinuria
Receptors◦ CR1: SLE◦ CR3, CR4: Leucocyte adhesion deficiency
recurrent threatening bacterial infection
Complement deficienciesComplement deficiencies
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Hereditary Angioneurotic Hereditary Angioneurotic EdemaEdema
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Terima kasih………..Terima kasih………..
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Referensi Referensi Murphy K, Travers P, Walport M,
Janeway’s Immunobiology, 7th edAbbas AK dan Lichtman AH, Basic
ImmnunologyRoitt, IM., Delves, PJ, Roitt’s
Essential ImmunologyBurmester, Colour Atlas of
Immunology