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THE COMPLEMENT
SYSTEM
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COMPLEMENT
A group of sequentially reacting proteins, which upon activation, mediate a number of biological reactions important to host defense
COMPLEMENT NOMENCLATURE
• “C” - designation for 11 of the complement proteins (C1, C2, etc.)
• Factor - designation for many alternative pathway components (factor B)
• Overbar - indicates an enzymatically active protein or complex
• Lower case letters - indicates a proteolytic cleavage fragment (C3a or C5a)
• “R” - designation for receptors in the complement system (CR1 or C5aR)
Proteins of the Complement System
Activation Regulation Receptors
SerumSoluble
MembraneBound
C1q, C1r, C1s,C2 - C9,Factors B & D,MBP, MASP-1-3,sMAP, ficolin
C1-INH, C4BP,factors H and I,S protein,Sp-40,40
CR1, CD59,DAF, MCP
CR1 - CR4C3aR, C5aR,CRIg, C1qR
Modular Structure of Complement Proteins
•Enzymes - (Serine Protease Domain)•C1s, C1r, C2, factors B, D and I
•Cytolytic – (MACPF/CDC superfamily)•C6, C7, C8 and C9
•Regulatory and Receptor (SCR Domain)•DAF, MCP, C4BP, CR1, CR2 and factor H
•“True” Complement Proteins•C3, C4 and C5
•Collectins - (Collagen Stalk, Gobular Domain)•C1q, MBP and Ficolin
Complement Biosynthetic SitesComplement Biosynthetic Sites
•HepatocytesHepatocytes•Monocyte/MacrophageMonocyte/Macrophage•HematopoieticHematopoietic•FibroblastsFibroblasts•EndothelialEndothelial•ReproductiveReproductive•AdipocytesAdipocytes•AstrocytesAstrocytes•NeuronsNeurons
COMPLEMENT PATHWAYSCOMPLEMENT PATHWAYS
CLASSICALCLASSICAL MBP/Ficolin ALTERNATIVE MBP/Ficolin ALTERNATIVE
C3C3
C5C5
C3aC3a
C5aC5a
C3bC3b
C5b + C6-C9C5b + C6-C9TERMINALTERMINAL
ProperdinProperdin
MASP-1MASP-1
Complement Host Defense FunctionsComplement Host Defense Functions
C5C5
C3C3
Lytic complex formationLytic complex formation
ChemotaxisChemotaxisInflammationInflammation
ChemotaxisChemotaxisInflammationInflammation
OpsonizationOpsonizationNeutralizationNeutralizationB cell activationB cell activation
C3a
C3b
C5a
C5b
Complement Activation
• Classical Pathway - Ag-Ab complexes
• Mannan-Binding Protein Pathway - Mannose, N-acetylglucosamine
• Alternative Pathway - LPS, zymosan
C1q and C1 Structure
C1q
C1s C1r
C1=C1q,C1s2,C1r2
CLASSICAL PATHWAY ACTIVATIONMOVIE
ALTERNATIVE PATHWAY ACTIVATIONMOVIE
C3a/C5a Biological Functions
• Anaphylatoxic and Chemotactic molecules
• Degranulation of mast cells, basophils and eosinophils (histamine release)
• Induce increased vascular permeability, edema
• Induce cytokine release, adhesion molecule and acute phase protein expression
• Induces/augments respiratory burst
C5b Biological Functions
• Initiation of the membrane attack complex: the nonproteolytic association of C5b, C6, C7, C8 and C9 leading to the formation of a membranolytic pore-forming complex
• Signal transduction for numerous cellular events
C3b Biological Functions
• Opsonization of Ag-Ab complexes for clearance
• Solubilization of immune complexes
• Neutralization of invading pathogens
COMPLEMENT REGULATION
CLASSICAL MBP ALTERNATIVE
C3
C5
C3a
C5a
C3b
C5b + C6-C9TERMINAL
COMPLEMENT REGULATIONCOMPLEMENT REGULATIONCOMPLEMENT REGULATIONCOMPLEMENT REGULATION
• Regulation is in proportion to the amount of activatorRegulation is in proportion to the amount of activator
• Limited half-life for the convertases, through Limited half-life for the convertases, through
regulatory proteinsregulatory proteins
• Inhibitory proteins to control early activationInhibitory proteins to control early activation
• Carboxypeptidases to inactivate the anaphylatoxinsCarboxypeptidases to inactivate the anaphylatoxins
• Inhibitory proteins to modulate MAC formation proteins to modulate MAC formation
• Regulation is in proportion to the amount of activatorRegulation is in proportion to the amount of activator
• Limited half-life for the convertases, through Limited half-life for the convertases, through
regulatory proteinsregulatory proteins
• Inhibitory proteins to control early activationInhibitory proteins to control early activation
• Carboxypeptidases to inactivate the anaphylatoxinsCarboxypeptidases to inactivate the anaphylatoxins
• Inhibitory proteins to modulate MAC formation proteins to modulate MAC formation
DAF
DAF
Inhibition
DecayAcceleration
Regulation of Complement Activation
C3b
C3b C3b
factor B
BbBb
InhibitionInhibitionofof C9C9 bindingbinding
Regulation of Complement ActivationRegulation of Complement Activation(Terminal Pathway)(Terminal Pathway)
CD59CD59
C9C5b-8
Complement Deficiencies &Treatment Options
• Activation Components - recurrent bacterial infections - antibiotics, replacement therapy? (C2, factors B and D, MBP and properdin deficiencies)SLE (C1 and C4 deficiencies)
• Terminal Components - recurrent bacterial infections - antibiotics, replacement therapy? (C5-C9 deficiencies)
Complement Deficiencies &Treatment Options
• Regulatory Components HANE (C1-INH deficiency) – replacement therapy, kallikrein inhibitorsPNH (DAF, CD59 deficiency) – anti-C5 AbaHUS (CD46 deficiency)
• Receptors – SLE (low CR1 expression), life-threatening bacterial infections (CR3, CR4 deficiencies) – bone marrow transplantation