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