1. THE COMPLEMENT SYSTEM

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3. COMPLEMENT A group of sequentially reacting proteins, which upon activation, mediate a number of biological reactions important to host defense

4. 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)

5. Proteins of the Complement System Activation Regulation Receptors Serum Soluble Membrane Bound 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 - CR4 C3aR, C5aR, CRIg, C1qR

6. 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

7. Complement Biosynthetic Sites HepatocytesHepatocytes Monocyte/MacrophageMonocyte/Macrophage HematopoieticHematopoietic FibroblastsFibroblasts EndothelialEndothelial ReproductiveReproductive AdipocytesAdipocytes AstrocytesAstrocytes NeuronsNeurons

8. COMPLEMENT PATHWAYS CLASSICAL MBP/Ficolin ALTERNATIVE C3 C5 C3a C5a C3b C5b + C6-C9 TERMINAL Properdin MASP-1

9. Complement Host Defense Functions C5 C3 Lytic complex formation ChemotaxisInflammationChemotaxisInflammationOpsonizationNeutralization B cell activation C3a C3b C5a C5b

10. Complement Activation Classical Pathway - Ag-Ab complexes Mannan-Binding Protein Pathway - Mannose, N-acetylglucosamine Alternative Pathway - LPS, zymosan

11. C1q and C1 Structure C1q C1s C1r C1=C1q,C1s 2,C1r 2

12. CLASSICAL PATHWAY ACTIVATION MOVIE

13. ALTERNATIVE PATHWAY ACTIVATION MOVIE

14. 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

15. 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

16. C3b Biological Functions Opsonization of Ag-Ab complexes for clearance Solubilization of immune complexes Neutralization of invading pathogens

17. COMPLEMENT REGULATION CLASSICAL MBP ALTERNATIVE C3 C5 C3a C5a C3b C5b + C6-C9 TERMINAL

18. COMPLEMENT 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 regulatory proteinsLimited half-life for the convertases, through regulatory proteins Inhibitory proteins to control early activationInhibitory proteins to control early activation Carboxypeptidases to inactivate the anaphylatoxinsCarboxypeptidases to inactivate the anaphylatoxins proteins to modulate MAC formationInhibitory 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 regulatory proteinsLimited half-life for the convertases, through regulatory proteins Inhibitory proteins to control early activationInhibitory proteins to control early activation Carboxypeptidases to inactivate the anaphylatoxinsCarboxypeptidases to inactivate the anaphylatoxins proteins to modulate MAC formationInhibitory proteins to modulate MAC formation

19. DAF Inhibition Decay Acceleration Regulation of Complement Activation C3b factor B Bb

20. Inhibition ofC9binding of C9 binding Regulation of Complement Activation (Terminal Pathway) CD59 C9 C5b-8

21. 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)

22. Complement Deficiencies & Treatment Options Regulatory Components HANE (C1-INH deficiency) – replacement therapy, kallikrein inhibitors PNH (DAF, CD59 deficiency) – anti-C5 Ab aHUS (CD46 deficiency) Receptors – SLE (low CR1 expression), life- threatening bacterial infections (CR3, CR4 deficiencies) – bone marrow transplantation