1 / 22

THE COMPLEMENT SYSTEM

THE COMPLEMENT SYSTEM. Help!. 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.)

akiva
Download Presentation

THE COMPLEMENT SYSTEM

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. THE COMPLEMENT SYSTEM

  2. Help!

  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 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 Serum Soluble Membrane Bound CR1 - CR4 C3aR, C5aR, CRIg, C1qR CR1, CD59, DAF, MCP

  6. Modular Structure of Complement Proteins • Enzymes - (Serine Protease Domain) • C1s, C1r, C2, factors B, D and I • Collectins - (Collagen Stalk, Gobular Domain) • C1q, MBP and Ficolin • 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

  7. Complement Biosynthetic Sites • Hepatocytes • Monocyte/Macrophage • Hematopoietic • Fibroblasts • Endothelial • Reproductive • Adipocytes • Astrocytes • Neurons

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

  9. Chemotaxis Inflammation Opsonization Neutralization B cell activation Chemotaxis Inflammation Lytic complex formation Complement Host Defense Functions C3a C3 C3b C5a C5 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 C1=C1q,C1s2,C1r2 C1q C1s C1r

  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 C3a C3b C5 C5a C5b + C6-C9 TERMINAL

  18. COMPLEMENT REGULATION • Regulation is in proportion to the amount of activator • Limited half-life for the convertases, through regulatory proteins • Inhibitory proteins to control early activation • Carboxypeptidases to inactivate the anaphylatoxins • Inhibitory proteins to modulate MAC formation

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

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

  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

More Related