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COMPLEMENT SYSTEM

COMPLEMENT SYSTEM. The complement system is a set of plasma proteins that act in a cascade to attack and kill extracellular pathogens. Most of the complement proteins and glycoproteins are produced in the liver in an inactive form. Activation is induced by proteolitic cleavage.

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COMPLEMENT SYSTEM

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  1. COMPLEMENT SYSTEM

  2. The complement system is a set of plasma proteins that act in a cascade to attack and kill extracellular pathogens. Most of the complement proteins and glycoproteins are produced in the liver in an inactive form. Activation is induced by proteolitic cleavage. Non antigen-specific enzyme cascade – elimination of extracellular pathogens and immuncomplexes.

  3. ACTIVATION OF THE COMPLEMENT SYSTEM COMPLEMENT ACTIVATION REQURIETMENT OF INFLAMMATORY CELLS OPSONIZATION OF PATHOGENS KILLING OF PATHOGENS

  4. AMPLIFICATION OF THE COMPLEMENT CASCADE Limited proteolysis Inactive precursors enzyme Activating surface

  5. COMPLEMENT SYSTEM CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY Antigen-antibody complex Mannose Pathogen surface MBL MASP-1/MASP-2 Serin protease C4, C2 C3 B, D C1q, C1r, C1s Serin protease C4, C2 C4a* C3a, C5a C3 CONVERTASE C3b Terminal C5b – C9 Inflammatory peptid mediators Phagocyte recruitment Opsonization Binding to phagocyte CR3 Immune complex removal MAC Pathogen/cell lysis

  6. A C1 COMPLEX Low affinity binding to the C-terminal of antibody Multiple interaction with immune complexes

  7. The classical pathway of complement activation is initiated by binding of C1q to antibody on a bacterial surface

  8. MANNAN-BINDING LEKTIN ACTIVATES THE COMPLEMENT SYSTEM

  9. Eukariotic cells Mannose GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES Prokariotic cells Galactose Glucoseamin Neuraminidase Mannose

  10. C3 CGEQ One of the proteins present at the highest concentration in serum 1.2mg/ml THE CENTRAL COMPONENT OF THE COMPLEMENT SYSTEM CLEAVAGE SITE Is it a lot??? 3900.000.000.000.000 molecules/ml

  11. ACTIVATION OF C3 C3 CGEQ CGEQ R R O O CGEQ CGEQ R R R R R OH OH OH OH OH C3a C3b Active thioester Cell Inflammation Binding Bacterium

  12. The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane Liveand dead bacteria MAC in the cell membrane

  13. DAF MCP C1Inh CD59 Properdin Factor H positive feedback Regulation of complement system membrane protein C1Inh: C1-inhibitor DAF: Decay Accelerating Factor MCP: Membrane Cofactor Protein soluble molecule

  14. Regulatory proteins on human cells protect them from complement-mediated attack

  15. CD59 prevents assembly of terminal complement components into a membrane pore

  16. C3b C3b C3b C3b C3b phagocytosis The role of complement system in in vivo Lectin and alternative pathway classical pathway C3 MAC lysis C3a C4a C5a opsonisation

  17. Bacterium ComplementReceptor Macrophage OPSONIZATION C3b

  18. Local inflammatory responses can be induced by the small complement fragments C3a, C4a, and especially C5a

  19. Elimination mechanisms of immunocomplexes produced in vivo Y Y Y Y inhibition Y Y Y Y Y Y Y Y solubilization precipitation • detection of • soluble complexes • size • ppt (PEG, etc.) • Anti-Ig • Anti-C3 • C1q binding • binding to cells • C3 receptor • Fc receptor C1q C1r, s C4, 2 rbc inflammation CR1 C3a lyses C5,6,7,8,9 C3 Y CR3 C3b memory B-cells (FDC) Y FcR phagocytosis cytotoxicity

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