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 SYSTEM CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY COMPLEMENT ACTIVATION REQURIETMENT OF INFLAMMATORY CELLS OPSONIZATION OF PATHOGENS KILLING OF PATHOGENS

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

5. Antigen-antibody complex MannosePathogen surface C1q, C1r, C1s Serin protease C4, C2 MBL MASP-1/MASP-2 Serin protease C4, C2 C3 B, D COMPLEMENT SYSTEM CLASSICAL PATHWAYMB-LECTIN PATHWAYALTERNATIVE PATHWAY C3 CONVERTASE C4a* C3a, C5a Inflammatory peptid mediators Phagocyte recruitment C3b Opsonization Binding to phagocyte CR3 Immune complex removal Terminal C5b – C9 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 Glucoseamin Mannose Galactose Sialic acid GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES Mannose Prokariotic cells

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

11. MAC in the cell membrane Live and dead bacteria The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane

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

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

14. The role of complement system in in vivo Lectin and alternative pathway classical pathway C3 C3b opsonisation phagocytosis C3b C5a C4aC3a MAC lysis

15. Bacterium Complement Receptor Macrophage OPSONIZATION C3b

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

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

18. MUTATION OF MEMBRANE BOUND COMPLEMENT PROTEINS RESULTS IN IMMUNODEFICIENCY MIRL = CD59 DAF accelerates the decay of classical and alternative C3 convertase

20. DEFICIENCY OF C3 OR ITS ACTIVATION –Susceptibility to pyogenic bacteria – inefficient opsonization DEFICIENCY OF C5-C9 –Neisseria – NO complement mediated lysis DEFICIENCY OF EARLY C1-C4 –No C3b and C4b fragments  No CR1-mediated erythrocyte transport of immune complexes –Accumulation of immune complexes in blood, lymph, extracellular fluid  deposition in tissues  tissue demage  macrophage activation  inflammation DEFICIENCY IN COMPLEMENT INHIBITORY FACTORS –I factor – uncontrolled C3  C3b  C3 depletion  inefficient opsonization –Decay Accelerating Factor DAF or CD59 MAC inhibitor – autoimmune-like condition  lysis of autologous erythrocytes  paroxysmal nocturnal hemoglobulinuria –C1 inhibitor – uncontrolled activation of the classical pathway  vasoactive C2  accumulation of fluid in tissues – epiglottal swelling may lead to death by suffocation DEFECTS IN COMPLEMENT COMPONENTS IMPAIR ANTIBODY RESPONSES ACCUMULATION OF IMMUNE COMPLEXES