The complement system

The complement system is a part of the immune system that helps or complements the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the innate immune system, which is not adaptable and does not change over the course of an individual's lifetime.
consists of three pathways: 1. alternative
2. classical
3. lectin pathway

1. THE COMPLEMENT SYSTEM PRESENTED BY : Sushma P.R M.Sc. Biotech 2 nd sem Dept. of biotechnology PRESENTED TO : Dr. T.T.S Ramachandra Murthy HOD, Dept. of Biotechnology Brindavan college

2. Research in complement started in 1890s when Jules Bordet at the Institut P asteur of Paris conducted experiment using sheep antiserum. He named those substances as Alexins. Paul E hrlich coined the term complement. HISTORY

3. It is named “complement system” because it was first identified as a heat-labile component of serum that “complemented” antibodies in the killing of bacteria . Consists of serum and cell surface proteins involved in defense against pathogens and tissue damage mediated by antibodies The Complement system is the major effector of humoral branch of immune system . Plays major role in both innate and adaptive immunity. INTRODUCTION

4. Opsonisation Chemotaxis Cell lysis Immune clearance Activation of inflammatory response Functions of the complement system

5. Over 30 serum and cell surface proteins : Complement components (in serum inactive, activated sequentially as a cascade ) Complement receptors (cell surface, recognize activated components ) Regulatory proteins of complement (both in serum and cell surface, inhibit activated components ) Components are designated by numbers (E.g. ; C1 – C9) or latters (E.g. : Factor D). The components of complement system

6. Complement proteins : Made as zymogens - activation by cleavage. Example: C4 Exception: C2: C2a = large fragment C2b = small fragment a = smaller fragment Diffusion & signaling b= larger fragment. remains bound to microbe C4a C4b They are mainly synthesized by hepatocytes Also produced by blood monocytes, tissue macrophages and epithelial cells of he gastrointestinal and genitourinary tract .

7. Three pathways for Complement activation: 1. Classical Pathway 2. Alternative Pathway 3 . Lectin or MBL Pathway Pathways for activation require multiple steps categorized as : 1. Recognition 2. Enzyme activation 3. Biological activity Unique proteins for 1 st 2 steps common proteins

8. THE CLASSICAL PATHWAY Part of adaptive immune system Relies on Ag – Ab complex to get activated

9. The classical pathway is initiated by: 1. Ab binding to the pathogen. 2. C1 proteins binds to the Fc of Ab. C1 Protein C1q - 18 polypeptides 6 arms with globular heads- Binds Fc on IgG or IgM to get activated 2 C1r + 2 C1s are activated by activated C1q.

10. Planar structure of IgM Doesn’t have any exposed C1q binding site. Staple structure of IgM At least 3 binding sited for C1q are exposed.

11. Cleavage of C3 reveals a thioester bond and i t will bind to cell surface of pathogen. P athogen Pathogen

12. C3b C3b is an opsonin Opsonins are molecules that bind both to bacteria and phagocytes Opsonization increases phagocytosis by 1,000 fold. C3b s attached to microbial surface microbe

13. C4b-2a-3b functions as the classical C5 convertase :

14. FORMATION OF MEMBRANE ATTACK COMPLEX C5b Cell membrane Pathogen

15. C6 Cell membrane Pathogen

16. Cell membrane Pathogen C7

17. Cell membrane

18. Cell membrane Pathogen C8

19. Cell membrane Pathogen C9

20. Cell membrane Pathogen

21. Cell membrane Pathogen

22. Cell membrane Pathogen

23. Cell membrane Pathogen

24. Cell membrane Pathogen

25. Cell membrane Pathogen

26. Functions of C3a and C5a C3a and C5a increases the inflammatory response by binding to mast cells and causing them to release histamine. Most powerful chemotactic factor known for leukocytes . Neutrophil Macrophage Granules containing inflammatory agents like histamine

27. The Alternative Pathway Also called as Properdin pathway Part of innate immunity. Antibody Independent . The alternative pathway is slower than the Classical pathway. Molecules of C3 undergo cleavage at continuous low level in normal plasma.

28. Activation of Alternative pathway C3 contains in unstable thioester bond. This unstable bond makesC3 subject to slow spontaneous hydrolysis to C3b and C3a The C3b is able to bind to foreign surface antigens. Mammalian cells contain sialic acid which inactivates C3b

29. Factor B C3b on the surface of a foreign cells binds to another plasma protein called factor B This binding of Factor B results in the exposure of a binding site for another enzyme called Factor D

30. Factor D The binding of factor B to C3b allows a protein enzyme called Factor D to cleave Factor B to Ba and Bb . Factor Bb remains bound to C3b while Ba and Factor D disperse away. The complex C3bBb is C3 convertase of alternative pathway Ba

31. Properdin- Factor P Stabilizes C3b-Bb so it may cleave more C3. May cleave over a million C3 molecules! Protects Bb-C3b from inactivation by complement control mechanisms.

32. C5 activation C3b-C3b-Bb functions as the C5 convertase in the alternative pathway.

33. MAC formation

34. Independent of antibodies. Lectins are proteins that bind to specific cb targets. Activated by Mannose binding lectin (MBL) – lectin that binds to mannose residues on the microbes. MBL is similar to C1q in structure and function. Lectin Binding Pathway

35. Activation of lectin pathway First step is binding of Mannose Binding Lectin (MBL) to mannose residue on the surface of microbes. To the MBL bound to microbe, MBL – Associated Serine Proteases (MASP – 1 and MASP – 2) will bind . MASP 1 and 2 is similar in structure and function to C1s andC1r This complex will cleave C4 and C2

36. 1. Facilitates Opsonization : Extremely important when pathogen carries a capsule . Effector functions of complement system

37. 2.Cell lysis

38. 3. Immune complex clearance

39. a nd C3b 4. Inflammatory response and chemotaxis

40. OVERVIEW

41. THANK YOU