Immunology/ Pharmacy Students Complement System Lecture 5 Dr. Mohammad Odibate

1. Immunology/ Pharmacy Students • Complement System • Lecture 5 Dr. Mohammad Odibate Department of Microbiology and immunology Faculty of Medicine, Mu’tah University

2. Objectives • You should know the followings: • The definition of complement system • The different pathways associated with complement activation • Why dose complement system is activated? • How dose complement system activate inflammatory response, lyses of foreign cells, and phagocytosis? • The disorders associated complement system

3. Innate immunity Third line defense Adaptive Immunity Second line defense First line defense Target

4. Innate immunity Second line defense of the innate immune system Cellular Immunity: Phagocytes Natural killer cells Humoral Immunity: - Complement - Interleukins - Enzymes

5. APC Bacterium Bacterium Bacterium

6. APC APC T B

7. Complement Proteins Bacterium

8. The definition of complement system? A set of over 20 different protein molecules always found in the blood C6 C2 C3 C5 C7 C4 C8 C9 C1 MBL Produced mainly by the liver cells Present in the blood as inactive enzymes called proenzymes There are no cells in the system

9. Complement pathways activation Classical Pathway Complement activation Killing of pathogen

10. Complement pathways activation 2 3 Complement Proteins = Classical Complement Pathway Bacterium 1

11. Classical Complement Pathway C1 C8 C6 C3 Blood vessel C9 C7 C2 C4 C5 Inflammation

12. C1 C2 C3 C5 C6 C7 C4 C1q C8 C2a C4a C3a C5a C9 C2 C3 C3b C5 C5b C6 C2b C4 C4b C7 Membrane Attack Complex (MAC) C8 C9 Classical Complement Pathway

13. C2a C4a C3a C5a C5 convertase C3 convertase C2 C3 C3b C5 C5b C6 C2b C4 C4b C7 C8 C9 Classical Complement Pathway

14. Classical Complement Pathway

15. Complement pathways activation Classical Pathway Complement activation Killing of pathogen

16. Complement pathways activation Infection 5-7 days ? Classical pathway Alternative Pathways Mannan Binding Lectin Pathway

17. Time required for antibody production after first exposure to an antigen Infection

18. Complement pathways activation Classical Pathway Alternative Pathway Complement activation Killing of pathogen

19. Alternative Complement Pathway C1 C8 C6 C3 Blood vessel C9 C7 C2 C4 C5 C1 C8 C6 C3 C9 C7 X C2 C4 C5 X Inflammation

20. Activators alternative complement pathway Certain components of viral envelop Aggregates of IgA Lipopolysaccharide Cells Lack complement inhibitors

21. What protect our cells form complement system? MAC-inhibitory protein (CD59) 2. Decay-Accelerating Factor (DAF) C4b C3b C5bC6C7 C9 DAF DAF CD59 Body cell Body cell C4b and C3b interaction with DAF inhibits the stimulation of complement on the surface of body cells CD59 inhibits the recruitment of C9 which inhibits the formation of MAC

22. Alternative Complement Pathway C3 C3 C5 Factor B Ba C3a C3a C5a C6 Membrane Attack Complex (MAC) C5 C3 C3 Bb C7 C3b C5b C3b Factor B C8 LPS Gram negative bacterium C9

23. Complement pathways activation Mannan Binding Lectin Pathway Classical Pathway Alternative Pathway Complement activation Killing of pathogen

24. Mannan Binding Lectin Pathway + Lectin protein carbohydrate containing mannose

25. Mannan Binding Lectin Pathway MBL C1 C8 C6 C3 Blood vessel C9 C7 C2 C4 C5 C1 C8 C6 C3 C9 C7 C2 C4 C5 Inflammation

26. Mannan Binding Lectin Pathway C4 convertase MASP-1 MBL C4 MASP-2 The same as in the classical pathway mannose sugar mannose residues on the surface of a large number of pathogens including bacteria, viruses, protozoa and fungi.

27. Complement pathways activation Mannan Binding Lectin Pathway Classical Pathway Alternative Pathway Lectin binding to mannose on pathogen surfaces Complement activation Killing of pathogen

28. Biological activities of complement components

29. Biological activities of complement components C2a C4a C3a C5a C3b C5b C6 C2b C4b C7 C8 C9

30. Complement pathways activation Mannan Binding Lectin Pathway Classical Pathway Alternative Pathway Lectin binding to Mannose on pathogen surfaces Complement activation Recruitment of inflammatory cells (Chemotaxins) Killing of pathogen

31. Biological activities of complement components C3a, C5a Recruitment of Inflammatory cells Chemotaxis C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a C5a Inflammation site

32. Biological activities of complement components C3a, C5a Recruitment of Inflammatory cells Chemotaxis Step1: stationary cell Step 2: Gradient sensing Step 3: Pseudopod extension Step 4: Direction of motility

33. Complement pathways activation Mannan Binding Lectin Pathway Classical Pathway Alternative Pathway Lectin binding to Mannose on pathogen surfaces Complement activation Recruitment of inflammatory cells (Chemotaxins) Opsonization Killing of pathogen

34. Biological activities of complement components C3b Opsonization Macrophage Bacteria Macrophage requires more time to phagocytize this number of bacteria

35. Biological activities of complement components C3b Opsonization Opsonin: to prepare for eating C3b C2b C4b C3bR Bacteria C3b act as opsonin which makes phagocytosis easier and faster

36. Biological activities of complement components MBL Opsonization Opsonization MBL act as opsonin

37. Complement pathways activation Mannan Binding Lectin Pathway Classical Pathway Alternative Pathway Lectin binding to Mannose on pathogen surfaces Complement activation Recruitment of inflammatory cells (Chemotaxins) Opsonization Anaphylatoxins Killing of pathogen

38. Biological activities of complement components Anaphylatoxins C3a, C4a, C5a

39. Diseases associated with complement system IgA nephropathy (Berger disease) Polymerization Deposition in the glomerular mesangium Patient with respiratory tract infection

40. Diseases associated with complement system Henoch-Schönlein purpura (HSP) HSP is a small-vessel vasculitis in which complexes of IgA and complement component are deposited on arterioles, capillaries, and venules. HSP involves the skin and connective tissues, scrotum, joints, gastrointestinal tract and kidneys

41. Diseases associated with complement system Angioedema C1 esterase C2a C4a C3a C5a Massive stimulation of mast cells and histamine releasing leading to generalized edema C2a X C4a C3a C5a C2a C4a C3a C5a C4b C3b C5b C6 C2b C7 C8 C9

42. Diseases associated with complement system Angioedema

43. Diseases associated with complement system Paroxysmal Nocturnal Hemoglobinuria (PNH) C4b C3b C5bC6C7 C9 Body cell Body cell Glycosylphosphatidylinositol (GPI)

44. Upon the completion of this lecture you should know the followings: • The definition of complement system? • The three pathways that activate the complement system? • Why complement system is activated? • The advantages of complement activation? • The processes of complement in eliciting inflammatory response, lyses foreign cells, and phagocytosis? • The disorders associated complement system Objectives