Complement system

Complement system

1. THE COMPLEMENT SYSTEM (INNATE IMMUNITY) PRESENTED BY DR.VAMSHIKRISHNA, MD (H)

2. What is complement system? Complement system consists of series of proteins which complement or augment the function of Antibodies and other cells of innate immunity like Macrophages. The complement system can be brought into action by antibodies generated by the adaptive immune system.

3. Antibodies formed in Adaptive immunity

4. Source for complement proteins. Liver cells- more than twenty complement proteins (C1,C2 etc…) They are produced in liver and are released into circulatory system as inactive complement proteins.

5. Other sources for complement proteins productions: Macrophages, Complement Protein 1 – C1- produced by GIT mucosa.

6. Function of Complement Proteins. It is part of the  innate immune system (Humoral Immunity). They Complement the immune system and the inflammatory function .

7. Complement Pathways 1- THE CLASSICAL PATHWAY 2- THE ALTERNATIVE PATHWAY

8. THE CLASSICAL PATHWAY The classical pathway is initiated by: Antibodies ( IgM or IgG ) binding to the Pathogen. C1 binding to the Fc portion of Antibody

9. The C1 is a complex protein made of q,r,s molecules. C1 C1q C1r C1s

10. When C1q molecule binds to antibodies, its C1rs molecules splits C4 and then C2, producing C4a, C4b, C2a, and C2b. C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b. C3b later joins with C4b2b to make C5 convertase (C4b2b3b complex).

11. The C5 convertase enzyme then cleaves C5 to C5a, a potent anaphylatoxin, and C5b. The C5b then recruits and assembles C6, C7, C8 and multiple C9 molecules to assemble the  Membrane Attack Complex (MAC) . This MAC creates a hole or pore in the membrane that can kill or damage the pathogen or cell.

12. C1 C4b C4a C2b C2a C3b C3a  C3-convertase (C4b2b complex) C5-Convertase (C4b2b3b complex) C5b C5a C9 C8 C7 C6 Fc portion of Antibody Antigen C1q molecule binding to antibodies Fc portion

13. C5b C9 C8 C7 C6 C9c C9 C9 C9 C9 MEMBRANE ATTACK COMPLEX MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes osmotic  lysis of the target cell. Macrophage cell types help clear complement-coated pathogens.

14. THE ALTERNATIVE PATHWAY The alternative pathway does not rely on pathogen-binding antibodies like the classical pathway.  In alternative pathway the C3 molecule directly binds to the antigen of the pathogen and it cleaves to C3b and C3a. The surface-bound C3b may now bind  factor B  to form C3bB. This complex will be cleaved into Ba and Bb. Bb will remain associated with C3b to form C3bBb, which is the alternative pathway C3 convertase

15. Once the alternative C3 convertase enzyme is formed on a pathogen or cell surface, it may bind covalently another C3b, to form C3bBbC3b, the C5 convertase .  This enzyme then cleaves C5 to C5a, a potent anaphylatoxin, and C5b. The C5b then recruits and assembles C6, C7, C8 and multiple C9 molecules to assemble the  Membrane attack complex (MAC). This creates a hole or pore in the membrane that can kill or damage the pathogen or cell.

16. C3b C3a Factor Bb Ba C3 convertase (C3bBb complex) C3b C3a C3bBbC3b (C5 convertase ) C5b C5a C9 C8 C7 C6

17. C5b C9 C8 C7 C6 C9c C9 C9 C9 C9 MEMBRANE ATTACK COMPLEX MEMBRANE ATTACK COMPLEX FORMATION IS COMMON IN BOTH PATHWAYS AND THIS LATE STAGE OF FORMATION OF MAC IS CALLED AS COMMON FINAL PATHWAY

18. ACTIVATION PATHWAY CLASSIC ALTERNATIVE ACTIVATOR Antigen–Antibody Complex spontaneous hydrolysis of C3 C3-CONVERTASE C4b2b C3bBb C5-CONVERTASE C4b2b3b C3bBbC3b MAC C5b+C6+C7+C8+C9

19. The complement system has the potential to be extremely damaging to host tissues, meaning its activation must be tightly regulated. The complement system is regulated by  complement control proteins, which are present at a higher concentration in the blood plasma than the complement proteins themselves. REGULATION

20. Some complement control proteins are present on the membranes of self-cells preventing them from being targeted by complement. One example is  CD59 , also known as protectin , which inhibits C9 polymerisation during the formation of the  membrane attack complex . The classical pathway is inhibited by  C1-inhibitor , which binds to C1 to prevent its activation. C3-convertase can be inhibited by  Decay accelerating factor  (DAF).

21. PATHOLOGY OF COMPLEMENT SYSTEM Complement deficiency: Asthma Systemic lupus erythematosus Glomerulonephritis Inflammatory bowel disease Rejection of transplanted organs. Autoimmune disorders.

22. Deficiencies of the terminal pathway predispose to: Autoimmune and infections  (particularly  Neisseria meningitidis , due to the role that the  membrane attack complex  ("MAC") plays in attacking  Gram-negative  bacteria). Infections with  N. meningitidis  and  N. gonorrhoeae  are the only conditions known to be associated with deficiencies in the MAC components of complement. People with MAC deficiencies experience recurrent infections with  N. meningitidis .