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 C9C8 C7 C6 C9 c C9 C 9 C 9 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.
- 15. 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
- 16. • 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.
- 17. C3b C3a Factor Bb Ba C3 convertase (C3bBb complex) C3b C3a C3bBbC3b (C5 convertase) C5b C5a C9 C8 C7 C6
- 18. C5b C9C8 C7 C6 C9 c C9 C 9 C 9 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
- 19. 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
- 20. • 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
- 21. • 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).
- 22. PATHOLOGY OF COMPLEMENT SYSTEM Complement deficiency: • Asthma • Systemic lupus erythematosus • Glomerulonephritis • Inflammatory bowel disease • Rejection of transplanted organs. • Autoimmune disorders.
- 23. • 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.