COMPLEMENT of the world together SYSTEM.pptx

Role

1. ROLE OF COMPLEMENT IN HEALTH AND DISEASE PRESENTED BY : Dr. Namrata Girhe MODERATOR: Dr. Snehal Dawane

2. INDEX

3. DEFINATION The term complements refers to set of serum proteins that cooperates with both innate and adaptive immune system to eliminate blood and tissue pathogen. Research on complement began in the 1890’s when Jules bordet at the Institute Pasteur in Paris showed that sheep antiserum to the bacterium Vibrio cholerae cause membrane destruction of bacteria and he called it Alexin . The term ‘ complement’ coined by Paul Ehrlich . Complement synthesize mostly by liver (hepatocytes) also by blood monocytes, tissue macrophages, fibroblast and epithelial cells of GIT and GUT. They constitute about 5% of normal serum proteins and their level does not increase following either infection or vaccination

4. GENERAL PROPERTIES Bind to Fc region of antibody (also called as fixing or consumption) Role of antigen (complements only fix to those antibodies which are bound by antigen , it do not bind to free antibodies) Species non specific ( present in all mammals, birds, amphibians and fish and can cross reacts amongs each other) Heat labile ( gets denatured by heating at 56 degree Celsius for 30 min.)

5. FUNCTIONAL CATEGORIES

6. COMPLEMENT PATHWAYS CLASSICAL PATHWAY : Antibody dependant pathway ,it triggered by antigen antibody complex formation. ALTERNATIVE PATHWAY : This is an antibody independent pathways , triggered by antigen directly. LECTIN PATHWAY : Also antibody independent but resembles classical pathway.

7. Stages of compliment activation Intiation of pathway Formation of C3 convertase Formation of C5 convertase Formation of membrane attack complex (MAC)

8. CLASSICAL PATHAWAY First binding portion of C1 is C1q, which reacts with the Fc portion of the antibody IgM OR IgG which is already bound to antigen C1q is hexamer , having 6 globular heads. Intiation begins only when C1q attaches Fc portion of antibody by atleast 2 of its globular binding site. hence only one IgM antibody can activate classical pathway because it’s a pentamer where as 2 IgG antibodies require for initiation at it is monomeric Intiation of pathway

9. Electron micrograph of C1q

10. THIS IS ELECTRON MICROGRAPH OF IgM PENTAMERIC ANTOBODY PLANER FORM STAPLE FORM

11. Formation of C3 convertase C1s acts as esterase (C1s esterase) which cleaves C4 to form C4a (anaphylatoxin) and C4b C4b in presence of magnesium ions cleaves C2 intoC2a and C2b (has kinin like activity) C14b2a is referred as C3 convertase

12. Formation of C5 convertase C3 convertase hydrolyses many C3 molecule into C3b and C3a. C3a acts as anaphylatoxin. C3b combines with C14b2a to form C14b2a3b which acts as C5 convertase.

13. Formation of membrane attack complex (MAC) C5 convertase cleave C5 into C5a (an anaphylatoxin) and C5b. C5b is extremely labile, gets stabilised by combining with C6 and C7 and forms C5b67 which then combine with C8. C5b6789 (membrane complex) has catalytic property which binds to C9 and then polymerises into a tubular channels of 10 nm diameter. Penetration of polyC9 into targets cell forms channels or pores.

14. This tubular channel behaves hydrophobic outside and hydrophilic inside leading to allow free passage of ions into cell leading to cellular swelling and lysis. This cytolysis called as complement mediated cytotoxicity.

15. Complement mediated cytotoxicity

16. ALTERNATIVE PATHWAY This is independent of antibody It is consider as part of innate immunity Unlike classical pathway ,components C1,C4,C2 are not involved instead it requires factor B, factor D, and properdin INITIATION OF ALTERNATIVE PATHWAY First, free C3 in serum is hydrolyses to generate C3a which diffuses out , C3b fragment attaches to foreign cell surface antigen

17. INITIATORS OF ALTERNATIVE PATHWAY

18. FORMATION OF C3 CONVERTASE Factor B binds C3b coated foreign cells. Factor D acts on factor B and cleaves it into Ba (diffuses out) and Bb(remains attached) C3bBb is C3 convertase of alternative pathway. This C3 convertase has short half life (5 min) hence it combines with another complement protein called properdin which increase its half life to 30 min. Remaining 2 steps , formation of C5 convertase and Membrane attack complex (MAC) is same as classical pathway.

19. ALTERNATIVE TICK OVER PATHWAY :

20. ALTERNATIVE PROPERDIN ACTIVATED PATHWAY ALTERNATIVE PROTEASE ACTIVATED PATHWAY THROMBIN BLOOD PLATELETS

21. LECTIN PATHWAY Its works independent of antibody. Part of innate immunity. Lectin pathway involves all complement components which are involved in classical pathway except C1. Instead of C1, host lectin protein called mannose binding lectin mediate initiation for lectin pathway.

22. Initiation of lectin pathway MBL acts as C1q. MBL associated serine proteases (MASP) acts as C1r ,C1s and mimic their function. Remaining steps are same as classical pathway.

23. EFFECTOR FUNCTION OF COMPLEMENT Target cell lysis by MAC Inflammatory response Opsonization Removing the immune complexes from blood Viral neutralization (lectin and alternative pathway)

24. COMPLEMENT RECEPTOR

25. REGULATION OF COMPLEMENT PATHWAYS

26. COMPLEMENT DEFICIENCIES MECHANISM EXAMPLES SHOWN BY GNB Long polysaccharide side chain of bacteria can prevent membrane attack complex insertion Escherichia coli, salmonella Noncovalent interaction between bacterial cell wall components can prevent MAC insertion Neisseria gonorrhoeae Elastases destroy C3a and C5a peusdomonas SHOWN BY GPC Thick peptidoglycan cell wall prevents MAC insertion Staphylococcus streptococcus Bacterial capsule forms a physical barrier between C3b and CR1 interaction Streptococcus pneumoniae SHOWN BY OTHER MICROBES Protein mimicking complement regulatory proteins Vaccinia virus Herpes simplex virus Epstein bar virus Trypanosoma cruzi , Candia albicans

27. COMPLEMENT DEFICIENCIES PATHWAY INVOLVED DISEASE /PATHOLOGY COMPLEMENT PROTEIN DEFICIENCIES C1,C2,C3,C4 C1,C2,C4 =classical pathway C3= common deficiency Systemic lupus erythematosus (SLE), Glomerulonephritis and pyogenic infection PROPERDIN ,FACTOR D Alternative pathway Neisseria and pyogenic infection MEMBRANE ATTACK COMPLEX (C5-C9) Common deficiency Disseminated Neisseria infection COMPLEMENT REGULATORY PROTEIN DEFICIENCIES C1 esterase inhibitor Overactive classical pathway Hereditary angioneurotic edema DAF( Decay accelerating factor) and CD59 Deregulated C3 convertase increased RBC lysis PNH (paroxysmal nocturnal hemoglobinuria )

28. REFERENCES IMMUNOLOGY BY KUBY (8 TH EDITION) ESSENTIALS OF MEDICAL MICROBIOLOGY BY DR. APURBA S SASTRY (3 RD EDITION) TEXTBOOK OF MICROBIOLOGY BY ANANTHANARAYANAN AND PANIKER