Complement system

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1. Complement system Dr . Mahendra Swamy MBBS, MD(Microbiology)

2. - Introduction - Complement components - General properties - Complement cascade/pathway - Biological effects - Evasion of Complement system - Complement deficiencies

3. Introduction The term "complement" was coined by Paul Ehrlich. Complements complement the action of Antibodies. They are group of proteins present in plasma. They constitute 5% of overall plasma proteins. They are present in inactive form. Activated by a ntigen-antibody reaction.

4. During activation, some complement components are split into two parts. The larger part of the molecule called "b" while the smaller fragment called "a" may diffuse away. In most cases it is the "b" fragment binds to the surface of the cell to be lysed. Activation of complement results in the production of several biologically active molecules, which contribute to nonspecific immunity and inflammation . Their levels are estimated in unexplained inflammation/edema, autoimmune diseases.

5. Complement components Consist of 30 distinct serum proteins. P roduced by hepatocytes, macrophages and intestinal epithelial cells . Complement proteins are zymogens ( proenzymes ). When activated, they become proteases & activate other c omplement proteins. Reaction goes on in a cascade manner. Their levels do not increase following infection.

6. General properties Their levels do not increase following infection/immunization. They are heat labile. They cause lysis of cells (Cytolysis) They bind only to the immune-complexes & not to free antibodies. They are species nonspecific. They bind to the Fc portion of antibodies.

7. Complement cascade/pathway Three pathways: Classical pathway : Antibody dependent pathway: Triggered by Immune complexes. It involves all components from C1 to C9. Alternate pathway : Antibody independent pathway: Triggered by Antigen alone. Initiators of Alternate pathway are: Lipopolysaccharide from gram negative bacilli, fungal cells, virus infected cells, tumor cells, cobra venom factor etc. It involves all components except C1, C2 & C4. It involves two other important factors like factor B & factor D.

8. Lectin pathway : Antibody independent pathway. It is mediated through interaction of lectin proteins of host with mannose residue present on microbial surface. It involves all components except C1. Stages of complement activation : Initiation of pathway Formation of C3 convertase Formation of C5 convertase Formation of Membrane attack complex (MAC)

9. C3a, C4a, C5a are Anaphylatoxins C5b-C9 complex is Membrane attack complex (MAC) MAC - Forms pores on the cell membranes of organisms leading to free passage of ions & water into cell, thus there is cell swelling & cell lysis .

10. Biological effects/Functions of Complements Phagocytosis : Complements bind to their receptors on Phagocytes & facilitate uptake & destruction of pathogens by Phagocytes. Cell lysis : MAC makes pores on the surface of cells and lead to cell lysis . Inflammatory response : Complements released during cascade like C3a , C4a, C5a are anaphylatoxins which cause Mast cell degranulation which bring about inflammatory response. Opsonization : C3b & C4b are the major opsonins that bind to immune complexes & enhance their phagocytosis.

11. 5 . Hypersensitivity reaction : Complements participate in both type 2 HST (Transfusion reaction) & type 3 HST reactions (Serum sickness/ Arthus reaction). 6. Play role in autoimmune diseases like autoimmune hemolytic anaemia . 7. Play role in Endotoxin mediated shock : Endotoxin mediated C3 fixation & Platelet adherence leading to DIC (Disseminated Intravascular Coagulation). 8. Chemotaxis : Movement of phagocytic cells towards bacterial cells with the help of C5a . 9. Immune clearnace : C3b bind to immune complexes and they are then removed from blood in liver/spleen. 10. Neutralization of Viruses : Complements neutralize viruses by lysis of viruses/ opsonization of viruses/blocking their attachment sites.

12. Evasion of Complement system Mechanism of Evasion Examples Lipopolysaccharide side chains prevent insertion of MAC E coli MAC fails to enter bacterial membrane Neisseria gonorrhoea Elastases inactivate C3a & C5a Pseudomonas Thick cell wall prevent insertion of MAC Staphylococcus/ Streptococcus Bacterial capsule provides extra physical barrier Streptococcus pneumoniae Proeins mimicking complement regulator proteins Vaccinia virus, EB virus, Herpes simplex virus etc

13. Complement deficiencies & associated syndromes Deficiency Syndrome C1 inhibitor Hereditary angioneurotic edema C1, C2, C4 SLE & other collagen vascular diseases C3 & its regulator proteins Recurrent pyogenic infections C5-C9 Disseminated Neisseria infections

14. Thank you