Complement is a series of serum proteins involved in the immune response that help opsonize pathogens, attract phagocytes, and lyse bacteria and infected cells. It was discovered in 1894 and consists of around 30 circulating and membrane-bound proteins synthesized in the liver and by inflammatory cells. The classical, lectin, and alternative pathways activate different complement components through cleavage by C1, mannose-binding lectin, or spontaneous hydrolysis. Activated components have roles in opsonization, anaphylaxis, and membrane attack. Deficiencies increase risk for infections and autoimmune diseases depending on the pathway and component affected.

1. Complement

7. Activation product of complement proteins (nomenclature) When enzymatically cleaved, the larger moiety , binds to the activation complex or membrane and the smaller peptide is released in the microenvironment Letter “b” is usually added to the larger, membrane-binding, peptide and “a” to the smaller peptide ( e.g. , C3b/C3a, C4b/C4a, C5b/C5a), EXCEPT C2 (the larger, membrane-binding moiety is C2a; the smaller one is C2b) Activated component are usually over-lined: e.g. C1qrs

8. COMPLEMENT

9. Biological Activities of Classical Pathway Components Opsonin C4b Anaphylotoxin C4a Opsonin Activation of phagocytic cells C3b Anaphylotoxin; can activate basophils and mast cells to degranulate resulting in increased vascular permeability and contraction of smooth muscle cells, which may lead to anaphylaxis C3a Prokinin; cleaved by plasmin to yield kinin, which results in edema C2b Biological Activity Component

10. Biological properties of C-activation products Product Biological Effects Regulation anaphylactic as C3, but much more potent; attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release C5a ( chemotactic factor ) carboxy-peptidase-B (C3-INA) C5b67 protein-S chemotaxis, attaches to other membranes

11. Control of Classical Pathway Components C4 binding protein (C4-BP) and Factor I; C4-BP facilitates degradation of C4b by Factor I; C4-BP also prevents the association of C2a with C4b thus blocking formation of C3 convertase C4b C3a-INH C4a Factors H and I; Factor H facilitates the degradation of C3b by Factor I C3b C3a-inactivator C3a C1-inhibitor (C1-INH); dissociates C1r and C1s from C1q All Regulation Component

12. Biological effects of C5a

13. Overview of Complement-mediated Biological Effects

14. Biological Functions of Complement

15. Complement Deficiencies and Disease Classical Pathway Opsonization of immune complexes help keep them soluble, deficiency results in increased precipitation in tissues and inflammation Predisposition to SLE C1, C2, C4 Overproduction of C2b (prokinin) Hereditary Angioedema C1INH Mechanism Disease Pathway Component

16. Complement Deficiencies and Disease Lectin Pathway Inability to initiate lectin pathway Susceptibility to bacterial infections in infants or immunosuppressed MBL Mechanism Disease Pathway Component

17. Complement Deficiencies and Disease Alternative Pathway Inability to attack the outer membrane of Gram-negative bacteria Susceptibility to Gram-negative infections C5, C6, C7 C8, or C9 Lack of opsonization and inability to utilize the membrane attack pathway Susceptibility to bacterial infections C3 Lack of sufficient opsonization of bacteria Susceptibility to pyogenic (pus-forming) bacterial infections Factors B or D Mechanism Disease Pathway/Component

18. Complement Deficiencies and Disease Alternative Pathway cont. Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3 C3 deficiency and susceptibility to bacterial infections Factors H or I Lack of opsonization of bacteria Susceptibility meningococcal meningitis Properdin (X-linked) Mechanism Disease Pathway Component

19. Opsonization and phagocytosis

21. Enhancing B Cell Responses to Antigens

22. Removal of Immune Complexes

23. Removal of Necrotic cells and Subcellular Membranes

24. Responses to Viruses

26. Complement Fixation Assay (positive test)

27. Complement Fixation Assay (negative test)

28. The End