Overview The complement system is part of the innate immune system (vs adaptive) It is named “complement system” because it was first identified as a heat-labile component of serum that “complemented” antibodies in the killing of bacteria It is now known that it consists of over 30 proteins.

Biological function of complement system Ch. 7

“Classical” Pathway Begins with antibody binding to a cell surface and ends with the lysis of the cell The proteins in this pathway are named C1-C9 When complement is activated it is split into two parts a – smaller part B – larger part and usually the active part (except with factor 2)

“Classical Pathway” ACTIVATION C1q portion of C1 attaches to the Fc portion of an antibody Only IgG and IgM can activate complement Once activated C1s is eventually cleaved which activates C4 and C2 C4b & C2a come together to form the C4b2a which is the C3 convertase C3 convertase activates C3 to C3a and C3b

“Classical Pathway” ACTIVATION C3a binds to receptors on basophils and mast cells triggering them to release there vasoactive compounds (enhances vasodilation and vasopermeability) C3a is called an anaphylatoxin C3b serves as an opsonin which facilitates immune complex clearance C3b binds to C4bC2a to form the C5 convertase C4bC2aC3b C5 convertase cleaves C5 leading to the formation of the Membrane attack Complex (C5-C6-C7-C8-C9) The MAC “punches holes” in cell walls resulting in lysis

C3a binds to receptors on basophils and mast cells triggering them to release there vasoactive compounds (enhances vasodilation and vasopermeability) - ANAPHYLATOXIN C5a is a: Potent anaphylatoxin Chemoattractant for neutrophils C3 C1q C2 C4 C3a C5 C3b 2a 4a 4b 2b C5b C5a C5-Convertase C3-convertase C7 C8 C9 C6 Classical Pathway

“Alternative Pathway” Requires no specific recognition of antigen in order to cause activation ACTIVATION Spontaneous conversion from C3 to C3b occurs in body Normally, C3b is very short lived and quickly inactivated by proteins on the surface of the body’s own cell walls (DAF) However, bacteria or other foreign material may lack these surface proteins allowing C3b to bind and stay active

“Alternative Pathway” Factor B binds to C3b Factor B is then cleaved by factor D into Ba and Bb C3bBb remains which acts as a C3 convertase (C3  C3a and C3b) C3bBbC3b is formed which acts as a C5 convertase C5 is cleaved to C5a and C5b C5b then starts the assembly of the Membrane Attack Complex

Alternative Pathway D Bb B Ba C3a C3 C3b C3 Anaphylatoxin C5 C3-Convertase C5-Convertase C3a C3b C5b C5a D C7 B Bb Ba C8 C6 C9

MEMBRANE ATTACK COMPLEX C5-C9 MAC C9 C8 C7 C6 Bacterium Lysis C5a C5b C5 MBL MASP C4 C2 C4b2b C3 CONVERTASE C4b2b3b C5 CONVERTASE C4a C4b C2b C2a C3 “lectin Pathway” C3a C3b

Complement Regulation C1 inhibitor (C1INH) bind to and inactivate the serine protease activity of C1r, and C1s Factor I cleave C3b and C4b thereby reducing amount of C5 convertase available Factor H enhance activity of factor I on C3b As spontaneously produced C3b binds to autologous host membranes it interacts with DAF (decay accelerating factor), a membrane bound protein which can act to accelerate dissociation of C3 convertase of both pathways.

Summary - Activation Complement can be activated by the binding of antibody (Classical) or by the adherance of C3b to foreign material (Alternative) The two pathways converge at the formation of the C5 convertase (C4b2a3b or C3bBbC3b) The final common pathway is the formation of the membrane attack complex

Summary - Function Opsonization – C3b Chemotaxis – C5a (attracts neutrophils) Increases vasodilation & permeability of capillary beds via mast cell and basophil activation – C3a & C5a (Anaphylatoxins) Cellular Lysis via the MAC

Complement deficiencies and disease. Pathway/Component Disease Mechanism Classical Pathway C1INH Hereditary angioedema Overproduction of C2b (prokinin) C1, C2, C4 Predisposition to SLE Opsonization of immune complexes help keep them soluble, deficiency results in increased precipitation in tissues and inflammation Lectin Pathway MBL Susceptibility to bacterial infections in infants or immunosuppressed Inability to initiate the lectin pathway Alternative Pathway Factors B or D Susceptibility to pyogenic (pus-forming) bacterial infections Lack of sufficient opsonization of bacteria C3 Susceptibility to bacterial infections Lack of opsonization and inability to utilize the membrane attack pathway C5, C6, C7 C8, and C9 Susceptibility to Gram-negative infections Inability to attack the outer membrane of Gram-negative bacteria Properdin (X-linked) Susceptibility meningococcal meningitis Lack of opsonization of bacteria Factors H or I C3 deficiency and susceptibility to bacterial infections Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3