Elainne Kesuma (1-4206-005) Harvianto Siman Santosa (1-4206-033) COMPLEMENT SYSTEM Elainne Kesuma (1-4206-005) Harvianto Siman Santosa (1-4206-033) Photo Courtesy: Widhi Nugraha Sutedjo

COMPLEMENT SYSTEM Series of Protein which amplify response function of body toward infection, through innate and adaptive immunity The term complement define the ability of those protein to complement or combine the effects of several types of component of immune system (e.g. antibody)

Influence of Complement System Lysis (bacteria and tumor cells) Produce mediator for inflammation and promotes phagocytosis Enhance immune response which mediated by antibody Complement protein is synthesized by liver and phagocytic cell

Complement Activation Some of the complement components are proenzyme, which are needed to be broken down to form active enzyme The component of complement is named C1-C9 The activation can be done either by antigen-antibody complex or non-immune molecule

Complement Activation Classical Pathway Use IgM n IgG (class of immunoglobulin) The classical pathway of complement activation begins when C1 is cleaved due to interactions with Fc regions of IgM or IgG complexed with antigen. The cascade continues as C2 and C4 are cleaved, yielding a new protease complex with cleaves C3 to yield C5 convertase.

The classical pathway is triggered by activation of the C1-complex (C1q, two molecules of C1r, and two molecules of C1s thus forming C1qr2s2), which occurs when C1q binds to IgM or IgG complexed with antigens (a single IgM can initiate the pathway, while multiple IgGs are needed), or when C1q binds directly to the surface of the pathogen. Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two C1r (a serine protease) molecules. They then cleave C1s (another serine protease). The C1r2s2 component now 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 (the C3 convertase) to make C5 convertase (C4b2b3b complex).

Complement Activation Alternative Pathway Use chemical complex (endotoxin) and infection agent ( parasite) C1 is not involved Microbial surfaces directly activate the conversion of C3, which is completed through the interaction of Factor D with its substrate Factor B. Once the C3 convertase is formed (as C3bBb) the addition of an additional C3b molecule will result in formation of the C5 convertase. This will result in conversion of the C5-9 MAC.

The alternative pathway is triggered by spontaneous C3 hydrolysis directly due to the breakdown of the thioester bond via condensation reaction (C3 is mildly unstable in aqueous environment) to form C3a and C3b. It does not rely on a pathogen-binding antibodies like the other pathways. C3b is then capable of covalently binding to a pathogenic membrane surface if it is near enough. If there is no pathogen in the blood, the C3a and C3b protein fragments will be deactivated by rejoining with each other. Upon binding with a cellular membrane C3b is bound by factor B to form C3bB. This complex in presence of factor D will be cleaved into Ba and Bb. Bb will remain covalently bonded to C3b to form C3bBb which is the alternative pathway C3-convertase. The protein C3 is produced in the liver. The C3bBb complex, which is "hooked" onto the surface of the pathogen, will then act like a "chain saw," catalyzing the hydrolysis of C3 in the blood into C3a and C3b, which positively affects the number of C3bBb hooked onto a pathogen. After hydrolysis of C3, C3b complexes to become C3bBbC3b, which cleaves C5 into C5a and C5b. C5b with C6, C7, C8, and C9 (C5b6789) complex to form the membrane attack complex, also known as MAC, which is inserted into the cell membrane, "punches a hole," and initiates cells lysis. C5a and C3a are known to trigger mast cell degranulation. IgA is associated with activating the alternative path.

Complement Activation Lectin MB MBL ( Mannan Binding Lectin)/Mannose-binding lectin) Activated when there is no antibody present

The lectin pathway is homologous to the classical pathway, but with the opsonin, mannose-binding lectin (MBL), and ficolins, instead of C1q. This pathway is activated by binding mannose-binding lectin to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, MASP-1, and MASP-2 (very similar to C1r and C1s, respectively),which can then split C4 into C4a and C4b and C2 into C2a and C2b. C4b and C2a then bind together to form the C3-convertase, as in the classical pathway.

Biological effect of Complement System Opsonins : C3b binds to the surface of pathogens leading to greater internalization by phagocytic cells Chemotactic: stimulate neutrophil movement Anaphylatoxins: C3a C4a and C5a triggering degranulation of mast cells as well as increasing vascular permeability and smooth muscle contraction Cytolysis : Insertion of C5b6789 complex to the cell surface which caused lysis of bacteria, erythrocyte, and tumor cell

Deficiency of Complement Frail to infectious disease C2 deficiency = pyogenic bacteria infection Alternative pathway component deficiency (properdin) = frail to meningococcus

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