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The complement system consists of a group of proteins that circulate in the blood and are part of the innate immune response. These proteins are heat-labile. They were discovered as a batericidal component. These proteins have enzymatic activity. The can be activated in three different ways. termed the classic pathway, the alternative pathway and the lectin pathway.  

Classical pathway.  This pathway  starts with the activation of complement complex 1 (C1).  The C1 complex is formed by one molecule of the protein C1q  bound to two proteins of C1r and two of C1s.  Antibody-antigen complexes can activate the C1 complex. Conformational change of C1 by the antigen-antibody complex binding result in the activation of the serine protease C1r which, in turn, cleave C1s.  C1s is also a serine protease.  When activated, the C1 complex enzymatic complex is capable of cleaving C2 and C4.  The cleavage products C4b and C2a form a complex C4b2a  (also called the C3 convertase) which cleaves C3 into C3a and C3b. C3b in turn forms a complex with C4b2a to form another complex called the C5 convertase (or C4b2a3b complex).  

Alternative pathway.  This pathway starts with the spontaneous cleavage of a thioester bond in C3 which in turn forms C3a and C3b.   This allows C3b to bind covalently to the membranes of pathogens if present in close proximity.  Otherwise it can recombine with C3a.  Alternatively C3b can bind factor B  and form C3bB.  Factor B can be cleaved by factor D into Ba and Bb.   The complex C3bBb is the alternative pathway C3-convertase. From this point on a complex C3bBbC3b cleaves C5 into C5a and C5b and, in turn, C5b forms a complex with C6, C7, C8 and C9 (C5b6789) that forms the membrane attack complex (MAC), which forms a pore in the cell membrane.

Lectin pathway: In this pathway mannose binding lectin (MBL) (a protein with structural similarities to C1q)activates the MBL-associated serine proteases, MASP-1, and MASP-2.  These proteases are similar to C1r and C1s.    This 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. Ficolins can also function as MBL and in combination with MASP activate the complement cascade.  


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