Intrinsic Regulation of Complement Activation

The rapid spontaneous decay of the multimolecular enzymes of each pathway that cleave C3 and C5 serves as the primary feature that prevents a complement activation event from amplifying uncontrollably (Table 1). Furthermore, several highly specific complement regulatory proteins exist that each inhibit portions of the complement activation cascades. In addition to limiting amplified complement activation, there seem to be three more functions served by these "control" proteins. One is to prevent continuous complement activation in plasma due to imperfect specificity. One is to protect cells against autologous complement attack arising from imperfect specificity. The final function is to allow leukocytes to function in a complement activation site without becoming damaged and for them simultaneously to derive information from the surrounding milieu.

C1 esterase inhibitor (C1-INH) inactivates the catalytic subunits of C1 and is the only known protein to have this function. Both subunits of C1 are serine proteinases, and C1-INH is a member of a larger class of related proteins whose function is to inhibit serine proteinases. C1-INH also can inhibit kallikrein and Hageman factor and has activity against factor XIIa. The inborn deficiency of this control protein serves as an example of uncontrolled complement activation in humans. This gives rise to hereditary angioneurotic edema, a disease characterized by sudden systemic complement activation via the classical pathway.

Factor I (C3b, C4b-inhibitor) produces complement inhibition by enzymatically degrading C3b and C4b, those forms of C3 and C4 that participate in generation of further complement activation, to inactive forms. Factor I requires a cofactor in this degradation reaction (factor H, membrane cofactor protein, C4-binding protein, or CR1) to bind to the C3b and C4b. Genetic deficiency of factor I produces clinical susceptibility to bacterial infection, as the natural rate of spontaneous C3b generation is much accelerated in the absence of factor I, leading to secondary critical depletion of C3 and factor B. Thus, this control protein, in analogy to C1-INH, also ensures that the proper specificity for complement activation is maintained, in this case for the alternative pathway, and that futile fluid-phase turnover is avoided.

Additional circulating proteins that down regulate complement are Factor H and C4 binding protein. Both serve to displace ligands from their targets of inhibition, Bb from

Table II Functions of Complement.

Via C3a, C4a, C5a

Attract leukocytes to site of complement activation

Activate leukocytes

Alterations in vascular smooth muscle

Endothelial activation

Mast cell activation

Via C5b-9

Cellular disruption Microbial killing Via C3

Covalent attachment of C3b "targeting label" to activator surface Molecular adjuvant for antibody formation and phagocytosis Clearance of immune complexes Via membrane complement receptors

Protection against autologous complement attack Mediation of molecular adjuvant roles Increased cell-cell adhesion

C3b in the case of H and C2a from C4b in the case of C4-binding protein. C3b and C4b then acquire susceptibility to factor I and are degraded.

A unique feature of complement activation is that the activation-dependent cleavage of C4, C3, and C5 generates their respective "b" fragments with a highly reactive thio-lester group. What molecules or surfaces fix these fragments is primarily determined by spatial availability. While the covalent bonding (other than to water) generally occurs on the activating surface, as a membrane-bound Ig-C1 complex lays down C4 and C3 around itself to generate C5 cleavage by the classical pathway, and as membrane-bound C3b serves as the scaffold for alternative pathway-dependent C3 and C5 cleavage. However, activated but unreacted C3b, C4b, and C5b fragments are available in solution very briefly, and thus can also bond to a nearby surface that was not the initial activator. This can give rise to assembly of C3 cleaving enzymes and MACs on the membranes of cells that are not directly involved in the complement activation, are not themselves complement activators, and are therefore to be damaged as innocent bystanders. As mentioned earlier, the spontaneous decay of the C3b,Bb and C4b,C2a complexes combined with the preferential interaction of C3b with factor H (and then factor I) on nonactivat-ing surfaces should prevent bystander injury to homologous tissue. However, this must be imperfect as a second class of complement control proteins exists to protect host cells from nearby complement activation reactions. These are, therefore, membrane proteins.

Decay accelerating factor (DAF, CD55) is expressed on the surface of essentially all cell types and accelerates the proteolytic activity of factor I on membrane-bound C4b and C3b. It has homology to the circulating proteins of similar function, C4bp and factor H, and prevents a membrane-bound C3b from becoming a nidus of assembly of a C3-cleaving enzyme. The disease, paroxysmal nocturnal hemoglobinuria, is complement mediated and is associated with absent erythrocyte membrane.

Membrane cofactor protein (CD46) has cofactor activity for factor-I-mediated degradation of C3b and is expressed by fibroblasts, epithelium, and endothelium. Transfection experiments into CHO cells as well as experiments with antibody directed against native MCP suggest that MCP preferentially protects against alternative pathway attack, with DAF filling the same role for the classical pathway.

The leukocyte and erythrocyte cell surface C3b receptor (CR1 or complement receptor type 1 or CD35) overlaps with these two proteins in its ability to capture and degrade C3b and C4b. CR1 can also block C1 interactions with antibody. CR1 has major additional important functions, as will be discussed later.

Cell surface proteins also exist that interfere with the assembly of a MAC (homologous restriction factor, pro-tectin, CD59, C8-binding protein). CD59 is expressed by endothelium, erythrocytes, leukocytes, and epithelium. CD59 has been found to be shed from cardiac myocytes in areas of ischemia, suggesting a mechanism of complement damage in ischemic tissue.

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