Complement activation usually is initiated on a pathogen surface, and the activated complement fragments that are produced usually bind nearby on the pathogen surface or are rapidly inactivated by hydrolysis. Even so, all complement components are activated spontaneously at a low rate in plasma, and these activated complement components will sometimes bind proteins on host cells. Section 2-10 introduced the soluble host proteins factor I and factor H and the membrane-bound proteins MCP and DAF that regulate the alternative pathway of complement activation. In addition to these, several other soluble and membrane-bound complement-control proteins can regulate the complement cascade at various steps to protect normal host cells while allowing complement activation to proceed on pathogen surfaces (Fig. 2.36).
The activation of C1 is controlled by the C1 inhibitor (C1INH), which is a plasma serine protease inhibitor, or serpin. C1INH binds to the active enzymes C1r:C1s and causes them to dissociate from C1q, which remains bound to the pathogen (Fig. 2.37). In this way, C1INH limits the time during which active C1s is able to cleave C4 and C2. By the same means, C1INH limits the spontaneous activation of C1 in plasma. Its importance can be seen in the C1INH deficiency disease hereditary angioedema (HAE), in which chronic spontaneous complement activation leads to the production of excess cleaved fragments of C4 and C2. The large activated fragments from this cleavage, which normally combine to form the C3 convertase, do not damage host cells in such patients because C4b is rapidly inactivated by hydrolysis in plasma,
The complement system and innate immunity.
Fig. 2.37 Complement activation is regulated by a series of proteins that serve to protect host cells from accidental damage. These act on different stages of the complement cascade, dissociating complexes or catalyzing the enzymatic degradation of covalently bound complement proteins. Stages in the complement cascade are shown schematically down the left side of the figure, with the regulatory reactions on the right. The alternative-pathway C3 convertase is similarly regulated by DAF, CR1, MCP, and factor H.
and the convertase does not form. However, the small fragment of C2, C2b, is further cleaved into a peptide, the C2 kinin, that causes extensive swell-ing—the most dangerous being local swelling in the larynx that can lead to suffocation. Bradykinin, which has similar actions to those of C2 kinin, is also produced in an uncontrolled fashion in this disease, as a result of the lack of inhibition of kallikrein, another plasma protease and component of the kinin system (discussed in Section 3-3). Kallikrein is activated by tissue damage and is also regulated by C1INH. Hereditary angioedema is fully corrected by replacing C1INH. A similar, extremely rare human disease stems from a partial deficiency of carboxypeptidase N (CPN), a metalloproteinase that inactivates the anaphylatoxins C3a and C5a as well as bradykinin and kallikrein. Humans with partial CPN deficiency exhibit recurrent angioedema due to delayed inactivation of serum C3a and bradykinin.