Previous: Introduction: Plasma cascade systems with emphasis on the role of C1-inhibitor

Introduction

Plasma cascade systems with emphasis on the role of C1-inhibitor

Complement system
The complement system was first described around the turn of the century as a cytolytic mechanism responsible for lysing bacteria or erythrocytes sensitised with antibody. The term complement was used since the cytolytic principle complemented the action of the antibody. Today more than 30 proteins are known to participate in the complement system. More than half are inhibitory proteins, which indicates the potency of this system. A full blown activation of complement is highly detrimental to the host and can occur in conditions where one or several inhibitory proteins are lacking (139). One example is the very recent discovery of a porcine factor H deficiency causing lethal glomerulonephritis (140,141), for which human analogues exists (142,143).

Fig. 5

The complement system acts to lyse susceptible cells, to opsonize and to promote phagocytosis of target particles, and to solubilize immune-complexes. Activation generates peptides, e.g. the anaphylatoxins, that mediate features of the inflammatory response by attracting neutrophils, releasing histamine, increasing capillary leakage and contracting smooth muscle. Complement is thus activated in autoimmune conditions, infections, trauma or when foreign materials like prostheses or a cardiopulmonary by-pass are introduced into the circulation or tissues (144). Activation is achieved by two independent routes with partially overlapping functions (145): the classical pathway, triggered mainly by immunoglobulins, and the alternative pathway, essentially initiated by cell membrane components. Both of them promote the generation of an enzyme-complex (C3 convertase) able to cleave the pivotal protein of the complement system, C3, thus initiating the common terminal pathway with the formation of a terminal complement complex (TCC) with inflammatory and lytic properties (144). (Fig. 6).

Fig. 6

The dichotomy of the early part of the complement system has recently been exploited therapeutically, as e.g. when infusing large doses of C1-INH concentrate to prevent acute rejection of transplanted organs or to hinder the complement mediated damage of ischemic heart muscle cells during reperfusion, as these events are mainly mediated through the classical pathway (146,147). The selective blocking of the classical pathway, leaves untouched the alternative pathway and the rest of the complement system, which are then capable of handling infection.

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