The physiological effects of complement 1 The inflammatory response

The cleaved peptides, C3a, C4a and C5a (anaphylatoxins) are functionally and structurally homologous (Greer, 1986). These can bind to specific receptors, C3a and C5a receptors (Lambris, 1988), to elicit a variety of cellular responses (Damerau, 1987; Rollins and Springer, 1985; Huey and Hugh, 1985; Johnson and Chenoweth, 1985). Signal transduction of the C5a receptor is mediated by a GTP-binding protein (G protein) (Siciliano et a l, 1990). The sequence of the C5a receptor (Boulay et al., 1991 ; Gerard and Gerard, 1991) has significant homology to other G protein coupled receptors (Boulay etal.,\99\). C5a is the most potent mediator of the inflammation response. This leads to chemotactic migration of neutrophilic granulocytes and monocytes, cell adhesion, enzyme release and the formation of arachidonic metabolites and active oxygen species. C3a and C5a can induce histamine release from mast cells and prostaglandins from macrophages, which have vasodilator activity and increase the efflux of macromolecules from the plasma. The C-terminal arginine of the anaphylatoxins has been found to be essential for activity. Control of the inflammatory response is mediated by the anaphylatoxin inactivator (carboxypeptidase N) which selectively removes this arginine (Bokisch and Müller-Eberhard, 1970; Plummer and Hurwitz, 1978).

1.6.2 Defence against infection

Complement can defend against infection, either in combination with antibodies, or independently of antibodies. C3b produced after alternative pathway activation binds to the surfaces of foreign cells. Since many host phagocytic cells have receptors for C3b (Fearon and Wong, 1983), these are brought into close contact with the foreign organism. This opsonizes the bacterium and encourages endocytosis by polymorphonuclear leukocytes and monocytes. The Fc, CRl and CR3 receptors on the phagocytes recognize the Fc portion on the antibody, C3b and iC3b respectively (Micklem and Sim, 1984; Gresham and Volanakis,

1986). If the amount of antibody attached via the Fc receptor is high enough, phagocytosis of the immune complex will commence. If there is insufficient antibody present, activation of the complement cascade may occur. This will increase efficiency of the binding of phagocytes

due to the deposition of C3b on foreign cell surfaces. It is generally considered that opsonization is more important than lysis in defence against infections.

1.6.3 Involvement in other systems

The complement cascade does not function in isolation, but also affects both the kallikrein/kinin and the coagulation/fibrinolysis systems (Kalter etal, 1985; Ziccardi, 1983). Activated factor XU (Hageman factor) splits prekallikrein to kallikrein and plasminogen to plasmin, and all these enzymes are able to cleave CT and initiate the complement cascade. Kallikrein and plasmin both cleave C3, and plasmin can cleave factor B. C lq can bind to fibrinogen and fibrin to localize C1 q at the site of a wound to provide efficient opsonization (Entwhistle and Furcht, 1988). Control over the three systems is exerted by CT inhibitor which is active against CTr and CTs, factor XU, plasmin and kinin-generating kallikrein, and also by carboxypeptidase N which inactivates C3a, C5a and kinin by splitting off the terminal arginine. Although protein S is a vitamin K dependent cofactor in the coagulation system (Comp et al, 1984), it also can form a complex with the complement protein C4bp (Hessing, 1991), although it does not affect the function of C4bp as a regulator of the C3 convertase (Dahlback et a l, 1983).

1.6.4 The role of complement in disease

Although some deficiencies of complement components have no obvious deleterious effects, many produce considerable morbidity and mortality. The analysis of disorders involving deficiencies in the complement cascade can highlight the functions of the components concerned. Most commonly, deficiencies in the components of the classical pathway proteins are identified in patients with symptoms resembling systemic lupus erythematosus (SLE) (Morgan and Walport, 1991), leading to the conclusion that perhaps a major role of complement in vivo is in the prevention of immune-complex disease (Lachmann, 1990). In addition to this, manifestations of renal disease, arthritis, Reynaud’s phenomenon and mucosal lesions are observed in individuals with deficiencies of the classical pathway components.

characterised by swelling of the mucous membranes. This is due to the increased activity of C4, C2 and kallikrein to produce the anaphylatoxin C4a, C2-kinin fragment and bradykinin. These fragments increase vascular permeability and hence oedema (Mollnes and Lachmann,

1988).

Factor D deficiencies are associated with recurrent bacterial infections (Kluin- Nelemans et al., 1984). Properdin deficiencies are inherited as an X-linked trait and lead to Neisseria infections in affected males (Nusinow et al., 1985). C3 deficiencies are characterized by recurrent pyrogenic infections, thus confirming the essential role that C3 plays in opsonizing bacteria for removal by phagocytic cells (Alper et al., 1972; Berger et al.,

1983). Deficiency in factor I causes an unrestricted amplification of the alternative pathway which depletes factor B and C3 (Nusinow etal., 1985). Factor H deficiencies have the same characteristics as those for factor I (Thompson and Winterbom, 1981) due to the fact that factor H is an obligate cofactor for factor I.

Deficiencies in the terminal pathway are linked with a susceptibility to recurrent infections by the bacterium Neisseria. Such infections are rare in Europe and the U.S.A. but relatively common in developing countries (Orren et al., 1987; Schlesinger et al., 1990). Deficiencies of the complement receptors CRl (Walport and Lachmann, 1988), CR2, CR3 and CR4 (Kishimoto et al., 1989) lead to a number of disease states, including immune- complex diseases, leukocyte adhesion and deficiency syndrome, hypertrophied gums and a tendency to have indolent staphylococcal skin infections. The lack of an inflammatory response is because the emigration of polymorphs and monocytes into the inflammatory region does not occur (Lachmann, 1990).

Patients with paroxysmal nocturnal haemoglobinuria (PNH) lack the ability to synthesize glycosylphosphatidylinositol (GPI) anchors which link a variety of host protection proteins to the cell membrane. These include DAF, HRF and CD59 (Table 1.2). This makes the cells highly susceptible to complement-mediated haemolysis (Lublin and Atkinson, 1989).

1.7 Domain structures and protein families in complement