BIOLOGICAL EFFECTS OF COMPLEMENT

The complement system is one of the most important humoral systems mediating many reactivities that contribute to host defence and initiating and amplifying inflammation, even in the preimmune phase where specific antibodies and lymphocytes are not available. Therefore it is not surprising that the complement cascades can be initiated by multiple ways in addition to antibody-antigen reactions. Activation of the complement cascade leads to the fragmentation of C3, C4 and C5 into low-molecular-weight hormone-like peptides, C3a, C4a, and C5a (111).

ANAPHYLATOXINS - Peptides derived from C3, C4 and C5

Anaphylatoxins are low-molecular weight, biologically active peptides that are defined functionally by their actions on small blood vessels, smooth muscle, mast cells, and peripheral blood leukocytes (111). Several laboratory studies have been carried out to establish, conclusively, that low-molecular-weight peptides with anaphylatoxin activity can be generated enzymatically from C3, C4, and C5 (i.e., C3a, C4a, and C5a, respectively) (112 114). Analyses of the complete amino acid sequences of C3a, C4a, and C5a from man and from a variety of animal species have revealed striking similarities among these peptides, suggesting a common evolutionary origin. C3a was the first anaphylatoxin to have its complete primary structure elucidated (115). C4a has a pentapeptide structure, and contracts smooth muscle, although it is approximately 500-fold less active in this respect than the C3a pentapeptide (116). C5a functions also as a chemoattractant, inducing the migration of leukocytes into an area of complement activation. These molecules induce smooth muscle contraction and enhance vascular permeability. They bind to specific receptors and induce the release of vasoactive amines such as histamine from mast cells and basophils, and lysosomal enzyme release from granulocytes (particularly C3a and C5a) (117,118).

The activities of the anaphylatoxins, C3a and C5a, are abolished by anaphylatoxin inactivator (AI), which removes the carboxyl-terminal arginine from both molecules yielding C3a des Arg and C5a des Arg, respectively (119). The anaphylatoxin inactivator simply functions as a regulator of anaphylatoxin activity. The physical and/or the chemical properties that render human C3a and C5a so susceptible to the action of the anaphylatoxin inactivator are unknown.

In addition to stimulating effector functions of neutrophils and monocytes, human anaphylatoxins exhibit immunoregulatory activities. When added to lymphocytes and macrophages in vitro, C3a, C5a, and C5a des Arg can influence both humoral and cell mediated immune responses (120) . Human C3a, for example, but not C3a des Arg, suppresses antigen-specific as well as polyclonal antibody responses of both mouse spleen cells and human peripheral blood leukocytes. Similar effects have been observed in experiments using synthetic peptides corresponding to the carboxyl-terminal portion of human C3a (121), and they have been attributed either to C3a-mediated generation of suppressor T-lymphocytes ( 122), or to C3a-mediated generation of a prostaglandin by mononuclear leukocytes ( 123) . Synthetic peptides corresponding to the carboxyl-terminal portion of human C3a also have been found capable of inhibiting human T-lymphocyte migration and generation of lymphokines (124). Human C5a and C5a des Arg, on the other hand, have been found capable of augmenting antigen-specific as well as non-specific humoral immune responses of both mouse spleen cells and human peripheral blood leukocytes (125 127). Human C5a and C5a des Arg also potentiate antigen- and alloantigen-induced human T lymphocyte proliferative responses as well as human T-lymphocyte-mediated cytotoxic reactions. Although helper T-cells are required for C5a-mediated potentiation of polyclonal antibody responses, C5a may not act directly on lymphocytes. Rather, evidence has been presented that C5a enhances humoral immune reactions in vitro by binding to macrophages and, possibly, by stimulating production of interleukin-1 (128).

OTHER COMPLEMENT COMPONENTS

The high-molecular-weight fragments of C3 and C4, C3b and C4b, bound to membranes of cells or bacteria are recognised by various cells having receptors for C3b or C4b, such as phagocytic cells (macrophages, monocytes, and polymorphonuclear leukocytes), B lymphocytes, neutrophils, erythrocytes, and platelets (129). Therefore, C3b and C4b molecules serve as a bridge between a complex or target cell bearing C3b or C4b and the responding cell having a receptor for C3b or C4b. The consequences of C3b- or C4b mediated bridging depend on the responding cell type; binding to phagocytic cells causes opsonin-like activity and, therefore, triggers phagocytosis. Adherence to nonprimate platelets induces specific release of vasoactive amines and nucleotides from the platelet. Since B lymphocytes have receptors for C3b and C4b, it is postulated that bridging brings antigens in direct contact with antibody-forming cells and that, therefore, bound complement components may play a role in the induction of an immune response (130).

Induced by the activation of both complement pathways, the formation of the multimolecular C5b-9 complex on a cell membrane results in an impairment of osmotic regulation which may cause cytolysis. This hydrophobic C5b-9 complex is incorporated into the lipid bilayer of the membrane leading to the formation of a transmembrane channel allowing bidirectional flow of ions and macromolecules, and initiating osmotic lysis of the cell. It should be noted that stable complexes of C5b, C6, and C7 can bind non-specifically to cell membranes and, together with C8 and C9, provoke lysis. Such "reactive lysis" or "bystander lysis" can account for injury to cells not recognised by specific antibodies (131). As well as having various lytic activities, the MAC also has other nonlytic effects including stimulation of interleukin-1 production by glomerular mesangial cells (132), stimulation of platelet procoagulant activity (133), and stimulation of endothelial cells to secrete von Willebrand factor and to express the adhesion promoting protein, GMP-140 (134). The MAC may also facilitate cell-cell and cell substrate adhesion (135). Complement-mediated lysis has been shown for many kinds of cells: erythrocytes, platelets, bacteria, viruses possessing a lipoprotein envelope, and lymphocytes.

The biological importance of the complement system for the maintenance of a functional host defence is impressively illustrated by the markedly increased susceptibility to infection and the predisposition to diseases observed in some congenital or acquired deficiencies of complement components or complement regulatory proteins.