The Complement System

The complement system (C system, Fig. 1) represents a non-specific de­fense system against pathogens, but can also be directed toward specific tar­gets by antibodies. It is made up of a co-operative network of plasma proteins and cellular receptors, and is largely charged with the following tasks:

-Opsonization of infectious pathogens and other foreign substances, with the aim of more efficient pathogen elimination. Bound complement factors can: enhance the binding of microbes to phagocytozing cells; result in the activation of inflammatory cells; mediate chemotaxis; induce release of inflammatory mediators; direct bactericidal effects; and induce cell lysis.

Fig. 1 The classic activation pathway is initiated by antigen-antibody com­plexes, the alternative pathway by components of microbial pathogens. The pro­duction of a C3 convertase, which splits C3 into C3a and C3b, is common to both pathways. C3b combines with C3 convertase to generate C5 convertase. C5b, pro­duced by C5 convertase, binds to the complement factors 6-9 to form a mem­brane attack complex (MAC). C3b degradation products are recognized by recep­tors on B lymphocytes; they stimulate the production of antibodies as well as pathogen phagocytosis. The cleavage products C3a and C4a are chemotactic in their action, and stimulate expression of adhesion molecules.

Nomenclature: the components of the alternative pathway (or cascade) are desig­nated by capital letters (B, D, H, I; P for properdin), those of the classical pathway (or cascade) plus terminal lysis are designated by ”C” and an Arabic numeral (1-9). Component fragments are designated by small letters, whereby the first fragment to be split off (usually of low molecular weight) is termed ”a” (e.g., C3a), the re­maining (still bound) partis called ”b” (e.g., C3b), the next split-off piece ”c,” and so on. Molecules often group to form complexes; in their designations the indi­vidual components are lined up together and are usually topped by a line.

-Solubilization of otherwise insoluble antigen-antibody complexes.

-Promotion of the transport of immune complexes, and their elimination and degradation.

-Regulation of the immune response, achieved via their influence on antigen presentation and lymphocyte function.

Over 20 proteins of the complement system have been identified to date, and are classified as either activation or control proteins. These substances account for about 5% of the total plasma proteins (i.e., 3-4g/l). C3 is not only present in the largest amount, but also represents a central structure for complement activation. A clear difference exists between “classic" antibody-induced complement activation and “alternative” activation via C3 (Fig. 1).

During classic activation of complement, C1q must be bound by at least two antigen-antibody immune complexes, to which C4 and C2 then attach themselves. Together, these three components form a C3 convertase, which then splits C3. Pentameric IgM represents a particularly efficient C activator since at least two Ig Fc components in close proximity are required for C1q binding and activation.

During alternative activation of complement, the splitting of C3 occurs directly via the action of products derived from microorganisms, endotoxins, polysaccharides, or aggregated IgA. C3b, which is produced in both cases, is activated by the factors B and D, then itself acts as C3 convertase. Subsequent formation of the lytic complex, C5-C9 (C5-9), is identical for both classic and alternative activation, but is not necessarily essential since the released chemotaxins and opsonins are often alone enough to mediate the functions of microbe neutralization and elimination. Some viruses can activate the complement system without the intervention of antibodies by virtue of their ability to directly bind C1q. This appears to be largely restricted to retro­viruses (including HIV). Importantly, without a stringent control mechanism complement would be activated in an uncontrolled manner, resulting in the lysis of the hosts own cells (for instance erythrocytes).

Those complement components with the most important biological effects include:

-C3b, results in the opsonization of microorganisms and other antigens, either directly or in the form of immune complexes. “C-marked” microorgan­isms then bind to the appropriate receptors (R) (e.g., CRI on macrophages and erythrocytes, or CR2 on B cells).

-C3a and C5a, contribute to the degranulation of basophils and mast cells and are therefore called anaphylatoxins. The secreted vasoactive amines (e.g., histamine) raise the level of vascular permeability, induce contraction of the smooth musculature, and stimulate arachidonic acid metabolism. C5a initi­ates the chemotactic recruitment of granulocytes and monocytes, promotes their aggregation, stimulates the oxidative processes, and promotes the re­lease of the thrombocyte activating factor.

-“Early” C factors, in particular C4, interact with immune complexes and inhibit their precipitation.

-Terminal components (C5-9), together form the so-called membrane at­tack complex, MAC, which lyses microorganisms and other cells.

Some components mediate general regulatory functions on B-cell responses, especially via CR1 and CR2.

Immunological Cell Death

Fig. 2 summarizes the mechanisms of cell death resulting from immuno­logical cell interactions and differentiation processes, as they are understood to date.

Fig. 2 Oxygen radicals and nitrous oxides (a), MAC resulting from complement activation (b) and perforin (c) all cause membrane damage which results in cell death. Ligand binding of Fas/APO (d), interrupted signal receptor conduction (e), corticosteroid binding to receptors and intracellular structures (f), and DNA da­mage (g) all result in alterations of intracellular signaling cascades and lead to cel­lular apoptosis. (Fas = F antigen; APO = apoptosis antigen; TNF = tumor necrosis factor; Bcl2 = B-cell leukemia-2 antigen [a protein that inhibits apoptosis].)

References

Zinkernagel, R. M. (2005). Medical Microbiology. Thieme.