The complement system is made up of complement factors, which circulate in the blood in an inactive form, and of regulatory proteins (inhibitors, activators, and receptors), by the expression of which the system is highly regulated. The complement system is a multienzyme cascade and is the major component of innate immunity; it plays a crucial role in the microbial killing, controlling the formation of immune complexes, in the clearance of apoptotic cells, and modulating the acquired immunity. The evidence of its role in acquired immunity is now more solid. The pathways of complement activation are as follows:
• The classical pathway (C1q-C1r-C1s, C4, C2 factors), mainly triggered by the antigen–antibody complex.
• The alternative pathway (factors C3, B, D, P, H), triggered by lipopolysaccharides and surface polysaccharides of viruses, bacteria, fungi, parasites, by altered self-antigens of tumor cells.
• The lectin pathway (factors C4, C2), similar to the classical pathway, but triggered by mannose-binding lectin, which specifically recognizes residues of mannose and other sugars present on bacterial and other pathogenic surfaces. All pathways of complement activation con verge through factor C3 into the common terminal path way (factors C3, C5, C6, C7, C8, C9), which culminates in the formation of the lytic attack complex at the cell membrane. The decrease in complement proteins may be due to a genetically determined synthesis deficit or to consumption by activation of the system, whereas the increase in their concentration is of no clinical importance per se. Since C3 is the central point where the three activation pathways converge and C4 is a fundamental factor of the classical pathway and the lectin pathway, the measurement of these two proteins provides with good approximation an evaluation of the activation status of the complement system. The reference values in plasma for adults, according to the IFCC international standardization (CRM 470), are 0.9–1.8 g/L for C3 and 0.1–0.4 g/L for C4.
The request for the measurement of complement proteins is therefore appropriate in patients with severe, recurrent, atypical or not easily resolvable infections or with important allergic manifestations (congenital immunodeficiency suspected). It is also appropriate in the diagnostic and monitoring pathway of patients with diseases sustained by immune complexes (such as systemic lupus erythematosus, cryoglobulinemias, and vasculitis in general). It should be noted that the sole immunochemical measurement of complement proteins is not appropriate to define the problem: only the functional evaluation of the complement system (CH50 and APCH50) is able to identify the actual deficiency of activity of the classical, alternative, or common pathway.
