The association between inherited deficiencies of the classical pathway
complement components (C1q, C1r, C1s, C4, C2 and C3) and
immune complex disease shows that
complement is involved in protection against the development of
immune complex disease (ICD). This protection is conferred by the ability of the
complement system to keep
antigen antibody complexes (IC) small and soluble. Two mechanisms exist, prevention of immune precipitation (PIP), which inhibits the formation of large insoluble lattices when IC are formed in the presence of
complement (nascent IC), and solubilisation of preformed
immune precipitates (
SOL). PIP is probably the more important as it is unlikely that, in vivo, IC are ever formed in the absence of
complement. PIP displays an absolute dependency upon the classical pathway while
SOL is alternative pathway dependent. However, for optimal efficiency
SOL requires an intact classical pathway. Thus the classical pathway plays a role in both PIP and
SOL. The end result of both processes is the covalent binding of C3b to the IC lattice, which not only keeps IC soluble, but permits binding to CR1 for removal from the circulation. The sera of patients with ICD contain
a factor (s) which inhibits PIP. The sera of RA patients inhibits PIP and purified
IgM-RF has been shown to inhibit this function. However a second inhibitor of PIP has recently been purified, a
glycoprotein (Mr 60 kd) (gp60) which is present in normal serum and in increased concentration in RA sera. Gp60 binds to the Fc piece of
IgG, but not to
IgA or
IgM, and competes with C1q for a binding site on
IgG Fc. Thus gp60 appears to act by preventing binding and activation of C1 by
IgG containing IC.