Although C1q binds with low affinity to some subclasses of IgG in solution, the binding energy required for C1q activation is achieved only when a single molecule of C1q can bind two or more IgG molecules that are held within 30–40 nm of each other as a result of binding antigen. This requires that multiple molecules of IgG be bound to a single pathogen or to an antigen in solution. For this reason, IgM is much more efficient than IgG in activating complement. The binding of C1q to a single bound IgM molecule, or to two or more bound IgG molecules (see Fig. 10.35), leads to activation of the protease activity of C1r, triggering the complement cascade.
10-20 Complement receptors and Fc receptors both contribute to removal of immune complexes from the circulation.
Fc receptors confer the distinct effector functions to the various antibody isotypes by interacting with their Fc regions. One such function is the clearance from the circulation of antigen:antibody complexes (immune complexes), which can include toxins, or debris from dead host cells and microorganisms, bound by neutralizing antibodies. Immune complexes can be cleared by the binding of the antibody’s Fc region to Fc receptors expressed on various phagocytic cells in tissues. This clearance is also helped by complement activation (described in the last section), which occurs when the Fc region activates C1q. The deposition of C4b and C3b onto the immune complex aids clearance by binding to complement receptor 1 (CR1) on the surface of erythrocytes (see Section 2-13 for a description of the different types of complement receptors). The erythrocytes transport the bound complexes of antigen, antibody, and complement to the liver and spleen. Here, macrophages bearing CR1 and Fc
CR1 on the erythrocyte surface has an important role in the clearance of immune complexes from the circulation. Immune complexes bind to CR1 on erythrocytes, which transport them to the liver and spleen, where they are removed by macrophages expressing receptors for both Fc and bound complement components.
receptors remove the complexes from the erythrocyte surface without destroying the cell, and then degrade the complexes (Fig. 10.37). Even larger aggregates of particulate antigen, such as bacteria, viruses, and cell debris, can be coated with complement, picked up by erythrocytes, and transported to the spleen for destruction.
Complement-coated immune complexes that are not removed from the circulation tend to deposit in the basement membranes of small blood vessels, most notably those of the renal glomerulus, where the blood is filtered to form urine. Immune complexes that pass through the basement membrane of the glomerulus bind to CR1 present on the renal podocytes, cells that lie beneath the basement membrane. The functional significance of these receptors in the kidney is unknown; however, they have an important role in the pathology of some autoimmune diseases. In the autoimmune disease systemic lupus erythematosus (SLE) (see Section 15-16), excessive levels of circulating immune complexes lead to their deposition in large amounts on the podocytes, damaging the glomerulus; kidney failure is the principal danger in this disease. The strongest genetic risk factor for SLE is C1q deficiency, although this is very rare. Mutations in complement receptors 2 and 3 and the Fc receptor FcγRIIIa are also associated with increased susceptibility to develop lupus, implying the involvement of both complement receptors and FcR pathways in clearing immune complexes.