How pre-existing, germline-derived antibodies and complement may help induce a primary immune response to nonself.

In the hypothesis that pre-existing, germline-encoded antibodies (naturally occurring antibodies, NAb) bind to conserved epitopes on invading nonself antigens, bound NAbs may initiate complement deposition and become targets of nascent C3b, which generates C3b-C3b-NAb complexes that remain associated with the nonself antigen (C3b-C3b-NAb...antigen). The inactivated form of these complexes (C3dg-C3dg-NAb...nonself antigen) may bind bivalently and thus firmly to B cells via CR2, a process stimulating antigen presentation. In some cases, CR2-bound 'C3dg-C3dg-NAb...antigen complexes' may further be recognized by immunoglobulin (Ig) determinants on B cells, whereby an immune response is elicited. As conserved epitopes on the nonself antigen are already complexed to NAbs, only B cells carrying Ig determinants specific for nonself epitopes may be stimulated. This hypothesis can explain directed affinity maturation towards nonself, protection from a strong immune response to conserved epitopes, down-regulation of antibody formation and unresponsiveness to high-dose antigen.