Control of B cells expressing naturally occurring autoantibodies
Résumé
Naturally occurring autoantibodies (Nabs) are typically polyreactive, bind with low affinity to a discrete set of autoantigens and are encoded by variable region genes in germline configuration. They differ from disease-associated autoantibodies (autoAb), which are mostly monoreactive, somatically mutated and of high affinities. Structure-function studies have shown that polyreactivity of NAbs relies on the somaticaly generated complementarity determining region, CDR3, of the heavy chain. This finding suggested that NAb-producing B cells were positively selected from the pre-immune B cell repertoire. The biological significance of this selection remains,however, unclear. Data originating mainly from transgenic mice have shown that mature NAb-producing B cells are frequently ignorant toward their antigen, possibly due to their low afinity, though active tolerance mechhanisms are not excluded. An important issue is whether NAb-producing B cells constitute the pool from which pathologic autoAB emerge after autoantigen-driven maturation. We summarize results obtained in mouse models, showing that some infectious agents are able to induce an autoantigen-driven activation of certain NAb-producing B cells. However direct proof that selection by autoantigen may lead to somatic hypermutation are still lacking. Other data tend to suggest that pathologic autoAbs may derive from non-autoimmune B cells that have diversified by somatic hypermutation of their variable region genes.