Control of B cells expressing naturally occurring autoantibodies.
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 somatically 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 affinity, though active tolerance mechanisms are not excluded. An important issue is whether NAb-producing B cells constitute the pool from which pathologic auto Ab 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 auto Abs may derive from non-autoimmune B cells that have diversified by somatic hypermutation of their variable region genes.
Clinical Immunology Department, National Referral Center for Systemic Autoimmune Diseases, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Jean Louis
JL
Pasquali
Thierry
T
Martin
D000818:Animals; D000915:Antibody Affinity; D000918:Antibody Specificity; D001323:Autoantibodies / Q000145:classification / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003141:Communicable Diseases / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000276:immunology; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation
D001323:Autoantibodies; D001324:Autoantigens; D022801:Complementarity Determining Regions; D007135:Immunoglobulin Variable Region