title: Antigen-specific responses in autoimmunity and tolerance.
abstract: Autoantibodies to the hormone insulin arise spontaneously in the insulin autoimmune syndrome and in the prodrome of type I diabetes. Further, administration of insulin to individuals without autoimmune disease routinely results in antibodies that bind autologous hormone. These observations suggest that physiological levels of hormones, such as insulin, are below critical thresholds for signaling tolerance induction, a state termed clonal ignorance. In contrast, studies from our laboratory on the genetic origins and structure of V genes used by insulin antibodies suggest that the anti-insulin repertoire is tightly regulated. We have shown that B cells in mice harboring an insulin antibody transgene are functionally silenced. These findings verify that tolerance is active for small molecules, even when they are present at low concentrations. Despite active tolerance, insulin antibodies are sustained in the repertoire of normal animals by several mechanisms, including activation by TI antigen signals, unique display of conformational epitopes, and the recruitment of B cells previously selected by responses to other antigens. This essay reviews our current understanding of escape pathways for anti-insulin B cells.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-2681, USA. james.thomas@mcmail.vanderbilt.edu
authors.forename: J W
authors.initials: JW
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000916:Antibody Diversity; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D017635:Clonal Anergy; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D005320:Fetal Macrosomia / Q000209:etiology; D015322:Gene Rearrangement, B-Lymphocyte; D020868:Gene Silencing; D005803:Genes, Immunoglobulin; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008958:Models, Molecular; D009994:Osmolar Concentration; D011247:Pregnancy; D011254:Pregnancy in Diabetics; D011487:Protein Conformation; D019076:Transgenes
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D007135:Immunoglobulin Variable Region; D007328:Insulin