Immunologic Research

, Volume 23, Issue 2–3, pp 235–244 | Cite as

Antigen-specific responses in autoimmunity and tolerance

  • James W. Thomas


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 autologoushormone. 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.

Key Words

Insulin Autoantibodies V Region Genes Clonal Ignorance Cronal Anergy Tolerance Diabetes Mellitus 


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Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  1. 1.Division of Rheumatology and Clinical ImmunologyVanderbilt Univeristy School of MedicineNashville

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