Hyperresponsiveness, Resistance to B-Cell Receptor—Dependent Activation-Induced Cell Death, and Accumulation of Hyperactivated B-Cells in Islets Is Associated With the Onset of Insulitis but not Type 1 Diabetes

  1. Shabbir Hussain1,
  2. Konstantin V. Salojin1 and
  3. Terry L. Delovitch12
  1. 1Autoimmunity/Diabetes Group, Robarts Research Institute, London, Ontario, Canada
  2. 2Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
  1. Address correspondence and reprint requests to Dr. Terry L. Delovitch, Director, Autoimmunity/Diabetes Group, Robarts Research Institute, 1400 Western Rd., London, Ontario N6G 2V4, Canada. E-mail: del{at}robarts.ca

Abstract

B-cells proliferate after B-cell receptor (BCR) stimulation and are deleted by activation-induced cell death (AICD) during negative selection. We report that B-cells from type 1 diabetes−susceptible NOD and type 1 diabetes−resistant but insulitis-prone congenic NOD.B6Idd4B and NOR mice, relative to B-cells from nonautoimmune disease−prone C57BL/6 and BALB/c mice, display a hyperproliferative response to BCR stimulation and lower activation threshold in the absence or presence of interleukin 4 (IL-4). This hyperproliferation is associated with an increased proportion of NOD and NOR B-cells that enter into the S phase of the cell cycle and undergo cell division. The relative resistance to BCR-induced AICD of B-cells from NOD, NOR, and NOD.B6Idd4B mice, all of which develop insulitis, correlates with the presence of a higher percentage of hyperactivated B-cells in the spleen and islets of these mice than in nonautoimmune disease−prone C57BL/6 and BALB/c mice. The NOD islet-infiltrated activated B-cells are more responsive to further stimulation by IL-4 than activated spleen B-cells. Our results suggest that resistance to AICD and accumulation of hyperactivated B-cells in islets is associated with the onset of an inflammatory insulitis, but not type 1 diabetes.

Footnotes

  • T.L.D. holds stock in Diabetogen Biosciences.

    • Accepted May 20, 2004.
    • Received February 26, 2004.
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