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

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 Shabbir Hussain 1 , Konstantin V. Salojin 1 and Terry L. Delovitch 1 2 1 Autoimmunity/Diabetes Group, Robarts Research Institute, London, Ontario, Canada 2 Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada 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.B6 Idd4B 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.B6 Idd4B 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. AICD, activation-induced cell death APC, antigen-presenting cell BCR, B-cell receptor CFSE, 5- (and 6-) carboxyfluorescein diacetate succinimidyl ester FasL, Fas ligand FITC, fluorescein isothiocyanate IAA, insulin autoantibody IL, interleukin MHC, major histocompatibility complex PE, phycoerythrin PLN, pancreatic lymph node sIgM, surface IgM TCR, T-cell receptor Footnotes T.L.D. holds stock in Diabetogen Biosciences. Accepted May 20, 2004. Received February 26, 2004. DIABETES