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.
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.
Hussain
Shabbir
S
Autoimmunity/Diabetes Group, Robarts Research Institute, London, Ontario, Canada.
Salojin
Konstantin V
KV
Delovitch
Terry L
TL
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002453:Cell Cycle / Q000276:immunology; D002455:Cell Division; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D013154:Spleen / Q000276:immunology
D011947:Receptors, Antigen, B-Cell