Priming and effector dependence on insulin B:9–23 peptide in NOD islet autoimmunity


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Abstract

NOD mice with knockout of both native insulin genes and a mutated proinsulin transgene, alanine at position B16 in preproinsulin (B16:A-dKO mice), do not develop diabetes. Transplantation of NOD islets, but not bone marrow, expressing native insulin sequences (tyrosine at position B16) into B16:A-dKO mice rapidly restored development of insulin autoantibodies (IAAs) and insulitis, despite the recipients' pancreatic islets lacking native insulin sequences. Splenocytes from B16:A-dKO mice that received native insulin–positive islets induced diabetes when transferred into wild-type NOD/SCID or B16:A-dKO NOD/SCID mice. Splenocytes from mice immunized with native insulin B chain amino acids 9–23 (insulin B:9–23) peptide in CFA induced rapid diabetes upon transfer only in recipients expressing the native insulin B:9–23 sequence in their pancreata. Additionally, CD4+ T cells from B16:A-dKO mice immunized with native insulin B:9–23 peptide promoted IAAs in NOD/SCID mice. These results indicate that the provision of native insulin B:9–23 sequences is sufficient to prime anti-insulin autoimmunity and that subsequent transfer of diabetes following peptide immunization requires native insulin B:9–23 expression in islets. Our findings demonstrate dependence on B16 alanine versus tyrosine of insulin B:9–23 for both the initial priming and the effector phase of NOD anti-islet autoimmunity.

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