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Genes within the Idd5 and Idd9/11 Diabetes Susceptibility Loci Affect the Pathogenic Activity of B Cells in Nonobese Diabetic Mice¹

Pablo A. Silveira, Harold D. Chapman^*, Jessica Stolp, Ellis Johnson^*, S. Lewis Cox, Kara Hunter, Linda S. Wicker and David V. Serreze^2,*

^* The Jackson Laboratory, Bar Harbor, ME 04609; Immunology and Inflammation Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; and Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom

Autoreactive T cells clearly mediate the pancreatic β cell destruction causing type 1 diabetes (T1D). However, studies in NOD mice indicate that B cells also contribute to pathogenesis because their ablation by introduction of an Igµ^null mutation elicits T1D resistance. T1D susceptibility is restored in NOD.Igµ^null mice that are irradiated and reconstituted with syngeneic bone marrow plus NOD B cells, but not syngeneic bone marrow alone. Thus, we hypothesized some non-MHC T1D susceptibility (Idd) genes contribute to disease by allowing development of pathogenic B cells. Supporting this hypothesis was the finding that unlike those from NOD donors, engraftment with B cells from H2^g7 MHC-matched, but T1D-resistant, nonobese-resistant (NOR) mice failed to restore full disease susceptibility in NOD.Igµ^null recipients. T1D resistance in NOR mice is mainly encoded within the Idd13, Idd5.2, and Idd9/11 loci. B cells from NOD congenic stocks containing Idd9/11 or Idd5.1/5.2-resistance loci, respectively, derived from the NOR or C57BL/10 strains were characterized by suppressed diabetogenic activity. Immature autoreactive B cells in NOD mice have an impaired ability to be rendered anergic upon Ag engagement. Interestingly, both Idd5.1/5.2 and Idd9/11-resistance loci were found to normalize this B cell tolerogenic process, which may represent a mechanism contributing to the inhibition of T1D.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ P.S. was supported by a Peter Doherty Fellowship from the National Health and Medical Research Council (NHMRC) and grants from the Cecilia Kilkeary Foundation, the Clive and Vera Ramaciotti Foundation, the NHMRC (402727), and the Juvenile Diabetes Research Foundation (JDRF). D.V.S. was supported by Grants from the National Institutes of Health (DK46266 and DK51090) and the JDRF.

² Address correspondence and reprint requests to Dr. David V. Serreze, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609. E-mail address: dvs{at}jax.org

³ Abbreviations used in this paper: T1D, type 1 diabetes; HEL, hen egg lysozyme; Chr., chromosome; NOR, nonobese resistant; MZ, marginal zone; FO, follicular; BM, bone marrow; SBM, syngeneic BM; LN, lymph node; AICD, activation-induced cell death; PI, propidium iodide.

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