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Enhanced responsiveness to T-cell help causes loss of B-lymphocyte tolerance to a beta-cell neo-self-antigen in type 1 diabetes prone NOD mice


Self-reactive B lymphocytes contribute to type 1 diabetes pathogenesis as APC and auto-Ab producers in NOD mice and humans. To shed light on the mechanisms responsible for the breakdown in B-lymphocyte self-tolerance to beta-cell Ag, we utilised a model whereby hen-egg lysozyme (HEL)-specific Ig Tg (IgHEL-Tg)-Tg B lymphocytes were allowed to develop in or were transferred into mice expressing the HEL Tg under an insulin promoter (insHEL-Tg). IgHEL-Tg B lymphocytes enhanced type 1 diabetes susceptibility of insHEL-Tg NOD mice. A comparison of the tolerogenic activity of IgHEL-Tg B lymphocytes with NOD and non-autoimmune-prone C57BL/6 genetic backgrounds showed that both were rendered anergic in the presence of insHEL when competing with polyclonal B lymphocytes. Nevertheless, NOD IgHEL-Tg B lymphocytes transferred into insHEL-Tg mice were more readily susceptible to rescue from anergy than their C57BL/6 counterparts, following provision of in vivo T-cell help. The different tolerogenic outcomes were an intrinsic property of B lymphocytes rather than being related to the quality of T-cell help, with the defective response being at least partially controlled by genes mapping to insulin-dependent diabetes (Idd) susceptibility loci on Chromosome 1 (Idd5) and 4 (Idd9/11).

Type Journal
ISBN 1521-4141 (Electronic) 0014-2980 (Linking)
Authors Cox, S. L.; Stolp, J.; Hallahan, N. L.; Counotte, J.; Zhang, W.; Serreze, D. V.; Basten, A.; Silveira, P. J.:
Published Date 2010-02-01
Published Volume 40
Published Issue 12
Published Pages 3413-25
Status Published in-print
DOI 10.1002/eji.201040817
URL link to publisher's version
OpenAccess link to author's accepted manuscript version