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,
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*
Program in Developmental Biology, Hospital for Sick Children Research Institute, Departments of
Surgery and
Immunology and
Institute of Medical Science, University of Toronto, Toronto, Canada; and
¶ Departments of Nephrology and Transplantation and Microbiology and Immunology, University of Western Ontario, London, Canada
Type 1 diabetes in nonobese diabetic (NOD) mice is characterized by
the infiltration of T and B cells into pancreatic islets. T cells
bearing the TCR V
3 chain are disproportionately represented in the
earliest stages of islet infiltration (insulitis) despite clonal
deletion of most V3+ immature thymocytes by the mammary
tumor virus-3 (Mtv-3) superantigen (SAg). In this report
we showed that a high frequency of NOD V3+ T cells that
escape deletion are activated in vivo and that this phenotype is linked
to the Mtv-3 locus. One potential mechanism of SAg
presentation to peripheral T cells is by activated B cells. Consistent
with this idea, we found that NOD mice harbor a significantly higher
frequency of activated B cells than nondiabetes-prone strains. These
activated NOD B cells expressed cell surface molecules consistent with
APC function. At the molecular level, the IgH repertoire of activated B
cells in NOD mice was equivalent to resting B cells, suggesting a
polyclonal response in vivo. Genetic analysis of the activated B cell
phenotype showed linkage to Idd1, the NOD MHC haplotype
(H-2g7). Finally, V3+ thymocyte deletion and
peripheral T cell activation did not require B cells, suggesting that
other APC populations are sufficient to generate both
Mtv-3-linked phenotypes. These data provide insight into
the genetic regulation of NOD autoreactive lymphocyte activation that
may contribute to failure of peripheral tolerance and the pathogenesis
of type I diabetes.
This article has been cited by other articles:
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  A. M. Marleau, K. L. Summers, and B. Singh Differential Contributions of APC Subsets to T Cell Activation in Nonobese Diabetic Mice J. Immunol., April 15, 2008; 180(8): 5235 - 5249. [Abstract] [Full Text] [PDF]
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S. Hussain and T. L. Delovitch Intravenous Transfusion of BCR-Activated B Cells Protects NOD Mice from Type 1 Diabetes in an IL-10-Dependent Manner J. Immunol., December 1, 2007; 179(11): 7225 - 7232. [Abstract] [Full Text] [PDF]
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J. Rolf, V. Motta, N. Duarte, M. Lundholm, E. Berntman, M.-L. Bergman, L. Sorokin, S. L. Cardell, and D. Holmberg The Enlarged Population of Marginal Zone/CD1dhigh B Lymphocytes in Nonobese Diabetic Mice Maps to Diabetes Susceptibility Region Idd11 J. Immunol., April 15, 2005; 174(8): 4821 - 4827. [Abstract] [Full Text] [PDF]
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S. Hussain and T. L. Delovitch Dysregulated B7-1 and B7-2 Expression on Nonobese Diabetic Mouse B Cells Is Associated with Increased T Cell Costimulation and the Development of Insulitis J. Immunol., January 15, 2005; 174(2): 680 - 687. [Abstract] [Full Text] [PDF]
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 S. Hussain, K. V. Salojin, and T. L. Delovitch 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 Diabetes, August 1, 2004; 53(8): 2003 - 2011. [Abstract] [Full Text] [PDF]
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