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Departments of
*Medicine,
Pediatrics, and
Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37212; and
Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136
Type 1 diabetes results from T cell-mediated destruction of insulin-producing β cells. Although elimination of B lymphocytes has proven successful at preventing disease, modulation of B cell function as a means to prevent type 1 diabetes has not been investigated. The development, fate, and function of B lymphocytes depend upon BCR signaling, which is mediated in part by Bruton’s tyrosine kinase (BTK). When introduced into NOD mice, btk deficiency only modestly reduces B cell numbers, but dramatically protects against diabetes. In NOD, btk deficiency mirrors changes in B cell subsets seen in other strains, but also improves B cell-related tolerance, as indicated by failure to generate insulin autoantibodies. Introduction of an anti-insulin BCR H chain transgene restores diabetes in btk-deficient NOD mice, indicating that btk-deficient B cells are functionally capable of promoting autoimmune diabetes if they have a critical autoimmune specificity. This suggests that the disease-protective effect of btk deficiency may reflect a lack of autoreactive specificities in the B cell repertoire. Thus, signaling via BTK can be modulated to improve B cell tolerance, and prevent T cell-mediated autoimmune diabetes.
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 This work was supported by National Institutes of Health Grants K08 DK070924, R01 AI051448, RO1 AI060729, and F32 DK083161; Juvenile Diabetes Research Foundation Grants 1-2005-167 and 1-2008-108; Vanderbilt Diabetes Center; Vanderbilt Physician-Scientist Development Award; and National Institutes of Health Loan Repayment Program. The Vanderbilt Medical Center Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404).
2 Address correspondence and reprint requests to Dr. Peggy L. Kendall, Vanderbilt University Medical Center, T3.219 Medical Center North, 21st and Garland, Nashville, TN 37232; E-mail address: peggy.kendall{at}vanderbilt.edu or Dr. James W. Thomas, Vanderbilt University Medical School, 1161 21st Avenue South, Medical Center North T3.219, Nashville, TN 37232; E-mail address: james.w.thomas{at}vanderbilt.edu
3 Abbreviations used in this paper: T1D, type 1 diabetes; BTK, Bruton’s tyrosine kinase; FO, follicular; MZ, marginal zone; Tg, transgenic; WMW, Wilcoxon-Mann-Whitney.
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