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* Departments of Medicine,
Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232
Autoimmune diabetes occurs when invading lymphocytes destroy insulin-producing 
cells in pancreatic islets. The role of lymphocytic aggregates at this inflammatory site is not understood. We find that B and T lymphocytes attacking islets in NOD mice organize into lymphoid structures with germinal centers. Analysis of BCR L chain genes was used to investigate selection of B lymphocytes in these tertiary lymphoid structures and in draining pancreatic lymph nodes. The pancreatic repertoire as a whole was found to be highly diverse, with the profile of L chain genes isolated from whole pancreas differing from that observed in regional lymph nodes. A V
14 L chain predominated within the complex pancreatic repertoire of NOD mice. Skewing toward V4 genes was observed in the pancreas when the repertoire of NOD mice was restricted using a fixed Ig H chain transgene. Nucleotide sequencing of expressed Vs identified shared mutations in some sequences consistent with Ag-driven selection and clonal expansion at the site of inflammation. Isolated islets contained oligoclonal B lymphocytes enriched for the germinal center marker GL7 and for sequences containing multiple mutations within CDRs, suggesting local T-B interactions. Together, these findings identify a process that selects B lymphocyte specificities within the pancreas, with further evolution of the selected repertoire at the inflamed site. This interpretation is reinforced by Ag-binding studies showing a large population of insulin-binding B lymphocytes in the pancreas compared with draining lymph nodes.
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 Grant K08 DK070924, Immunobiology of Blood and Vascular Systems T32 HL069765, National Institutes of Health Grant RO1 AI051448, JDRF 1-2005-167, The Vanderbilt Diabetes Center, The Vanderbilt Physician-Scientist Development Award and the National Institutes of Health Loan Repayment Program. The Vanderbilt DNA Sequencing Facility is supported by National Institutes of Health Grants CA68485 (to the Vanderbilt-Ingram Cancer Center), DK20593 (to the Vanderbilt Diabetes Research and Training Center), and HL65962 (to the Vanderbilt Pharmacogenomics Research Center).
2 Address correspondence and reprint requests to 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: TLS, tertiary lymphoid structures; GC, germinal center; T1D, type 1 diabetes; 7AAD, 7-aminoactinomycin D.
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  Y. Xiu, C. P. Wong, J.-D. Bouaziz, Y. Hamaguchi, Y. Wang, S. M. Pop, R. M. Tisch, and T. F. Tedder B Lymphocyte Depletion by CD20 Monoclonal Antibody Prevents Diabetes in Nonobese Diabetic Mice despite Isotype-Specific Differences in Fc{gamma}R Effector Functions J. Immunol., March 1, 2008; 180(5): 2863 - 2875. [Abstract] [Full Text] [PDF]
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