Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes

Peggy L. Kendall, Guowu Yu, Emily J. Woodward, James W. Thomas

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Autoimmune diabetes occurs when invading lymphocytes destroy insulin-producing β 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 Vκ14 L chain predominated within the complex pancreatic repertoire of NOD mice. Skewing toward Vκ4 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 V κs identified shared mutations in some sequences consistent with Ag-driven selection and clonal expansion at the site of iniammation. 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.

Original languageEnglish
Pages (from-to)5643-5651
Number of pages9
JournalJournal of Immunology
Volume178
Issue number9
DOIs
StatePublished - May 1 2007

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