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

Kendall PL, Yu G, Woodward EJ, Thomas JW
J Immunol. 2007 178 (9): 5643-51

PMID: 17442947 · DOI:10.4049/jimmunol.178.9.5643

Autoimmune diabetes occurs when invading lymphocytes destroy insulin-producing beta 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 Vkappa14 L chain predominated within the complex pancreatic repertoire of NOD mice. Skewing toward Vkappa4 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 Vkappas 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.

MeSH Terms (15)

Amino Acid Sequence Animals Autoimmune Diseases B-Lymphocytes Diabetes Mellitus, Type 1 Germinal Center Immunoglobulin Heavy Chains Immunoglobulin Variable Region Islets of Langerhans Mice Mice, Inbred NOD Molecular Sequence Data Mutation Pancreas Transgenes

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