Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes
Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes
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DOI：
10.4049/jimmunol.178.9.5643
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发表时间：
2007-05-01
影响因子：
4.4
通讯作者：
Thomas, James W.
中科院分区：
文献类型：
--
作者：
Kendall, Peggy L.;Yu, Guowu;Thomas, James W.
当入侵的淋巴细胞破坏胰岛中产生胰岛素的β细胞时，就会发生自身免疫性糖尿病。淋巴细胞聚集在炎症部位的作用尚不清楚。我们发现攻击NOD小鼠胰岛的B淋巴细胞和T淋巴细胞组织成具有生发中心的淋巴结构。通过BCR L链基因的分析，探讨B淋巴细胞在这些三级淋巴结构和引流胰腺淋巴结中的选择。研究发现，整个胰腺的功能库是高度多样化的，从整个胰腺中分离出的L链基因的特征与在区域淋巴结中观察到的不同。在NOD小鼠的复杂胰腺库中，一个V kappa 14l链占主导地位。当使用固定的Ig H链转基因限制NOD小鼠的基因库时，在胰腺中观察到向V kappa 4基因倾斜。表达的V kappa s的核苷酸测序发现，在一些序列中存在与ag驱动的选择和炎症部位克隆扩增一致的共同突变。分离的胰岛含有生发中心标记GL7和cdr中包含多个突变序列的寡克隆B淋巴细胞，表明局部T-B相互作用。总之，这些发现确定了胰腺中选择B淋巴细胞特异性的过程，并进一步演变了炎症部位的选择库。ag结合研究表明，与引流淋巴结相比，胰腺中有大量胰岛素结合的B淋巴细胞，这一解释得到了加强。中华免疫学杂志，2007,18(4):563 - 561。
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 V kappa 14 L chain predominated within the complex pancreatic repertoire of NOD mice. Skewing toward V kappa 4 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 kappa s 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 Journal of Immunology, 2007, 178: 5643-5651.