Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
J Autoimmun. 2012 Dec;39(4):347-53. doi: 10.1016/j.jaut.2012.04.005. Epub 2012 May 28.
Type 1 diabetes (T1D) is mediated by destruction of pancreatic β-cells by CD4 and CD8 T cells specific for epitopes on numerous diabetogenic autoantigens resulting in loss of glucose homeostasis. Employing antigen-specific tolerance induced by i.v. administration of syngeneic splenocytes ECDI cross-linked to various diabetogenic antigens/epitopes (Ag-SP), we show that epitope spreading plays a functional role in the pathogenesis of T1D in NOD mice. Specifically, Ag-SP coupled with intact insulin, Ins B(9-23) or Ins B(15-23), but not GAD65(509-528), GAD65(524-543) or IGRP(206-214), protected 4-6 week old NOD mice from the eventual development of clinical disease; infiltration of immune cells to the pancreatic islets; and blocked the induction of DTH responses in a Treg-dependent, antigen-specific manner. However, tolerance induction in 19-21 week old NOD mice was effectively accomplished only by Ins-SP, suggesting Ins B(9-23) is a dominant initiating epitope, but autoimmune responses to insulin epitope(s) distinct from Ins B(9-23) emerge during disease progression.
1 型糖尿病（T1D）是由针对众多糖尿病自身抗原上表位的 CD4 和 CD8 T 细胞介导的，导致葡萄糖稳态丧失。我们通过静脉内给予同基因脾细胞 ECDI 交联到各种糖尿病自身抗原/表位（Ag-SP）来诱导抗原特异性耐受，结果表明，表位扩展在 NOD 小鼠 T1D 的发病机制中起着功能作用。具体而言，Ag-SP 与完整的胰岛素、Ins B(9-23)或 Ins B(15-23)结合，但不与 GAD65(509-528)、GAD65(524-543)或 IGRP(206-214)结合，可保护 4-6 周龄的 NOD 小鼠免受临床疾病的最终发展；免疫细胞浸润到胰岛；并以 Treg 依赖性、抗原特异性方式阻断 DTH 反应的诱导。然而，仅在 19-21 周龄的 NOD 小鼠中诱导耐受才能有效实现，这表明 Ins B(9-23)是一个主要的起始表位，但在疾病进展过程中会出现针对不同于 Ins B(9-23)的胰岛素表位的自身免疫反应。
