Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Health, University of Colorado Denver, School of Medicine, Denver, CO 80206, USA.
Cold Spring Harb Perspect Med. 2012 Sep 1;2(9):a007765. doi: 10.1101/cshperspect.a007765.
The strong association between particular MHCII alleles and type 1 diabetes is not fully understood. Two ideas that have been considered for many years are that autoimmunity is driven by (1) low-affinity CD4(+) T cells that escape thymic negative selection and respond to certain autoantigen peptides that are particularly well presented by particular MHCII molecules, or (2) CD4(+) T cells responding to neoantigens that are absent in the thymus, but uniquely created in the target tissue in the periphery and presented by particular MHCII alleles. Here we discuss the recent structural data in favor of the second idea. We review studies suggesting that peptide antigens recognized by autoimmune T cells are uniquely proteolytically processed and/or posttranslationally modified in the target tissue, thus allowing these T cells to escape deletion in the thymus during T-cell development. We postulate that an encounter with these tissue-specific neoantigenic peptides presented by the particular susceptible MHCII alleles in the peripheral tissues when accompanied by the appropriate inflammatory milieu activates these T-cell escapees leading to the onset of autoimmune disease.
特定 MHCII 等位基因与 1 型糖尿病之间的强关联尚不完全清楚。多年来人们考虑了两个想法：自身免疫是由（1）低亲和力 CD4(+)T 细胞驱动的，这些细胞逃避了胸腺负选择，并对某些特别由特定 MHCII 分子呈递的自身抗原肽产生反应，或者（2）对胸腺中不存在但在外周靶组织中独特产生并由特定 MHCII 等位基因呈递的新抗原产生反应的 CD4(+)T 细胞。在这里，我们讨论了支持第二个想法的最新结构数据。我们回顾了一些研究，这些研究表明，自身免疫 T 细胞识别的肽抗原在靶组织中被独特地蛋白水解加工和/或翻译后修饰，从而使这些 T 细胞在 T 细胞发育过程中逃避胸腺中的删除。我们假设，在外周组织中遇到由特定易感 MHCII 等位基因呈递的这些组织特异性新抗原肽，并伴有适当的炎症环境，会激活这些 T 细胞逃避免疫，从而导致自身免疫疾病的发生。
