Ridgway W M, Ito H, Fassò M, Yu C, Fathman C G
Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, California 94305, USA.
J Exp Med. 1998 Dec 21;188(12):2267-75. doi: 10.1084/jem.188.12.2267.
The current paradigm of major histocompatibility complex (MHC) and disease association suggests that efficient binding of autoantigens by disease-associated MHC molecules leads to a T cell-mediated immune response and resultant autoimmune sequelae. The data presented below offer a different model for this association of MHC with autoimmune diabetes. We used several mouse lines expressing different levels of I-Ag7 and I-Ak on the nonobese diabetic (NOD) background to evaluate the role of MHC class II in the previously described NOD T cell autoproliferation. The ratio of I-Ag7 to I-Ak expression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD x NOD. I-Anull]F1, and NOD I-Ak transgenic mice demonstrated autoproliferative responses (after priming with self-peptides), whereas the NOD.H2(h4) (containing I-Ak) congenic and [NOD x NOD. H2(h4) congenic]F1 mice did not. Analysis of CD4(+) NOD I-Ak transgenic primed lymph node cells showed that autoreactive CD4(+) T cells in the NOD I-Ak transgenic mice were restricted exclusively by I-Ag7. Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacity of NOD I-Ag7 suggested a new hypothesis to explain the effects of MHC class II expression on the peripheral autoimmune repertoire in NOD mice. This new explanation suggests that the association of MHC with diabetes results from "altered" thymic selection in which high affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in humans) in susceptibility to insulin-dependent diabetes mellitus.
目前主要组织相容性复合体（MHC）与疾病关联的范式表明，疾病相关的MHC分子与自身抗原的有效结合会导致T细胞介导的免疫反应及由此产生的自身免疫后遗症。以下呈现的数据为MHC与自身免疫性糖尿病的这种关联提供了一种不同的模型。我们使用了几种在非肥胖糖尿病（NOD）背景下表达不同水平I-Ag7和I-Ak的小鼠品系，以评估MHC II类分子在先前描述的NOD T细胞自身增殖中的作用。在所研究的小鼠中，I-Ag7与I-Ak的表达比例与外周T细胞自身增殖表型相关。来自NOD、[NOD×NOD. I-Anull]F1和NOD I-Ak转基因小鼠的T细胞表现出自身增殖反应（在用自身肽致敏后），而NOD.H2(h4)（含有I-Ak）同源基因小鼠和[NOD×NOD. H2(h4)同源基因]F1小鼠则没有。对CD4(+) NOD I-Ak转基因致敏淋巴结细胞的分析表明，NOD I-Ak转基因小鼠中的自身反应性CD4(+) T细胞仅受I-Ag7限制。结合T细胞激活和选择的亲和力理论来考虑，所报道的NOD I-Ag7较差的肽结合能力提出了一个新的假说来解释MHC II类分子表达对NOD小鼠外周自身免疫库的影响。这个新的解释表明，MHC与糖尿病的关联是由“改变的”胸腺选择导致的，其中高亲和力的自身反应性（潜在自身反应性）T细胞逃避了阴性选择。该模型解释了NOD小鼠（以及人类）中纯合MHC II类分子表达在胰岛素依赖型糖尿病易感性中的必要性。
