The role of MHC sub-region in autoimmune susceptibility and suppressor CD8 T cells

系统性红斑狼疮(SLE)是一种多基因自身免疫性疾病，主要组织相容性复合体(MHC)II类基因多态性是一个关键的遗传因素。在SLE易感(NZB X NZW)F1小鼠中，MHC H-2^&lt；d/z&gt；杂合子(NZB的H-2^d和NZW的H-2^Z)对疾病有很大的影响；因此，同源的H-2^&lt；d/d&gt；纯合子F1小鼠不会发生严重的疾病。在这项研究中，我们利用EA缺乏的H-2内重组建立了A^&lt；d/d&gt；-同源(NZB X NZW)F1小鼠，并分析了E分子表达或不表达的情况，并分析了A和E类分子的作用。在这里，我们发现缺乏E分子的纯合子F1小鼠发生了与野生型F1小鼠相似的严重SLE，包括狼疮性肾炎、自身抗体产生和自发发生的T细胞激活。其他证据表明，E分子以剂量依赖的方式预防疾病；然而，这种效果很大程度上受到A分子单倍型的影响，因为野生型H-2^&lt；d/z&gt；F1小鼠尽管E分子表达，但仍会患上SLE。对树突状细胞呈递自身抗原染色质的可能性的研究表明，来自野生型F1小鼠的树突状细胞比来自A^&lt；d&d&gt；F1小鼠的树突状细胞诱导更大的染色质特异性T细胞反应，无论是否存在E分子，这表明自身抗原呈递是由A分子介导的，而不是由E分子介导的。我们的小鼠模型有助于分析MHC II类区域调节自身免疫反应过程的分子机制。

Systemic lupus erythematosus (SLE) is a multigenic autoimmune disease, and the major histocompatibility complex (MHC) class II polymorphism serves as a key genetic element. In SLE-prone (NZB x NZW) F1 mice, the MHC H-2^<d/z> heterozygosity (H-2^d of NZB and H-2^Z of NZW) has a strong impact on disease; thus, congenic H-2^<d/d> homozygous Fl mice do not develop severe disease. In this study, we used Ea-deficient intra-H-2 recombination to establish A^<d/d>-congenic (NZB x NZW) Fl mice, with or without E molecule expression, and dissected the role of class II A and E molecules. Here we found that A^<d/d> homozygous Fl mice lacking E molecules developed severe SLE similar to that seen in wild-type Fl mice, including lupus nephritis, autoantibody production, and spontaneously occurring T cell activation. Additional evidence revealed that E molecules prevent the disease in a dose-dependent manner; however, the effect is greatly influenced by the haplotype of A molecules, because wild-type H-2^<d/z> Fl mice develop SLE, despite E molecule expression. Studies on the potential of dendritic cells to present a self-antigen chromatin indicated that dendritic cells from wild-type Fl mice induced a greater response of chromatin-specific T cells than did those from A^<d/d> Fl mice, irrespective of the presence or absence of E molecules, suggesting that the self-antigen presentation is mediated by A, but not by E, molecules. Our mouse models are useful for analyzing the molecular mechanisms by which MHC class II regions regulate the process of autoimmune responses.