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类多态性是一个关键的遗传因素。在sled易发（NZB x NZW） F1小鼠中，MHC H-2^<d/z>杂合性（NZB的H-2^d和NZW的H-2^ z）对疾病有很强的影响；因此，同源H-2^<d/d>纯合子Fl小鼠不会发生严重的疾病。在本研究中，我们采用Ea-deficient intra-H-2重组方法，建立了A^<d/d>-congenic (NZB x NZW) Fl小鼠，分别表达或不表达E分子，并解剖了II类A和E分子的作用。我们发现缺乏E分子的A^<d/d>纯合子Fl小鼠发生了与野生型Fl小鼠相似的严重SLE，包括狼疮肾炎、自身抗体产生和自发发生的T细胞激活。其他证据显示，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A分子单倍型的影响，因为野生型H-2^<d/z> Fl小鼠发生SLE，尽管E分子表达。对树突状细胞呈递自身抗原染色质的潜力的研究表明，野生型Fl小鼠的树突状细胞比来自a ^<d/d> Fl小鼠的树突状细胞诱导染色质特异性T细胞的反应更大，无论是否存在E分子，这表明自身抗原呈递是由a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.