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物（MHC）Ⅱ类基因多态性是其重要的遗传因素。在SLE易感（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F1小鼠不会发展为严重的疾病。在这项研究中，我们使用Ea缺陷的H-2内重组来建立A ^<d/d>-同源（NZB x NZW）F1小鼠，具有或不具有E分子表达，并剖析II类A和E分子的作用。在此我们发现缺乏E分子的A ^<d/d>纯合子F1小鼠发生与野生型F1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细胞活化。另外的证据表明，E分子以剂量依赖性方式预防疾病;然而，该效果受到A分子单倍型的极大影响，因为野生型H-2 ^<d/z> Fl小鼠发展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，来自野生型F1小鼠的树突状细胞诱导的染色质特异性T细胞的应答比来自A ^<d/d> F1小鼠的树突状细胞更强，而与E分子的存在与否无关，这表明自身抗原呈递由A分子介导，而不是由E分子介导。我们的小鼠模型可用于分析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.