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

MHC亚区在自身免疫易感性和抑制性CD8 T细胞中的作用

基本信息

批准号：
15500303
负责人：
ZHANG Danqing
金额：
$ 1.98万
依托单位：
JUNTENDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15500303/
关键词：
Systemic lupus erthematosus (SLE)New zealand mice MNC class II E molecules H-2 congenic mice Intreagenic recombination NewZealandマウス MHC Class II congenicマウス recombinantマウス

项目摘要

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.

全身性红斑狼疮（SLE）是一种多基因自身免疫性疾病，主要的组织相容性复合物（MHC）II类多态性是关键遗传元素。在SLE-Prone（NZB X NZW）F1小鼠中，MHC H-2^<d/Z>杂合性（NZB的H-2^d的NZB和NZW的H-2^Z）对疾病具有很大的影响。因此，先天性的H-2^<d/d>纯合FL小鼠不会出现严重疾病。在这项研究中，我们使用EA缺陷型H-2重组来建立A^<d/d> congenic（NZB X NZW）FL小鼠，有或没有E分子表达，并解剖了II类A和E分子的作用。在这里，我们发现缺乏E分子的A^<d/d>纯合FL小鼠与野生型FL小鼠相似，包括狼疮肾炎，自身抗体产生以及自发发生T细胞激活。其他证据表明，E分子以剂量依赖性的方式预防了该疾病。然而，由于E分子表达，野生型H-2^<d/z fl小鼠的效果受到分子的单倍型的很大影响，因为E型H-2^<d/z> fl小鼠发展了SLE。关于树突状细胞呈现自我抗原染色质的潜力的研究表明，来自野生型FL小鼠的树突状细胞诱导了染色质特异性T细胞的反应比A^<d/d> fl小鼠的染色质特异性T细胞的反应更大，而不论E分子的存在或不存在E^<d/d> fl小鼠的反应，这表明自我抗抗菌的存在是由eRec介导的，而是通过eRec介导的。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。