Effect of TNF gene polymorphism on autoimmune disease

TNF基因多态性对自身免疫性疾病的影响

• 批准号: 07670259
• 负责人: HIROSE Sachiko
• 金额: $ 1.47万
• 依托单位: Juntendo University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670259/
• 关键词: TNF gene polymorphism; Microsatellite; New Zealand mice; Autoimmune disease; Congenic mouse; MHC class II; MHCクラスII分子

TNF gene is tightly linked to major histocompatibility complex in both human and mouse. In the promoter region of mouse TNFalpha gene, there is a simple sequence length polymorphism (microsatelite DNA polymorphism) among TNF haplotypes. To investigate the relationship between TNF polymorphism and the degree of TNF production, we introduced TNF^d haplotype from B10.PL(H-2^u : K^uA^uE^uTNF^dD^d) and NZB(H-2^d : K^dA^dE^dTNF^dD^d), and TNF^b haplotype from B6(H-2^b : K^bA^bE^bTNF^b) to NZW(H-2^z : K^uA^uE^uTNF^zD^z), and established NZW.PL(H-2^u : K^uA^uE^uTNF^bD^d), NZW.H-2^d(H-2^d : K^dA^dE^dTNF^dD^d) and NZW.H-2^b(H-2^u : K^uA^uE^uTNF^dD^d) congenic strains. Then, we compared amounts of TNF produced by peritoneal macrophages in vitro stimulated with LPS and INF_<gamma>, and serum TNF levels among these NZW,NZW.PL,NZW.H-2^d and NZW.H-2^b strains. The NZW strains showed much smaller amount of TNF production by macrophages and also lower level of serum TNF than another three NZW.PL,NZW.H- … More 2^d and NZW.H-2^b strains of mice did. These results indicate that TNF gene polymorphism affects the TNF levels and that TNF^z is alow TNF haplotype, as compared with TNF^d of TNF^b haplotypes.The development of antoimmune disease is tightly linked to the haplotype of mouse MHC,H-2. Based on our previous studies, we suggested that class II molecules, especially I-A,relate to this H-2 restriction. There was, however, the report that TNF gene linked to H-2 may be involved and that low TNF level of TNF^z haplotype of NZW mice is critical for the development of severe autoimmune disease in (NZB*NZW)F1 mice. We then investigated the relationship between TNF polymorphism and autoimmune disease, using established congenic strains. TNF production by perioneal macrophages and serum TNF level were much decreased in (NZB*NZW)F1 mice, because of TNF^z haplotype derived from NZW,as compared with (NZB*NZW.PL)F1 and (NZB*NZW.H-2^d)F1 mice. As for autoimmune disease, (NZB*NZW)F1 mice developed the most severe disease and (NZB*NZW.PL)F1 mice a little milder than (NZB*NZW)F1 mice. In contrast, the disease severity in (NZB*NZW.H-2^d)F1 mice was much reduced, as compared with another two F1 strains. (NZB*NZW.PL)F1 and (NZB*NZW.H-2^d)F1 mice have the same TNF haplotype and produce the same amount of TNF.The haplotypes of K,A and E regions of H-2 are differ between these two F1 strains. Thus, we concluded that haplotypes of K,A,and E,but not that of TNF,affect the autoimmune disease severity in these mouse strains. Less

TNF基因与人和小鼠的主要组织相容性复合体紧密连锁。在小鼠TNF α基因启动子区，TNF单倍型之间存在简单的序列长度多态性（微卫星DNA多态性）。为了研究TNF多态性与TNF产生程度的关系，我们从B10.PL中引入了TNF α d单倍型。（H-2 ^u：K^uA^uE^uTNF^dD^d）和NZB（H-2 ^d：K^dA^dE^dTNF^dD^d），和来自B6的TNF^B b单倍型（H-2 ^B：K^bA^bE^bTNF^B）至NZW（H-2 ^z：K^uA^uE^uTNF^zD^z），并建立了NZW。（H-2 ^u：K^uA^uE^uTNF^bD^d）、NZW.H-2 ^d（H-2 ^d：K^dA^dE^dTNF^dD^d）和NZW.H-2 ^b（H-2 ^u：K^uA^uE^uTNF^dD^d）同源株。比较了<gamma>NZW、NZW.PL、NZW.H-2_d和NZW.H-2_b四株小鼠腹腔巨噬细胞在LPS和INF_2刺激下产生TNF的量和血清TNF水平。NZW株巨噬细胞产生TNF的量和血清TNF水平均低于NZW、PL、NZW、H- ...更多信息 NZW.H-2b品系小鼠的免疫反应。这些结果表明TNF基因多态性影响TNF水平，TNF^z是一个较低的TNF单倍型，而TNF^B单倍型中的TNF^d是一个较低的TNF单倍型，自身免疫性疾病的发生与小鼠MHC H-2单倍型密切相关。基于我们以前的研究，我们认为II类分子，特别是I-A，与这种H-2限制有关。然而，有报道称与H-2连锁的TNF基因可能参与其中，并且NZW小鼠的TNF^z单倍型的低TNF水平对于（NZB*NZW）F1小鼠中严重自身免疫性疾病的发展至关重要。然后，我们研究了TNF多态性和自身免疫性疾病之间的关系，使用已建立的同源株。与（NZB * NZW.PL）F1和（NZB * NZW.H-2 ^d）F1小鼠相比，（NZB* NZW）F1小鼠由于TNF^z单倍型来源于NZW，其腹膜巨噬细胞产生的TNF和血清TNF水平显著降低。对于自身免疫性疾病，（NZB*NZW）F1小鼠发展最严重的疾病，并且（NZB*NZW.PL）F1小鼠比（NZB*NZW）F1小鼠轻微。与此相反，（NZB*NZW.H-2 ^d）F1小鼠的疾病严重程度比另外两个F1品系低得多。(NZB（NZW.PL）F1和（NZB*NZW.H-2 ^d）F1小鼠具有相同的TNF单倍型，产生相同量的TNF，H-2的K、A和E区的单倍型在这两个F1品系之间是不同的。因此，我们得出结论，单倍型K，A和E，但不是TNF，影响自身免疫性疾病的严重程度，在这些小鼠品系。少

项目成果

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Kaneko,Y.et al: "CD40-mediated stimulation of B1 and B2 cells:implication in autoantibody production in murine lupus." Eur.J.Immunol.26. 3061-3065 (1996)

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