Effect of TNF gene polymorphism on autoimmune disease

TNF基因与人和小鼠的主要组织相容性复合体密切相关。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，我们将B10.PL的TNF^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B6的TNF^b单倍型（H-2^b: K^bA^bE^bTNF^b）引入NZW(H-2^z: K^uA^uE^uTNF^zD^z)，并建立了NZW. pl （H-2^u: K^uA^uE^uTNF^dD^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）同源菌株。然后，我们比较了LPS和INF_< γ >体外刺激下腹腔巨噬细胞产生TNF的量以及NZW、NZW. pl、NZW. h -2^d和NZW. h -2^b菌株的血清TNF水平。与其他3株小鼠相比，NZW株巨噬细胞产生TNF的量明显减少，血清TNF水平也明显低于NZW. pl、NZW. h -…这些结果表明，TNF基因多态性影响TNF水平，与TNF^b单倍型的TNF^d相比，TNF^z是允许的TNF单倍型。抗免疫疾病的发展与小鼠MHC单倍型H-2密切相关。基于我们之前的研究，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相关的TNF基因可能参与其中，并且NZW小鼠TNF^z单倍型的低TNF水平对于（NZB*NZW）F1小鼠的严重自身免疫性疾病的发展至关重要。然后，我们利用已建立的同源菌株研究了TNF多态性与自身免疫性疾病之间的关系。与（NZB*NZW. pl）F1和（NZB*NZW. h -2^d）F1小鼠相比，（NZB*NZW）F1小鼠外周血巨噬细胞产生TNF和血清TNF水平明显降低，因为TNF^z单倍型来源于NZW。在自身免疫性疾病方面，（NZB*NZW）F1小鼠发病最严重，（NZB*NZW. pl）F1小鼠发病较（NZB*NZW）F1小鼠轻微。相比之下，与另外两个F1菌株相比，（NZB*NZW.H-2^d）F1小鼠的疾病严重程度大大降低。（NZB*NZW.PL）F1和（NZB*NZW.H-2^d）F1小鼠具有相同的TNF单倍型，产生相同数量的TNF。两个F1菌株H-2的K、A、E区单倍型不同。因此，我们得出结论，K、A和E的单倍型，而不是TNF的单倍型，影响这些小鼠品系自身免疫性疾病的严重程度。少

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