Studies of autoimmune disease using mice with genetic recombination

多基因效应是(NZB X NZW)F1小鼠严重自身免疫性疾病发展的原因，这种疾病类似于人类系统性红斑狼疮。利用H-2同系小鼠，我们证明了NZB的H-2^d和NZW小鼠的H-2^z的杂合性对于这些小鼠的免疫球蛋白抗DNA抗体和严重狼疮性肾炎的发生是必需的，并提出了F1独特的杂合型11类分子可能是一个限制性元件。这一观点得到了我们后代研究的支持，在这些研究中，与NZW株T细胞受体β链基因复合体连锁的一个或一群基因座结合H-2^d/H-2^Z杂合性与这些小鼠产生IgG抗DNA抗体有关。结合我们以前发现的(NZB X NZW)F1小鼠产生免疫球蛋白抗体对T细胞的严格依赖，似乎T细胞受体的独特结构与F1独特的hy…之间的相互作用桥联II类分子越多，合成的抗体效果越好。对NZB株和NZW株进行了核苷酸序列分析，发现NZW(H-2^z)Ebeta株与BlOPL株(H-2^u)除了两个N端两个氨基酸的差异(Ebeta^u为Arg^1 Gly^2，Ebeta^z为Val^1 Arg^2)外，其余均相同。NZW Abeta、Apha、Epha基因的第二外显子序列与H-2^u相同，NZB小鼠与Balb/c小鼠(H-2^d)的MHCⅡ类基因多态性相同。分析表明，NZW小鼠Ealpha1区的独特多态可能与F1独特的杂交E分子的形成有关，该杂合分子可能是在H-2^d/H-2^z杂合性中形成的。探讨这些F1特有的杂交II类分子在(NZB X NZW)F1小鼠自身免疫性疾病中的可能作用。使用几种II类转基因菌株的研究正在进行中。H-2同源基因小鼠。较少

The multi-gene effect is responsible for the development of severe autoimmune disease in (NZB X NZW)Fl mice, resembling human systemic lupus erythematosus. Using H-2 congenic mouse strains, we demonstrated that the beterozygosity of the H-2^d from NZB and H-2^z from NZW mouse is required for the development of IgG anti-DNA antibodies and severe lupus nephritis in these mice, and have proposed that the Fl unique hybrid class ll molecules may act as a restriction element. This idea was supported by our finding of progeny studies in which a locus or a cluster of loci linked to T cell receptor beta chain gene complex of the NZW strain in combination with H-2^d/H-2^Z heterozygosity is associated with the production of IgG anti-DNA antibodies in these mice. Together with our previous finding of the strict CD4^+ T cell dependency of IgG anti-DNA antibody production in (NZB X NZW)Fl mice, it appears that the interaction between the unique structures of the T cell receptors and the Fl unique hy … More brid class II molecules is preferable for IgG anti-DNA antibody synthesis. We then analyzed the polymorphism of class II genes of NZB and NZW strains by the nucleotide sequence analysis, and found that NZW(H-2^z) Ebeta is identical to that of BlOPL(H-2^u) except for two N-terminal two amino acid differences (Arg^1 Gly^2 for Ebeta^u and Val^1 Arg^2 for Ebeta^z). The second exon sequences of NZW Abeta, Aalpha, Ealpha genes were shown to be identical to those of H-2^u. MHC class II polymorphism of NZB mice appeared to be identical to that of Balb/c mice(H-2^d). Analysis suggested that unique polymorphism in Ealpha alpha 1 domain of NZW mice which is so far found only in u and z haplotypes may contribute to the formation of Fl unique hybrid E molecule which should be formed in H-2^d/H-2^z heterozygosity. To investigate the possible roles of these Fl unique hybrid class II molecule on autoimmuno disease of (NZB X NZW) Fl mice. studies are under way using several strains of class II transgenic. H-2 congenic mice. Less