Regulation of B cell tolerance by 129-derived chromosome 1 loci in C57BL/6 mice
Regulation of B cell tolerance by 129-derived chromosome 1 loci in C57BL/6 mice
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DOI：
10.1002/art.23553
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发表时间：
2008-07-01
影响因子：
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通讯作者：
Botto, Marina
中科院分区：
文献类型：
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作者：
Fossati-Jimack, Liliane;Cortes-Hernandez, Josefina;Botto, Marina
目标。系统性红斑狼疮是一种多因素疾病，具有很强的遗传成分。先前的研究表明，C57BL/6 （B6）背景下129衍生的1号染色体间隔（Sle 16）足以诱导体液性自身免疫。本研究的目的是阐明该基因座导致外周耐受性丧失的机制。将抗单链DNA（抗ssdna）敲入基因转基因小鼠(V（H)3H9R/V kappa 8R和V(H)3H9R）与携带Sle16位点的B6基因系B6.129chr1b杂交。对1号染色体上突变基因位于129chr1b区间的基因靶动物进行了平行研究。V(H)3H9R/V kappa 8R与129chr1b区间的结合导致B细胞能量受损，循环中发现转基因IgM和IgG抗ssdna抗体。血清中存在IgG2a(a)抗ssdna抗体和IgM(a)抗sm抗体，表明自身反应性转基因B细胞发生了类转换和表位扩散。129chr1b位点似乎具有显性作用，因为在携带单个等位基因的小鼠中也检测到转基因抗体。基因靶向动物表现出相似的表型。B6基因背景上单个129chr1b位点的存在损害了B细胞的能量，阻止了抗dna转基因B细胞的缺失，并诱导了受体的修饰。本研究的结果还强调，在1号染色体上有目标基因的小鼠中观察到的自身免疫表型可能仅仅是由129和B6亲本菌株之间的上位性相互作用引起的。
Objective. Systemic lupus erythematosus is a multifactorial disease with a strong genetic component. Previous studies have shown that a 129-derived chromosome 1 interval (Sle 16) on the C57BL/6 (B6) background is sufficient to induce humoral autoimmunity. The aim of the present study was to elucidate the mechanisms by which this locus contributes to the loss of peripheral tolerance.Methods. Anti-single-stranded DNA (anti-ssDNA)-knockin transgenic mice (V(H)3H9R/V kappa 8R and V(H)3H9R) were crossed with a B6 congenic line named B6.129chr1b that carries the Sle16 locus. A parallel study of a gene-targeted animal, whose mutated gene is located within the 129chr1b interval on chromosome 1, was also performed.Results. The combination of V(H)3H9R/V kappa 8R with the 129chr1b interval resulted in impaired B cell anergy, and transgenic IgM and IgG anti-ssDNA antibodies were found in the circulation. The presence of IgG2a(a) anti-ssDNA and IgM(a) anti-Sm antibodies in sera indicated that the autoreactive transgenic B cells underwent class switching and epitope spreading. The 129chr1b locus appeared to have a dominant effect, since transgenic antibodies were also detected in mice carrying a single allele. The gene-targeted animals showed a similar phenotype.Conclusion. The presence of a single 129chr1b locus on the B6 background impaired B cell anergy, prevented deletion of anti-DNA transgenic B cells, and induced receptor revision. The findings of this study also emphasize that the autoimmune phenotype observed in mice with targeted genes located on chromosome 1 may simply arise from epistatic interactions between the 129 and B6 parental strains.