Sobel E S, Mohan C, Morel L, Schiffenbauer J, Wakeland E K
Department of Medicine, Division of Rheumatology and Clinical Immunology, Center for Mammalian Genetics, College of Medicine, University of Florida, Gainesville 32610, USA.
J Immunol. 1999 Feb 15;162(4):2415-21.
Sle1 is a potent autoimmune susceptibility locus on chromosome 1 originally identified in a genome scan of testcross progeny between the systemic lupus erythematosus-prone NZM2410 strain and C57BL/6. We subsequently produced B6.NZMc1, a congenic strain carrying the NZM2410-derived Sle1 genomic interval on the B6 background and demonstrated that Sle1 mediated the loss of tolerance to chromatin in both the B and T cell compartments. In this communication, we show by adoptive transfer experiments that the autoimmune phenotypes of Sle1 are completely reconstituted in B6 radiation chimeras receiving B6.NZMc1 bone marrow but not by the reciprocal reconstitution, demonstrating that Sle1 is functionally expressed in B cells. In additional experiments, cotransfer of mixtures of bone marrow derived from B6.NZMc1 and nonautoimmune congenic B6 mice carrying allelic T and B cell markers showed that only B cells derived from B6.NZMc1 bone marrow produced anti-chromatin autoantibodies. In contrast, increased expression of CD69 was equivalent in CD4+ T cells derived from either B6.NZMc1 or congenic B6 bone marrow, suggesting that either T cell population could be activated subsequent to loss of tolerance in the B cell compartment. These findings indicate that the expression of Sle1 in B cells is essential for the development of autoimmunity.
Sle1是位于1号染色体上的一个强大的自身免疫易感基因座，最初是在对系统性红斑狼疮易感的NZM2410品系与C57BL/6品系杂交后代的基因组扫描中发现的。随后，我们培育出了B6.NZMc1近交系，它在B6背景上携带源自NZM2410的Sle1基因组区间，并证明Sle1在B细胞和T细胞区室中均介导了对染色质耐受性的丧失。在本通讯中，我们通过过继转移实验表明，在接受B6.NZMc1骨髓的B6辐射嵌合体中，Sle1的自身免疫表型完全得以重建，但反向重建则不然，这表明Sle1在B细胞中功能性表达。在其他实验中，将源自B6.NZMc1的骨髓与携带等位基因T和B细胞标记的非自身免疫近交B6小鼠的骨髓混合物进行共转移，结果显示只有源自B6.NZMc1骨髓的B细胞产生抗染色质自身抗体。相比之下，CD69的表达增加在源自B6.NZMc1或近交B6骨髓的CD4+T细胞中相当，这表明在B细胞区室耐受性丧失后，任一T细胞群体都可能被激活。这些发现表明，Sle1在B细胞中的表达对于自身免疫的发展至关重要。
