Genetic factors Involved in the Pathogenesis of Autoimmune Disea

系统性红斑狼疮（SLE）是一种复杂的多基因自身免疫性疾病，临床表现多样。许多病理归因于与自身抗体连续形成的免疫复合物沉积到各种组织;因此，发病机制与自身反应性B细胞的遗传失调有关。然而.由于SLE表型的多基因遗传的复杂性是相当可观的，易感性位点和基因还没有被精确地鉴定。为了解决这些困难，我们设计了SLE的遗传学研究使用小鼠狼疮模型。主要的困难是与这样一个事实，即不同的SLE表型（临床表现和免疫学异常）的每个特定方面主要是由一组不同的易感基因座分别控制。正上位和负上位基因的相互作用常常困扰SLE表型的遗传分析。对自身反应性B细胞的出现、克隆扩增、分化和成熟的遗传调控研究表明，SLE易感性的不同对自身反应性B细胞的发育有不同的调控作用。有几个位置候选多态性基因可能是异常B细胞表型的原因。目前正在利用基因操作和重组小鼠进一步研究易感基因及其功能。这些知识将导致阐明SLE发病机制中自身反应性淋巴细胞失调的遗传和细胞机制。

Systemic lupus erythematosus (SLE) is a complex, multigenic autoimmune disease with a wide spectrum of clinical manifestations. Much of the pathology is attributed to deposition to various tissues of immune complexes continuously formed with autoantibodies ; thus, the pathogenesis is related to genetic dysregulation of self-reactive B cells. However. as the complexity of polygenic inheritance of SLE phenotypes is considerable, susceptibility loci and genes have not been identified precisely. To solve some such difficulties, we designed genetic studies on SLE using murine lupus models. Major difficulties were related to the fact that each specific aspect of diverse SLE phenotypes(clinical manifestations and immunological abnormalities)is mostly controlled separately by a different set of susceptibility loci. Involvement of positive and negative epistatic gene interactions often puzzles genetic analyses of SLE phenotypes. Studies on genetic regulations of emergence, clonal expansion, differentiation and maturation of self-reactive B cells showed that they are regulated at different stages by different of SLE-susceptibility. There were several positional candidate polymorphic genes that were potentially responsible for the abnormal B cell phenotypes. Further studies on the identification of susceptibility genes and their functions are ongoing using genetically manipulated and recombinant mice. Such knowledge will lead to elucidation of genetic and cellular mechanisms involved in dysregulation of self-reactive lymphocytes in the pathogenesis of SLE.