Section of Rheumatology, University of Chicago, Chicago, IL 60637, USA.
Transl Res. 2010 Mar;155(3):109-17. doi: 10.1016/j.trsl.2009.08.012. Epub 2009 Sep 25.
Genetic association studies in systemic lupus erythematosus (SLE) have been extremely successful in recent years, identifying several loci associated with disease susceptibility. Much work remains to integrate these loci into the functional pathogenic pathways that characterize the disease. Our working hypothesis is that many genetic variations linked to SLE and autoimmunity mediate the risk of disease by altering cytokine profiles or responses to cytokine signaling. Genetic polymorphisms that affect cytokine signaling could alter thresholds for immune responses, resulting in proinflammatory presentation of self-antigens and the subsequent misdirection of adaptive immunity against self, which is observed in autoimmune disease. SLE is clinically heterogeneous and genetically complex, and we expect that individual genes and cytokine patterns will be more or less important to different disease manifestations and subgroups of patients. Defining these genotype-cytokine-phenotype relationships will increase our understanding of both initial disease pathogenesis as well as subsequent response/nonresponse to various therapies. In this review, we summarize some recent work in the area of SLE cytokine genetics and describe the implications for SLE, autoimmunity, and immune system homeostasis, which are revealed by these investigations.
近年来，系统性红斑狼疮（SLE）的遗传关联研究取得了巨大成功，确定了几个与疾病易感性相关的基因座。将这些基因座整合到描述疾病的功能发病途径中仍有许多工作要做。我们的工作假设是，许多与 SLE 和自身免疫相关的遗传变异通过改变细胞因子谱或对细胞因子信号的反应来介导疾病的风险。影响细胞因子信号的遗传多态性可能会改变免疫反应的阈值，导致自身抗原的促炎呈递，随后适应性免疫对自身的错误导向，这在自身免疫性疾病中观察到。SLE 临床表现异质性和遗传复杂性，我们预计个别基因和细胞因子模式对不同的疾病表现和患者亚群的重要性程度不同。定义这些基因型-细胞因子-表型关系将增加我们对疾病初始发病机制以及对各种治疗反应/无反应的理解。在这篇综述中，我们总结了 SLE 细胞因子遗传学领域的一些最新工作，并描述了这些研究揭示的 SLE、自身免疫和免疫系统稳态的意义。
