Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Northwell Health, Feinstein Institute for Medical Research, Hofstra-Northwell School of Medicine, 350 Community Dr, Hempstead, NY, 11030, USA.
Curr Rheumatol Rep. 2019 Jan 15;21(1):2. doi: 10.1007/s11926-019-0803-3.
Systemic lupus erythematosus (SLE) is characterized by a breakdown of immune tolerance, resulting in inflammation and tissue destruction. While the primary causes of SLE are still obscure, the disorder is highly heritable. Genetic risk variants, on their own, are rarely causal or fully explain disease pathogenesis. We discuss the possibility that IRF5, a SLE susceptibility gene, has both genetic and non-genetic contributions to disease pathogenesis.
Genetic variants within and around IRF5 robustly associate with SLE risk. In SLE blood cells, IRF5 risk variants associate with elevated IRF5 expression and IFN production. Whether the observed increase in expression is due to risk variants or other disease-associated factors is not clear. Data from Irf5 mice backcrossed to multiple models of murine lupus support that IRF5's role in disease pathogenesis is non-genetic. Studies of IRF5 expression and function in genotyped healthy donors will address the question of whether IRF5 dysregulation in SLE is driven by genetic or non-genetic factors.
系统性红斑狼疮（SLE）的特征是免疫耐受的破坏，导致炎症和组织损伤。虽然 SLE 的主要病因仍不清楚，但这种疾病具有高度遗传性。遗传风险变异本身很少是因果关系的，也不能完全解释疾病的发病机制。我们讨论了 SLE 易感基因 IRF5 对疾病发病机制既有遗传贡献，也有非遗传贡献的可能性。
IRF5 内和周围的遗传变异与 SLE 风险显著相关。在 SLE 血细胞中，IRF5 风险变异与 IRF5 表达和 IFN 产生的升高有关。观察到的表达增加是由于风险变异还是其他与疾病相关的因素尚不清楚。与多种小鼠狼疮模型回交的 Irf5 小鼠的数据支持 IRF5 在疾病发病机制中的作用是非遗传的。对基因分型的健康供体中 IRF5 表达和功能的研究将解决 SLE 中 IRF5 失调是由遗传还是非遗传因素驱动的问题。
