Functional insights into the IRF5 genetic variants marking SLE risk.

 描述（由申请人提供）：拟议研究的目标是确定干扰素调节因子5（IRF5）狼疮风险变体如何转化为系统性红斑狼疮（SLE）的生物风险。全基因组关联研究（GWAS）已经确定IRF5是与SLE易感性最强相关的基因之一。虽然IRF5与狼疮的遗传关联是明确的，但IRF5风险变体促进狼疮易感性的确切机制仍然未知。我们假设IRF8在正常情况下可能是IRF5活性的负调节因子，而在狼疮中IRF5外显子6风险变体能够逃避这种负调节，从而激活I型IFN，导致异常免疫激活。为了解决这个问题，我们将（SA1）使用分子和生物化学方法表征pDC中的IRF 5外显子6变体，（SA2）研究IRF 8对IRF 5外显子6变体的影响，以及（SA3）SLE患者中IRF 5外显子6变体对IRF 5激活的影响。如果IRF8阻断IRF5活化，这将是获得对狼疮中I型IFN异常产生和免疫活化的机制理解的重要一步。

 DESCRIPTION (provided by applicant): The goal of the proposed research is to determine how the interferon regulatory factor 5(IRF5) lupus risk variant translates into biological risk of systemic lupus erythematosus (SLE). Genome wide association studies (GWAS) have identified IRF5 as one of the most strongly associated genes with susceptibility to SLE. Although the genetic association of IRF5 with lupus is clear, the exact mechanism by which IRF5 risk variant promotes susceptibility for lupus is still unknown. We hypothesize that IRF8 could be a negative regulatory factor of IRF5 activity under normal conditions, while in lupus the IRF5 exon 6 risk variants are capable of escaping this negative regulation thereby activating type I IFNs leading to aberrant immune activation. To address this question, we will (SA1) characterize IRF5 exon 6 variants in pDCs using molecular and biochemical approaches, (SA2) investigate the effects of IRF8 on IRF5 exon 6 variants, and (SA3) effect of IRF5 exon 6 variation on IRF5 activation in SLE patients. If IRF8 blocks IRF5 activation, this will be a significant step to gain the mechanistic understanding of aberrant production type I IFNs and immune activation in lupus.