Role of beta2 integrin in lupus nephritis

项目摘要 狼疮性肾炎（LN）是一种使人衰弱的炎症性疾病，由系统性狼疮引起， 红斑狼疮（SLE，狼疮）。不明确的遗传和环境因素易患狼疮患者 治疗肾病约40%的狼疮患者表现出肾功能损害， 终末期肾病（ESRD）。女性尤其是育龄青年女性较多 提示肾小球早期损伤在LN发病中的作用。LN由糖皮质激素控制， 免疫抑制剂，具有许多副作用和相当大的长期毒性。因此 迫切需要改进的、有针对性的治疗。三个单核苷酸多态性（SNPs）， ITGAM基因编码区（编码CD 11b）与LN的发病率有很强的相关性（和 SLE）。然而，这些非同义突变如何赋予SLE风险尚不清楚，尽管它们可能与SLE相关。 似乎降低了CD 11b的生物学功能。考虑到肾小球白细胞流入增加， LN，这是自相矛盾的，因为CD 11b被广泛认为在白细胞浸润中起主要作用。这里我们 目前的数据表明，CD 11b活化在抑制Toll样受体（TLR）信号传导中起主要作用 途径。LN患者血清中IFN-I升高，suPAR是肾小球疾病的循环危险因素， 疾病由于这两种生物标志物都是在TLR途径的下游产生的，我们假设， 在LN中编码ITGAM SNP和这两种生物标志物的水平之间存在直接联系， 这是由于突变的CD 11b蛋白产物不能抑制TLR信号传导。我们也 假设CD 11b强制活化可减少TLR信号传导，足以减少IFN I， suPAR水平，从而改善疾病活动。我们还假设，CD 11b的激活使用一种 我们实验室最近发现的药理学小分子LA 1，或通过基因突变， 拯救突变型CD 11b蛋白的功能缺陷并抑制TLR依赖性炎症反应 发信号。因此，我们认为，CD 11b活化可能是一种新的治疗策略， LN新疗法的开发。在本提案中，我们提出了三个具体目标，以测试我们的 假设这些研究将有助于从机制上将与SLE相关的共同遗传因素联系起来 和LN与重要的临床生物标志物，并将为我们提供一个更好的理解， 疾病路径更重要的是，这些研究还将有助于确定CD 11b激活是否可能是一种 治疗LN的新机制，以及确定一种新的小分子LA 1的疗效， 潜在地导致LA 1（或其它类似药剂）作为治疗LN的新疗法的开发 患者这也可能导致针对特定易感性的第一种潜在疗法的发展 基因（ITGAM）在自身免疫性疾病。因此，这种全面的翻译研究具有潜力， 在将来对LN患者产生很大的有益影响。

Project Summary Lupus nephritis (LN) is a debilitating inflammatory disease that is caused by Systemic Lupus Erythematosus (SLE, lupus). Poorly defined genetic and environmental factors predispose lupus patients for renal disease. Approx. 40% of lupus patients show renal impairment and a large percentage develop end stage renal disease (ESRD). Women, especially young women of childbearing age, are more susceptible to LN, suggesting role of early glomerular injury in LN. LN is managed by glucocorticoids and immunosuppressive agents, with many side effects and considerable long-term toxicity. Therefore improved, targeted treatments are urgently needed. Three single nucleotide polymorphisms (SNPs) in the coding region of ITGAM gene (coding for CD11b), show strong correlation with the incidence of LN (and SLE). However, how these nonsynonymous mutations confer SLE risk is not clear, although that they appear to reduce the biological functions of CD11b. Given that glomerular leukocyte influx in increased in LN, this is paradoxical, as CD11b is widely considered to play a major role in leukocyte infiltration. Here, we present data that CD11b activation plays a major role in suppressing Toll like receptor (TLR) signaling pathways. IFN I is increased in sera of LN patients, and suPAR is a circulating risk factor for glomerular diseases. Since both biomarkers are generated downstream of the TLR-pathways, we hypothesize that there is a direct link between coding ITGAM SNPs and the levels of these two biomarkers in LN and that this is due to the failure of the mutant CD11b protein product to suppress TLR signaling. We also hypothesize that forced activation of CD11b can reduce TLR signaling, is sufficient to decrease IFN I and suPAR level, thereby ameliorating disease activity. We also hypothesize that activation of CD11b using a pharmacologic small molecule LA1 recently discovered in our laboratory, or via genetic mutations, can rescue the functional deficit of the mutant CD11b protein and suppress TLR-dependent inflammatory signaling. Therefore, we propose that CD11b activation can be a new therapeutic strategy for the development of novel therapeutics for LN. In this proposal, we present three specific aims to test our hypotheses. These studies will help mechanistically connect a common genetic factor associated with SLE and LN with important clinical biomarkers, and will provide us with an improved understanding of the disease pathways. More importantly, the studies will also help determine if CD11b activation could be a novel mechanism to treat LN, as well as define the efficacy of a novel small molecule, LA1, which could potentially lead to the development of LA1 (or other similar agents) as novel therapeutics to treat LN patients. This may also lead to the development of a first potential therapy targeting a specific susceptibility gene (ITGAM) in an autoimmune disease. Thus, this comprehensive translational study has the potential for making a large beneficial impact on the LN patients in the future.