Identifying autoimmune associated genes in patrolling monocytes that promote lupus nephritis

项目总结 狼疮性肾炎(LN)见于约50%的慢性自身免疫性疾病系统性红斑狼疮患者 红斑狼疮是这种疾病发病的一个严重原因，约10%的SLE病例导致终末期 肾脏疾病在确诊后5年内。LN在非欧洲血统的女性中发生的比例不成比例， 包括非洲裔美国人、西班牙裔美国人和亚洲人，尽管经过多年的研究，但很少有针对性的 治疗。最近批准了第一批两种特定的LN治疗药物，belimumab和voclosporin靶向 适应性免疫细胞(T细胞和B细胞)，是一个重要的里程碑。然而，这些疗法只有~40% 功效。因此，该领域的一个主要挑战是确定治疗或预防所有患者LN的治疗方法。那里 越来越多的证据表明，先天免疫细胞也对LN有贡献。特别是，非古典的，巡逻 单核细胞最近被认为与肾小球肾炎有关，这表明一种新的先天免疫 巡视单核细胞向肾脏募集对LN的作用机制 在疾病早期积累巡逻的单核细胞可能具有治疗效果。没有现有的 专门针对巡视单核细胞在肾脏或其他器官积聚的治疗方法，因此，更好 对驱动这一过程的基因和机制的了解为发现新的治疗方法提供了希望 LN的目标，也是本提案的重点。根据人类狼疮遗传风险基因座，我们将定义关键 LN患者肾内单核细胞聚集的相关基因。尽管许多遗传风险变种具有 已被证实与SLE风险增加有关，大多数基因的功能受这些变体调控 尚未在单核细胞等先天免疫细胞中得到系统评估。我们假设基因 与GWAS相关的风险变异可能是巡逻中单核细胞聚集的丰富调节因素 在肾小球毛细血管中，因此LN。了解遗传风险基因座如何影响巡逻 单核细胞在LN中的积聚，我们将使用体内CRISPR筛查，使用TLR7.1小鼠模型狼疮- 类似疾病，并在其他小鼠狼疮模型中得到验证。完成后，我们将照亮基因和 可能被新的治疗干预措施靶向的途径，这些干预措施可以在发病之前使用 肾炎。此外，与已识别基因相关的风险单倍型可以帮助预测 这种治疗方法以及对LN的风险。

PROJECT SUMMARY Lupus nephritis (LN) is seen in ~50% of individuals with the chronic autoimmune disease systemic lupus erythematosus and is a serious cause of morbidity in this disease, with ~10% of SLE cases leading to end stage renal disease within 5 years of diagnosis. LN occurs disproportionately in women of non-European ancestry, including African-Americans, Hispanics and Asians, and despite many years of study, there are few targeted treatments. The recent approval of the first two specific LN therapeutics, belimumab and voclosporin targeting adaptive immune cells (T and B cells), was an important milestone. However, these therapeutics only have ~40% efficacy. Thus, a major challenge in the field is to identify therapies that treat or prevent LN in all patients. There is growing evidence that innate immune cells also contribute to LN. In particular, non-classical, patrolling monocytes have recently been implicated in glomerulonephritis, suggesting that a novel innate immune mechanism through recruitment of patrolling monocytes to the kidney contributes to LN, and that interfering with accumulation of patrolling monocytes early in disease could be therapeutically efficacious. There are no existing therapies that specifically target patrolling monocyte accumulation in the kidney, or other organs, thus, a better understanding of the genes and mechanisms that drive this process holds promise for identifying new therapeutic targets for LN and is the focus of this proposal. Informed by human lupus genetic risk loci, we will define key genes involved in patrolling monocyte accumulation in the kidney in LN. Though many genetic risk variants have been identified as associated with increased risk for SLE, the function of most genes regulated by these variants have not been systematically assessed in innate immune cells such as monocytes. We hypothesize that genes associated with GWAS risk variants may serve as a rich source of regulators of patrolling monocyte accumulation in glomerular capillaries and therefore of LN. To understand how genetic risk loci contribute to patrolling monocyte accumulation in LN, we will use an in vivo CRISPR screen using the TLR7.1 mouse model of lupus- like disease with validation in additional mouse lupus models. Upon completion, we will illuminate genes and pathways that may be targeted by novel therapeutic interventions, which could be used prior to the onset of kidney nephritis. Additionally, risk haplotypes correlated with identified genes could help predict the efficacy of such therapeutic approaches as well as risk for LN.