Pathogenic role of innate immune cells in lupus nephritis

摘要 肾小球肾炎(GN)是与免疫相关的发病率和死亡率的主要原因。 疾病，如系统性红斑狼疮(SLE)。狼疮性肾炎的一个特征是出现自体- 针对核酸的反应性抗体，与补体因子一起形成特有的免疫 肾小球内有复合体(IC)沉积。这些IC被认为通过两个主要机制促进疾病， 即通过核酸识别Toll样受体(TLRs)和补体激活免疫细胞。 介导的细胞毒性。尽管这一概念是连贯的，但这种令人衰弱的疾病的治疗进展 一直是温和的，这项建议中显示的数据表明，先天的重要致病贡献 免疫细胞，特别是所谓的‘巡逻单核细胞’(PMO)。 在过去几年中，在识别遗传风险因素方面取得了重要进展。 对于系统性红斑狼疮。我们已经独立地确定了这些遗传风险因子之一，即TNIP1/ABIN1，即TLR信号 对C/eBPβ具有选择性负调节功能的分子。这种转录因子控制着各种 细胞分化方面，包括上述PMO的发展，一种具有新功能的细胞类型 血管内炎症。基于TnIP1的S性状作为人类系统性红斑狼疮的危险因素，我们实验室建立了Tnip1-/-小鼠， 我们发现它与人类SLE的主要特征相同，包括自身免疫性和严重的系膜病- 伴有IC沉积的增生性肾小球肾炎(PNAS，2011，周等人)。 在初步数据中，我们发现Tnip1-/-小鼠的GN是由TLRs驱动的，这与目前的模型一致。 然而，出乎意料的是，我们还发现GN的进展不依赖IC，但由先天免疫调节 细胞。我们确定了上述PMO的关键细胞类型，它在肾脏中大量积累 肾小球。引人注目的是，PMO的基因缺失可以防止肾脏损伤。因此，到目前为止，我们发现了一个 意外的细胞类型，即PMO，作为介导Tnip1-/-小鼠GN的罪魁祸首。根据其他证据， 包括前面提到的C/EBPβ在项目管理办公室开发中的作用，更重要的是，数据展示了 在SLE患者的肾小球中存在PMO，我们假设TLR驱动的PMO生物学调节的解除 通过ABIN1和C/EBP，β在狼疮和其他形式的肾小球肾炎中代表了一个新的关键致病性轴。 在这个项目中，我们将(I)描述解除管制的PMO生物学的关键步骤，即细胞分化和 肾小球滞留，(Ii)定义ABIN1用于控制C/EBPβ的分子机制，(Iii) 建立C/EBPβ通路和GN之间的因果联系和(Iv)确定PMO特异的药物靶点和 测试当前和新的、更具选择性的治疗方案，以了解它们对PMO生物学和狼疮性肾炎的影响。 总而言之，这个项目将描述PMO生物学在狼疮GN中的大部分未确定的机制 包括机械学和治疗学的观点。鉴于PMO介导的终末器官的概念新颖性 对于系统性红斑狼疮的损害，我们预计这里获得的数据将为治疗干预开辟新的领域。

ABSTRACT Glomerulonephritis (GN) is a leading cause of morbidity and mortality associated with immune-mediated diseases, such as systemic lupus erythematosus (SLE). A hallmark of lupus GN is the appearance of auto- reactive antibodies against nucleic acids which form, together with complement factors, characteristic immune complex (IC) deposits in kidney glomeruli. These IC are thought to promote disease by two major mechanisms, i.e. by activation of immune cells via nucleic-acid recognizing Toll-like receptors (TLRs) and by complement- mediated cytotoxicity. Despite the coherence of this concept, therapeutic progress for this debilitating disease has been modest, and data shown in this proposal suggest an important pathogenic contribution of innate immune cells, specifically so-called ‘patrolling monocytes’ (PMo). Important advances were made over the last years with respect to the identification of genetic risk factors for SLE. We had identified one of these genetic risk factors, i.e. TNIP1/ABIN1, independently as TLR signaling molecule with selective, negative regulatory function for C/EBPβ. This transcription factor controls various aspects of cell differentiation, including development of mentioned PMo, a cell type with emerging function in intravascular inflammation. Based on TNIP1’s trait as human SLE risk factor, our lab established Tnip1-/- mice, which we found to share major characteristics with human SLE, including autoimmunity and severe mesangial- proliferative GN with IC deposits (PNAS, 2011, Zhou et al). In preliminary data we show that GN in Tnip1-/- mice is driven by TLRs, consistent with the current model. Unexpectedly, however, we also found that GN proceeds independent of IC, but is mediated by innate immune cells. We identified the critical cell type as mentioned PMo, which accumulate at high numbers in kidney glomeruli. Strikingly, genetic deletion of PMo prevents kidney damage. As such, we identified a hitherto largely unsuspected cell type, i.e. PMo, as culprit that mediates GN in Tnip1-/- mice. Based on additional evidence, including mentioned function of C/EBPβ in PMo development and, importantly, data demonstrating the presence of PMo in glomeruli of SLE patients, we hypothesize that TLR-driven deregulation of PMo biology via ABIN1 and C/EBPβ represents a novel key pathogenicity axis in lupus and, possibly, other forms of GN. In this project, we will (i) characterize the key steps of deregulated PMo biology, i.e. cell differentiation and glomerular retention, (ii) define the molecular mechanism that is used by ABIN1 to control C/EBPβ, (iii) establish a causal link between the C/EBPβ pathway and GN and (iv) identify PMo-specific drug targets and test current and novel, more selective treatment options for their impact on PMo biology and lupus nephritis. Collectively, this project will characterize PMo biology as largely undefined mechanism in lupus GN from both mechanistic and therapeutic perspectives. Given the conceptual novelty of PMo-mediated end-organ damage in SLE, we expect that data obtained here will open new areas for therapeutic intervention.