The role of BTLA in the pathogenesis of glomerulonephritis

肾小球肾炎(GN)是一组异质性的炎症性肾脏疾病，可通过破坏肾滤过单位(肾小球)而导致终末期肾脏疾病。他们的分子机制还不完全清楚，这限制了我们的治疗选择广泛的免疫抑制。T细胞和树突状细胞(DC)已被确定为实验性GN小鼠模型的关键角色，即所谓的肾毒性肾炎(NTN)，这使它们成为治疗该疾病的有趣靶点。BTLA(B和T淋巴细胞衰减器)是一种免疫球蛋白超家族蛋白，在多种自身免疫性疾病模型中通过限制T细胞的激活而具有抗炎作用。我们最近发现经典DC的次要亚群(CDC1)在肾小球肾炎中具有强大的抗炎功能，而BTLA是肾小球肾炎过程中这些细胞中最显著的上调蛋白之一。在本项目中，我们将通过攻击BTLA基因敲除的肾炎小鼠，分析疾病的转归以及渗透免疫细胞亚群和全身免疫反应的机会，来研究BTLA在GN中的作用。在第二步中，我们将通过挑战混合骨髓嵌合体来关注BTLA在cDC1上的特定功能，混合骨髓嵌合体在DC亚群中选择性地缺乏BTLA。最后，我们将通过在肾小球肾炎过程中对Xcr1-Venus和Zbtb46-GFP骨髓嵌合体的多光子活体成像来分析两个主要的经典DC亚群(cDC1和cDC2)在炎症部位的动态募集行为和相互作用。通过结合这些不同的方法，我们相信这个项目将对肾小球肾炎的基本病理机制产生新的见解，这不仅将促进我们对疾病的理解，也将有可能为我们的患者揭示新的治疗策略。

Glomerulonephritides (GN) are a heterogeneous group of inflammatory kidney diseases that can lead to end-stage renal disease by destruction of the kidney filtering units (glomeruli). Their molecular mechanisms are incompletely understood, which limits our therapeutic options to broad immunosuppression. T-cells and dendritic cells (DCs) have been identified as key players in a mouse model of experimental GN, the so-called nephrotoxic nephritis (NTN), making them interesting targets for the treatment of the disease. BTLA (B and T lymphocyte attenuator) is an immunoglobulin superfamily protein, which has anti-inflammatory properties in several autoimmune disease models by limiting the magnitude of T-cell activation. We have recently shown that the minor subset of classical DCs (cDC1) has a robust anti-inflammatory function in glomerulonephritis and that BTLA is among the most significantly upregulated proteins in these cells during the course of the disease.In this project we will investigate the function of BTLA in GN by challenging Btla-knockout mice with nephrotoxic nephritis and analyzing the outcome of the disease and the chances in infiltrating immune cell subsets and the systemic immune response. In a second step we will focus on the specific function of BTLA on cDC1 by challenging mixed-bone marrow chimeras, that selectively lack BTLA in this DC subset. We will then evaluate the therapeutic potential by treating mice during GN with agonistic antibodies for BTLA.Lastly, we will analyze the dynamic recruitment behavior and interactions of the two major classical DCs subsets (cDC1 and cDC2) at the site of inflammation by multiphoton intravital imaging of Xcr1-Venus and Zbtb46-GFP bone marrow chimeras during the course of GN.By combing these different approaches, we are confident that this project will yield new insights on essential pathomechanisms in glomerulonephritis, which will not only advance our understanding of the disease but also have the potential to reveal new treatment strategies for our patients.