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Pathogenic role of innate immune cells in lupus nephritis

先天免疫细胞在狼疮性肾炎中的致病作用

基本信息

批准号：
10601014
负责人：
HANS HAECKER
金额：
$ 44.75万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-03 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10601014
关键词：
Affect Antigen-Antibody Complex Appearance Area Autoantibodies Autoimmune Diseases Autoimmunity Biology Cell Differentiation process Cells Characteristics Complement Complement-Dependent Cytotoxicity Critical Thinking Data Deposition Development Disease Drug Targeting Etiology Generations Genes Genetic Glomerular Capillary Glomerulonephritis Goals Human Immune Immune Complex Glomerulonephritis Immune Targeting Inflammation Injury to Kidney Kidney Kidney Glomerulus Link Lupus Lupus Nephritis Mediating Mesangial Proliferative Glomerulonephritis Modeling Molecular Morbidity - disease rate Mouse Strains Mus Myelopoiesis Nuclear Antigens Nucleic Acids Organ Organ failure Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pristane Process Receptor Activation Regulator Genes Risk Factors Role Signal Pathway Signaling Molecule Susceptibility Gene Symptoms Systemic Lupus Erythematosus TLR7 gene Testing Therapeutic Therapeutic Intervention Toll-like receptors Up-Regulation cell type chemokine receptor drug testing genetic risk factor immune activation improved innate immune mechanisms lupus-like monocyte mortality mouse model mycophenolate mofetil new therapeutic target novel novel therapeutic intervention novel therapeutics peripheral blood precursor cell prevent recruit renal damage sample fixation success tissue injury trait transcription factor

项目摘要

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.

摘要肾小球肾炎（GN）是与免疫介导的炎症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）。狼疮性肾炎的一个标志是出现自动- 针对核酸的反应性抗体，与补体因子一起形成特征性免疫复合物（IC）沉积在肾小球中。这些IC被认为通过两种主要机制促进疾病，即通过核酸识别Toll样受体（TLR）激活免疫细胞，介导的细胞毒性。尽管这一概念的一致性，治疗进展，这种衰弱的疾病一直是温和的，本提案中显示的数据表明先天性的重要致病作用免疫细胞，特别是所谓的“巡逻单核细胞”（PMo）。在过去几年中，在确定遗传风险因素方面取得了重要进展对于SLE。我们已经确定了这些遗传风险因素之一，即TNIP 1/ABIN 1，独立地作为TLR信号转导对C/EBPβ具有选择性负调控功能的分子。该转录因子控制各种细胞分化的方面，包括所提到的PMo的发育，PMo是在细胞分化中具有新兴功能的细胞类型。血管内炎症基于TNIP 1作为人类SLE危险因子的特性，本实验室建立了Tnip 1-/-小鼠，我们发现其与人类SLE的主要特征相同，包括自身免疫和严重的系膜- 增殖性GN伴IC沉积（PNAS，2011，Zhou et al）。在初步数据中，我们表明Tnip 1-/-小鼠的GN是由TLR驱动的，与当前模型一致。然而，出乎意料的是，我们还发现GN的发生不依赖于IC，而是由先天免疫介导的，细胞我们确定了关键的细胞类型，如PMo所述，其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损伤。因此，我们确定了迄今为止在很大程度上未被怀疑的细胞类型，即PMo，作为在Tnip 1-/-小鼠中介导GN的罪魁祸首。根据其他证据，包括C/EBPβ在PMo发展中的功能，重要的是，数据表明， SLE患者肾小球中PMo的存在，我们假设TLR驱动的PMo生物学失调通过ABIN 1和C/EBPβ代表狼疮中的一个新的关键致病轴，并且可能是其他形式的GN。在这个项目中，我们将（i）描述PMo生物学失调的关键步骤，即细胞分化，肾小球滞留，（ii）定义ABIN 1控制C/EBPβ的分子机制，（iii）建立C/EBPβ途径和GN之间的因果关系，以及（iv）鉴定PMo特异性药物靶点，测试当前和新的，更有选择性的治疗方案对PMo生物学和狼疮性肾炎的影响。总的来说，这个项目将PMo生物学的特点，在很大程度上是不确定的机制，在狼疮肾炎，从机械论和治疗学的角度来看。考虑到PMo介导的终末器官的概念新奇，由于SLE的损害，我们期望在此获得的数据将为治疗干预开辟新的领域。