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The role of complement citrullination in RA pathogenesis

补体瓜氨酸化在 RA 发病机制中的作用

基本信息

批准号：
9980293
负责人：
Felipe Andrade
金额：
$ 35.99万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-16 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980293
关键词：
Address Affect Amplifiers Antibodies Antigens Arthritis Autoantibodies Autoantigens Autoimmune Process B-Cell Activation B-Lymphocytes Biochemical Biological Assay Cells Clinical Complement Complement Activation Complement Factor H Complement Membrane Attack Complex Data Deposition Disease Disease Outcome Enzymes Event Feeds Immune Immune Targeting Immune response Immune system Impairment Infiltration Inflammation Inflammatory Joints Lytic Mass Spectrum Analysis Measures Mediating Modification Outcome Outcome Study Pathogenesis Pathogenicity Pathway interactions Patients Post-Translational Protein Processing Prevalence Process Production Protein-arginine deiminase Proteins Publishing Regulation Rheumatism Rheumatoid Arthritis Role Structure Subgroup Synovial Fluid Synovial Membrane Testing Therapeutic Intervention Tissues To autoantigen Work articular cartilage bone erosion cell injury chronic autoimmune disease citrullinated protein clinically significant cohort complement C3d,g complement system genetic regulatory protein in vitro Assay in vivo joint injury multiple reaction monitoring neutrophil novel response targeted treatment

项目摘要

PROJECT SUMMARY/ABSTRACT Understanding the mechanisms which drive immune responses to autoantigens is of high priority. In rheumatoid arthritis (RA), protein citrullination is a major target of the immune system. Significant data implicates the anti-citrullinated protein immune response in RA pathogenesis, with recent evidence suggesting that mechanisms which enhance citrullination are associated with the worst disease outcome. While different mechanisms likely promote citrullination in RA, our published and preliminary data suggest that citrullination and the complement system are interacting pathways that amplify each other to enhance autoantigen production and immune-mediated damage in a sizable subset of RA patients. Thus, we have found that cellular membranolysis mediated by complement is a potent inducer of protein citrullination in the RA joint, and that this process is associated with citrullination of critical regulatory components of the complement system (complement factor H (CFH), and C3), enhancing complement activation. The previous finding that anti-CFH antibodies are prevalent in RA further highlights the importance of CFH in this disease, adding an extra mechanism that may dysregulate complement in RA. Taken together, we propose that citrullination-induced complement dysregulation and anti-CFH antibodies are key amplifiers that propagate damage and citrullination activity in the RA joint. We will examine this hypothesis in 3 Specific Aims. In Aim 1, we will use mass spectrometry and biochemical assays to define the structural and functional effects of citrullination on CFH and C3, as well as the effect of these modified proteins on the induction of the terminal complement complex, neutrophil hypercitrullination and B cell activation mediated by citrullinated C3dg. Aim 2 will use multiple reaction monitoring (MRM) to quantify citrullinated CFH and C3 in synovial fluid from RA and other arthritides to define their association with complement deposition and lytic activity in the joint. Aim 3 will determine whether anti-CFH antibodies participate in the dysregulation of complement in RA by defining their prevalence and clinical significance in RA, their association with complement activation, and their effect on CFH function. These studies will define novel interacting mechanisms of disease amplification relevant to sustain inflammation and aggravate damage in the rheumatoid joint. Furthermore, the studies will show that these pathways are active in vivo in RA, identifying markers and subgroups for precise therapeutic intervention.

项目摘要/摘要理解驱动对自身抗原的免疫应答的机制是高度优先的。在在类风湿性关节炎（RA）中，蛋白质瓜氨酸是免疫系统的主要靶标。重要数据提示抗瓜氨酸化蛋白免疫应答参与RA发病机制，最近的证据表明增强瓜氨酸的机制与最严重的疾病结果有关。虽然不同虽然我们的研究结果表明，瓜氨酸可能是促进类风湿关节炎的一种机制，但我们发表的初步数据表明，和补体系统是相互作用的途径，产生和免疫介导的损害在一个相当大的子集的RA患者。因此，我们发现，补体介导的膜溶解是RA关节中瓜氨酸蛋白的有效诱导物，该过程与补体系统的关键调节成分瓜氨酸有关（补体因子H（CFH）和C3），增强补体激活。之前的研究发现，抗体在RA中普遍存在进一步强调了CFH在这种疾病中的重要性，增加了额外的 RA中补体失调的机制。总之，我们认为瓜氨酸诱导的补体失调和抗CFH抗体是传播损伤和瓜氨酸的关键放大器在RA关节活动。我们将在三个具体目标中检验这个假设。在目标1中，我们将使用质量光谱分析和生化测定，以确定瓜氨酸对CFH的结构和功能影响， C3，以及这些修饰的蛋白质对诱导末端补体复合物的作用，瓜氨酸化C3 dg介导的中性粒细胞高瓜氨酸血症和B细胞活化。目标2将使用多个反应监测（MRM），以定量RA和其他关节炎患者滑液中的瓜氨酸化CFH和C3 以确定它们与关节中补体沉积和溶解活性的关联。目标3将决定通过定义抗CFH抗体的患病率，在RA中的临床意义，它们与补体激活的关系，以及它们对CFH功能的影响。这些研究将定义与维持健康相关的疾病放大的新的相互作用机制。炎症和加重类风湿关节的损伤。此外，研究表明，这些在RA中，这些通路在体内是活跃的，从而鉴定用于精确治疗干预的标记物和亚组。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination.

DOI：
10.3389/fimmu.2016.00461
发表时间：
2016
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Konig MF;Andrade F
通讯作者：
Andrade F

Rheumatoid arthritis and citrullination.

DOI：
10.1097/bor.0000000000000452
发表时间：
2018-01
期刊：
Current opinion in rheumatology
影响因子：
5.1
作者：
Darrah E;Andrade F
通讯作者：
Andrade F

Comment on "Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis".

对“滑膜成纤维细胞-中性粒细胞相互作用促进类风湿性关节炎致病性适应性免疫”的评论。

DOI：
10.1126/sciimmunol.aao6234
发表时间：
2018
期刊：
Science immunology
影响因子：
24.8
作者：
Shi,Jing;Andrade,Felipe
通讯作者：
Andrade,Felipe

Rheumatoid Arthritis-Associated Autoimmunity Due to Aggregatibacter actinomycetemcomitans and Its Resolution With Antibiotic Therapy.

DOI：
10.3389/fimmu.2018.02352
发表时间：
2018
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Mukherjee A;Jantsch V;Khan R;Hartung W;Fischer R;Jantsch J;Ehrenstein B;Konig MF;Andrade F
通讯作者：
Andrade F