Novel Biomarkers in Rheumatoid Arthritis

类风湿关节炎的新型生物标志物

• 批准号: 8468995
• 负责人: WILLIAM FREDERICK CARSON RIGBY
• 金额: $ 16.75万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-11 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468995
• 关键词: Affect; Alleles; Antibodies; Antibody Formation; Antigen-Antibody Complex; Antigens; Arginine; Autoantibodies; B-Cell Activation; B-Lymphocytes; Biological Markers; Blood; CXCL13 gene; Cellular biology; Citrulline; Clinical; Complement; Complex; Copy Number Polymorphism; Development; Diploidy; Disease; Epitopes; Failure; Frequencies; Functional disorder; Gene Dosage; Genes; Genetic; Genome; HLA-DRB1; Human; Hyperactive behavior; Hypergammaglobulinemia; Immunoglobulin G; Lead; Link; Linkage Disequilibrium; Mediating; Mediator of activation protein; Modeling; Nature; Onset of illness; Outcome; Pathogenesis; Patients; Phenotype; Physiological; Play; Population; Proteins; Public Health; Relative (related person); Rheumatoid Arthritis; Risk Factors; Role; Serum; Severities; Severity of illness; Shapes; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; Testing; United States; Variant; amino group; autoreactive B cell; base; carbonyl group; chemokine; cohort; disease phenotype; human subject; hydroxyl group; innovation; novel; response; thioester; trafficking

DESCRIPTION (provided by applicant): This proposal tests a novel and innovative hypothesis in Rheumatoid Arthritis (RA) pathobiology. Specifically, we examine the role of complement C4B gene copy number variation (CNV) on RA pathogenesis and its interaction with HLA-DRB1 alleles (e.g. the shared epitope) in influencing RA phenotype (disease severity, B cell hyperactivity). Complement C4 proteins (C4A, C4B) are functionally distinguished by the nature of the covalent linkage they form with their targets: amino (C4A) vs thioester (C4B). Among their many essential roles, the acidic C4A and the basic C4B are important for the clearance of immune complexes. A deficiency of C4A is a well-established risk factor for human SLE, but the physiologic impact of C4B deficiency is under-studied. A diploid genome of a human subject contains zero to four copies of the C4B gene; serum levels of C4B strongly correlate with the number of C4B genes. In a RA population at Dartmouth, we observed that C4B deficiency (0-1 copy) is present in 43% of the seropositive patients, 31% of seronegative RA patients and 20% of non-RA patients or healthy controls (OR from 2.5 to 2.8). We hypothesize a particular role for C4B relative to C4A in RA mediated by its ability to clear immune complexes made up of anti-citrullinated protein antibodies (ACPA) and citrullinated antigens. We propose that the presence of deiminated-Arginines (i.e. citrullines with decreased numbers of amino groups) in these complexes results in a reduced ability of C4A to contribute to their clearance. As a result, the ability of the C4B-thioester carbonyl group to form a covalent linkage with a hydroxyl group of substrates for disposal makes C4B of much greater importance than C4A in the clearance of ACPA-immune complexes. Thus, deficient ACPA-based immune complex clearance associated with C4B deficiency would particularly enhance and favor maturation of anti-ACPA responses, promoting both seropositive RA and B cell hyperactivity. Hypothesis: We propose that C4B deficiency influences RA disease pathogenesis independent of the shared epitope (Aim 1). In Aim 2, we propose that C4B deficiency shapes RA phenotype and B cell hyperactivity (serum CXCL13, IgG and autoantibody levels).

描述（由申请人提供）：该提案检验了类风湿关节炎（RA）病理生物学中的新颖而创新的假设。具体而言，我们研究了补体C4B基因拷贝数变化（CNV）对RA发病机理的作用及其与HLA-DRB1等位基因（例如共享表位）在影响RA表型（疾病严重程度，B细胞多动物）中的相互作用。补体C4蛋白（C4A，C4B）在功能上以它们与目标形成的共价连锁的性质区分：氨基（C4A）与硫酯（C4B）。在其许多基本作用中，酸性C4a和基本C4B对于清除免疫复合物很重要。 C4A的缺乏是人类SLE的一个公认的危险因素，但是C4B缺乏的生理影响不足。人类受试者的二倍体基因组包含C4B基因的四个副本。 C4B的血清水平与C4B基因的数量密切相关。在达特茅斯（Dartmouth）的RA人群中，我们观察到43％的血清阳性患者中存在C4B缺乏症（0-1拷贝），31％的血清染色RA患者和20％的非RA患者或健康对照组（或2.5至2.8）。我们假设C4B相对于C4A在RA中的特定作用，这是由于其清除由抗硝化蛋白抗体（ACPA）和瓜氨酸抗原组成的免疫复合物的能力。我们建议在这些复合物中存在能力性的 - 精氨酸（即氨基数量减少）的存在导致C4a有助于其清除率的能力降低。结果，在清除ACPA-rimmune复合物中，C4B- thioeser羰基与羟基底物形成共价连接的能力比C4A更重要。因此，与C4B缺乏症相关的基于ACPA的免疫复杂清除率不足将特别增强和有利于抗ACPA反应的成熟，从而促进血清阳性RA和B细胞多动。假设：我们建议C4B缺乏影响RA疾病发病机理，而与共享表位无关（AIM 1）。在AIM 2中，我们提出C4B缺乏型会塑造RA表型和B细胞多动（血清CXCL13，IgG和自身抗体水平）。

项目成果

Serum C-X-C motif chemokine 13 is elevated in early and established rheumatoid arthritis and correlates with rheumatoid factor levels.

• DOI: 10.1186/ar4552
• 发表时间: 2014-04-25
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Jones JD;Hamilton BJ;Challener GJ;de Brum-Fernandes AJ;Cossette P;Liang P;Masetto A;Ménard HA;Carrier N;Boyle DL;Rosengren S;Boire G;Rigby WF
• 通讯作者: Rigby WF