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）：该提案测试了类风湿关节炎（RA）病理学中的新颖且创新的假设。具体来说，我们研究了补体 C4B 基因拷贝数变异 (CNV) 对 RA 发病机制的作用及其与 HLA-DRB1 等位基因（例如共享表位）的相互作用对 RA 表型（疾病严重程度、B 细胞过度活跃）的影响。补体 C4 蛋白（C4A、C4B）通过它们与其靶标形成的共价键的性质在功能上进行区分：氨基 (C4A) 与硫酯 (C4B)。在其众多重要作用中，酸性 C4A 和碱性 C4B 对于免疫复合物的清除非常重要。 C4A 缺乏是人类 SLE 的一个公认的危险因素，但 C4B 缺乏的生理影响尚未得到充分研究。人类受试者的二倍体基因组包含零到四个 C4B 基因拷贝； C4B 的血清水平与 C4B 基因的数量密切相关。在达特茅斯的 RA 人群中，我们观察到 43% 的血清阳性患者、31% 的血清阴性 RA 患者和 20% 的非 RA 患者或健康对照中存在 C4B 缺陷（0-1 个拷贝）（OR 从 2.5 到2.8）。我们假设 C4B 相对于 C4A 在 RA 介导中具有特殊作用，因为它能够清除由抗瓜氨酸蛋白抗体 (ACPA) 和瓜氨酸抗原组成的免疫复合物。我们认为这些复合物中脱亚胺化精氨酸（即氨基数量减少的瓜氨酸）的存在会导致 C4A 促进其清除的能力降低。因此，C4B-硫酯羰基与底物羟基形成共价键以进行处理的能力使得 C4B 在 ACPA 免疫复合物的清除中比 C4A 更重要。因此，与 C4B 缺陷相关的基于 ACPA 的免疫复合物清除缺陷将特别增强并有利于抗 ACPA 反应的成熟，从而促进血清阳性 RA 和 B 细胞过度活跃。假设：我们提出 C4B 缺陷影响 RA 疾病的发病机制，与共享表位无关（目标 1）。在目标 2 中，我们提出 C4B 缺陷会影响 RA 表型和 B 细胞过度活跃（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