Peripheral Blood Biomarkers of RA-associated Interstitial Lung Disease

RA 相关间质性肺病的外周血生物标志物

• 批准号: 8142414
• 负责人: DANA P ASCHERMAN
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142414
• 关键词: Address; Adult; Affect; Antibodies; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Automobile Driving; Binding; Biological Markers; Biopsy; Blood Proteins; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CXCL10 gene; CXCR3 gene; Categories; Characteristics; Cicatrix; Clinical; Clinical assessments; Complement 3; Complication; Connective Tissue Diseases; Data; Detection; Development; Disease; Early Diagnosis; Early treatment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Enzymes; Equilibrium; Excess Mortality; Eye; Growth Factor; Hamman-Rich syndrome; Heart; Immune; Immunoprecipitation; Immunotherapeutic agent; Incidence; Inflammation; Inflammatory; Interstitial Lung Diseases; Intervention; Joints; Lead; Lung; Lung diseases; Matrix Metalloproteinases; Measurement; Mediating; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Pathogenesis; Patients; Pattern; Peripheral; Play; Population; Predictive Value; Prevalence; Process; Proteins; Proteomics; Pulmonary Fibrosis; Relative (related person); Research; Resolution; Rheumatoid Arthritis; Rheumatoid Factor; Role; Scanning; Screening procedure; Serological; Serum; Serum Proteins; Severities; Signaling Molecule; Site; Skin; Smoking; Smoking Status; Staging; Stimulus; Structure of parenchyma of lung; Subgroup; Surrogate Markers; Synovial Membrane; Techniques; Therapeutic Intervention; Time; Tissues; United States; Up-Regulation; Veterans; X-Ray Computed Tomography; arthropathies; base; chemokine; clinically significant; cohort; comparative; cytokine; insight; member; molecular phenotype; mortality; novel; peripheral blood; protein expression; response; systemic autoimmune disease; therapeutic target; tool

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is the most common systemic autoimmune disease in the United States, affecting 1-2% of the adult population. Although joints and synovium are the primary targets in this disorder, extra-articular manifestations involving the eyes, skin, heart, vasculature, and lungs can lead to significant morbidity as well as excess mortality. Among the various pulmonary complications that occur in RA, interstitial lung disease (ILD) is the most damaging, with effects that range from subclinical inflammation/scarring to end stage pulmonary fibrosis. Because earlier, subclinical forms of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) may represent more treatable precursors of pulmonary fibrosis, non-invasive peripheral biomarkers are needed to identify this pulmonary complication in advance of clinical decompensation. Based on the hypothesis that CXCR3-binding chemokines and various matrix metalloproteinases play a significant role in driving inflammation as well as tissue damage in RA-ILD, Specific Aim 1 employs multiplex ELISA in RA patients with/without various forms of ILD to correlate the peripheral blood/serum levels of these signaling molecules and degradative enzymes with stage of lung disease. Extending the analysis of Specific Aim 1, Specific Aim 2 defines composite biomarker profiles of serum protein expression patterns in a parallel cohort of VA-derived RA patients with varying stages of ILD, validating the use of serum multiplex ELISA and elucidating the contribution of important secondary factors such as smoking. Finally, Specific Aim 3 complements this molecular phenotyping approach, utilizing immunoprecipitation and ELISA-based techniques to delineate serum anti-citrullinated protein autoantibody profiles that correlate with the presence or absence of ILD. Through the development of peripheral blood biomarker signatures associated with RA-ILD, these collective approaches will provide insight regarding the pathogenesis of RA-ILD and other forms of immunologically mediated lung disease. More importantly, defining the molecular phenotype of ILD will identify therapeutic targets facilitating early treatment intervention in this potentially devastating extra-articular complication of RA. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is the most common systemic autoimmune disorder in the United States Veteran population, though the exact prevalence is unknown. Among the most significant and serious extra-articular complications of RA is interstitial lung disease (ILD). Because early, subclinical forms of RA-ILD may be precursors to pulmonary fibrosis, readily obtainable biomarkers are needed to facilitate early diagnosis and therapeutic intervention in this condition that is likely tied to highly prevalent environmental risk factors such as smoking. In short, this proposal involves the development of novel peripheral blood biomarkers that will not only serve as tools in the clinical assessment of RA-ILD, but will also lend insight regarding pathogenesis and the role of smoking in this potentially devastating process. By extension, these studies will advance our understanding of other forms of connective tissue disease-associated ILD as well as smoking-related disorders that include idiopathic pulmonary fibrosis.

描述(由申请人提供)： 类风湿性关节炎(RA)是美国最常见的系统性自身免疫性疾病，影响1-2%的成年人。虽然关节和滑膜是这种疾病的主要靶点，但涉及眼睛、皮肤、心脏、血管和肺的关节外表现可导致显著的发病率和额外的死亡率。在RA发生的各种肺部并发症中，间质性肺疾病(ILD)危害最大，其影响范围从亚临床炎症/瘢痕形成到终末期肺纤维化。由于早期亚临床形式的类风湿性关节炎相关间质性肺疾病(RA-ILD)可能代表更多可治疗的肺纤维化先兆，因此需要非侵入性外周生物标志物在临床失代偿之前识别这种肺部并发症。基于CXCR3结合的趋化因子和各种基质金属蛋白酶在RA-ILD的炎症和组织损伤中起重要作用的假设，特异性目标1在有/没有各种形式的ILD的RA患者中采用多重ELISA法将这些信号分子和降解酶的外周血液/血清水平与肺部疾病分期相关联。扩展特定目标1的分析，特定目标2定义了具有不同ILD阶段的VA来源的RA患者的血清蛋白表达模式的复合生物标志物图谱，验证了血清多重ELISA的使用，并阐明了重要的次要因素，如吸烟的贡献。最后，特殊目标3补充了这种分子表型方法，利用免疫沉淀和基于ELISA的技术来描绘与ILD的存在或不存在相关的血清抗瓜氨酸蛋白自身抗体谱。通过开发与RA-ILD相关的外周血液生物标记物特征，这些集体方法将为RA-ILD和其他形式的免疫介导的肺部疾病的发病机制提供洞察力。更重要的是，明确ILD的分子表型将确定治疗靶点，促进这种潜在破坏性的RA关节外并发症的早期治疗干预。 公共卫生相关性： 类风湿性关节炎(RA)是美国退伍军人中最常见的系统性自身免疫性疾病，尽管确切的患病率尚不清楚。类风湿性关节炎最重要和最严重的关节外并发症是间质性肺病(ILD)。由于早期亚临床形式的RA-ILD可能是肺纤维化的先兆，因此需要容易获得的生物标志物来促进这种可能与吸烟等高度普遍的环境风险因素有关的疾病的早期诊断和治疗干预。简而言之，这项建议涉及开发新的外周血液生物标记物，这些标记物不仅将作为RA-ILD临床评估的工具，而且还将有助于深入了解发病机制和吸烟在这一潜在破坏性因素中的作用 进程。通过延伸，这些研究将促进我们对其他形式的结缔组织疾病相关的ILD以及包括特发性肺纤维化在内的与吸烟相关的疾病的理解。