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）： 类风湿关节炎（RA）是美国最常见的全身性自身免疫性疾病，影响成年人群的1-2％。尽管关节和滑膜是这种疾病的主要靶标，但涉及眼睛，皮肤，心脏，脉管系统和肺部的关节外表现可能会导致明显的发病率和过量死亡。在RA中发生的各种肺并发症中，间质性肺疾病（ILD）是最具破坏性的，其作用范围从亚临床炎症/疤痕到末期肺纤维化。因为较早的类风湿关节炎相关的间质性肺疾病（RA-ILD）的亚临床形式可能代表了肺纤维化的更可治疗的前体，因此需要非侵入性外围生物标记物来识别这种肺部并发性在临床解说之前。基于以下假设：CXCR3结合趋化因子和各种基质金属蛋白酶在驱动炎症以及RA-ild中的组织损伤中起重要作用，具体目标1在具有/没有各种形式的ILD的RA患者中采用多重ELISA与这些信号分子和义务率的外周血清疾病水平相关的RA患者，使其与外周血/血清相关联。扩展对特定目标1的分析，特定目标2定义了在VA衍生的RA患者的平行组中，血清蛋白表达模式的复合生物标志物谱，具有不同的ILD阶段，从而验证了血清多路复用ELISA的使用并阐明了重要二级因素（例如吸烟）的贡献。最后，特定的目标3可以补充这种分子表型方法，利用免疫沉淀和基于ELISA的技术来描述与存在或不存在ILD相关的血清抗抑制蛋白自身抗体曲线。通过发展与RA-ILD相关的外围血液生物标志物特征，这些集体方法将提供有关RA-ELD和其他形式的免疫学介导的肺部疾病的发病机理的见解。更重要的是，定义ILD的分子表型将确定促进早期治疗干预措施的治疗靶标，这是RA的潜在毁灭性关节外并发症。 公共卫生相关性： 类风湿关节炎（RA）是美国退伍军人人口中最常见的全身自身免疫性疾病，尽管确切的患病率尚不清楚。 RA最重要，最严重的关节外并发症是间质性肺疾病（ILD）。由于早期的RA-ild的亚临床形式可能是肺纤维化的前体，因此需要容易获得的生物标志物，以促进这种情况下的早期诊断和治疗干预，这很可能与高度普遍的环境风险因素（例如吸烟）有关。简而言之，该提案涉及开发新型的外围血液生物标志物，这些标志物不仅将在RA-ild的临床评估中充当工具，而且还将对发病机理和吸烟在这一潜在破坏性中的作用有所了解 过程。通过扩展，这些研究将提高我们对与结缔组织疾病相关的其他形式以及与吸烟有关的疾病的理解，包括特发性肺纤维化。