Dissection of the ACPA response in African-Americans with Rheumatoid Arthritis

非洲裔美国人类风湿关节炎 ACPA 反应剖析

• 批准号: 8250186
• 负责人: S Louis Bridges
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250186
• 关键词: Address; Affect; African American; Age; Alleles; Ancillary Study; Antibodies; Antibody Formation; Antibody Specificity; Antigens; Arginine; Autoantibodies; Autoantigens; Autoimmune Process; B-Lymphocytes; Bacteria; Biological Assay; Chronic; Chronic Disease; Citrulline; Clinical; Clonal Expansion; Clonality; Data; Data Collection; Development; Diagnosis; Diagnostic; Disease; Dissection; Enrollment; Environmental Risk Factor; Enzymes; Epitopes; Etiology; European; Evaluation; Exposure to; Fibrinogen; Funding; Generations; Genetic; Gingivitis; Grant; HLA-DRB1; Heavy-Chain Immunoglobulins; Human; Human body; Immunoglobulin Gene Rearrangement; Indium; Individual; Infection; Inflammatory; Joints; Lead; Light; Measures; Minority; Minority Groups; Molecular; Mutate; Mutation; Organ; Pathogenesis; Patients; Pattern; Peptide antibodies; Peptides; Periodontal Diseases; Periodontitis; Persons; Population; Porphyromonas gingivalis; Post-Translational Protein Processing; Prevention strategy; Proteins; Registries; Reporting; Research; Rheumatoid Arthritis; Role; Scientist; Serum; Severities; Smoking; Subgroup; Synovial Membrane; Synovitis; Testing; Time; Transcript; United States National Institutes of Health; Vimentin; base; bone; cigarette smoking; clinical phenotype; cyclic citrullinated peptide; disabling disease; enolase; filaggrin; genome wide association study; improved; innovation; novel; peripheral blood; prevent; prognostic; response; sample collection; skills

DESCRIPTION (provided by applicant): The cause of RA is unknown, but there is evidence of both genetic (e.g. HLA-DRB1) and environmental components (e.g. smoking and exposure to exogenous and self-antigens). RA is characterized by serum autoantibodies, including anti-citrullinated peptide/protein antibodies (ACPA), measured clinically by the anti-cyclic citrullinated peptide (CCP) antibody assay. Post- translational modification of arginine residues to citrulline residues is catalyzed by enzymes called peptidyl argininyl deiminases (e.g. PAD4), which are expressed both in humans and in bacteria that cause periodontal disease (P. gingivalis). There is an association of RA with periodontal disease, and serum antibodies to PAD4 have been reported in RA. The immunoglobulin gene rearrangements in RA synovium and peripheral blood B cells are highly mutated consistent with antigen-driven clonal expansion, but the key antigens are unknown. We will address important unanswered questions regarding the relationship of RA, periodontal disease, and B cells/autoantibodies in RA among African-Americans (Af-Amer), a minority population underrepresented in research. We will test the hypotheses that exposure to periodontogenic bacteria, through interaction with genetic (e.g. HLA-DRB1) and environmental factors (e.g. smoking) leads to serum ACPA and anti-PAD4 antibodies and high degrees of B cell clonality; that these factors may influence clinical phenotypes such as age at onset, and radiographic severity of RA in Af-Amer; and that antibodies from antigen-specific ACPA/CCP/PAD B cells in RA are cross-reactive to PAD, implicating causality. Our aims are: 1. To examine associations of serum ACPA to a variety of specific citrullinated epitopes and of serum anti-PAD4 Abs with clinical, genetic, and radiographic features in Af-Amer with anti- CCP+ RA; 2. To examine associations of periodontitis and exposure to P. gingivalis with serum ACPA profiles and anti-PAD4 Abs in Af-Amer with anti-CCP+ and anti-CCP-neg RA; 3. To compare the degree of clonality and mutation patterns of peripheral blood B cells from Af- Amer with and without anti-CCP Ab, ACPA, anti-PAD4 Abs; and to assess the reactivity of antibodies from citrullinated protein-specific and PAD4-specific B lymphocytes in RA. This application leverages three large ongoing clinical projects: the CLEAR Registry; the African-American RA Network and an ACR REF grant. We have exciting, innovative preliminary data showing isolation of antigen-specific anti-PAD4 B cells from peripheral blood in CCP+ RA. These novel studies will provide important new information on the pathogenesis of RA in Af- Amer and may lead to innovative ways to diagnose, treat, or prevent this disease. PUBLIC HEALTH RELEVANCE: The cause of rheumatoid arthritis (RA), a chronic disease affecting ~0.5-1% of populations worldwide and characterized by antibodies directed against normal proteins in the human body (autoantibodies), is unknown, but likely involves environmental triggers, such as smoking or infection in individuals genetically predisposed to developing the disease. In this study, we will examine the role of periodontal disease (gingivitis); exposure to bacteria causing gingivitis; cigarette smoking; and genetic factors in the generation of autoantibodies in RA and its radiographic severity (bone damage in affected joints) in African-Americans. The proposed studies will greatly enhance our understanding of the causes of RA in a minority population and will hopefully lead to better diagnostic, prognostic, treatment, and prevention strategies for this common, often disabling disease.

描述（由申请人提供）：RA的原因尚不清楚，但是有证据表明遗传（例如HLA-DRB1）和环境成分（例如吸烟和暴露于外源性和自我抗原）。 RA的特征是血清自身抗体，包括抗固醇柠檬酸肽（CCP）抗体测定法临床测量的抗上帝肽/蛋白质抗体（ACPA）。精氨酸残基转化为瓜氨酸残基的转化后修饰是由称为肽基精氨酸脱氨酸酶（例如PAD4）的酶催化的，这些酶在人类和引起牙周疾病的细菌中表达（P. gingivalis P. gingivalis）。 RA与牙周疾病有关联，RA中已经报道了与PAD4的血清抗体。 RA滑膜和外周血B细胞中的免疫球蛋白基因重排高度突变与抗原驱动的克隆膨胀一致，但关键抗原尚不清楚。我们将在非裔美国人（AF-amer）中解决有关RA，牙周疾病和B细胞/自身抗体关系的重要问题，这是研究中少数人群所代表的少数人群。我们将通过与遗传（例如HLA-DRB1）和环境因素（例如吸烟）相互作用来检验暴露于牙周源性细菌的假设，导致血清ACPA和抗Pad4抗体和抗PAD4抗体以及高度的B细胞克隆性；这些因素可能会影响临床表型，例如发病时代的年龄和AF-MAMER中RA的影像学严重程度； RA中的抗原特异性ACPA/CCP/PAD B细胞中的抗体具有交叉反应性，这意味着因果关系。我们的目的是：1。检查血清ACPA与各种特定的柠檬硫化表位和血清抗Pad4 ABS的关联以及抗CCP+ RA的AF-增强剂中的临床，遗传和放射学特征； 2。检查牙周炎和牙龈疟原虫的关联与血清ACPA轮廓和抗CCCP+和抗CCP-NEG RA的AF-AB-AB-PAD4 ABS相关； 3。比较具有和不含抗CCP AB，ACPA，抗Pad4 ABS的外周血B细胞的克隆性和突变模式的程度；并评估RA中瓜氨酸蛋白特异性和PAD4特异性B淋巴细胞的抗体的反应性。该应用程序利用了三个大型正在进行的临床项目：清晰的注册表；非裔美国人RA网络和ACR Ref Grant。我们有令人兴奋的创新初步数据，显示了CCP+ RA中外周血中抗原特异性抗Pad4 B细胞的分离。这些新的研究将提供有关AFAMER RA发病机理的重要新信息，并可能导致诊断，治疗或预防这种疾病的创新方法。 公共卫生相关性：类风湿关节炎的原因（RA）是一种慢性疾病，影响了〜0.5-1％的全球人口，其特征是针对人体中正常蛋白质的抗体（自身抗体），但可能涉及环境触发者，例如吸烟或遗传性疾病的疾病中的感染。在这项研究中，我们将研究牙周疾病（牙龈炎）的作用。暴露于引起牙龈炎的细菌；吸烟； RA自身抗体产生的遗传因素及其放射线严重程度（受影响关节的骨损伤）在非裔美国人中。拟议的研究将大大增强我们对少数族裔RA原因的理解，并希望能够为这种常见的，通常使疾病提供更好的诊断，预后，治疗和预防策略。