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

说明(申请人提供)：类风湿性关节炎的病因尚不清楚，但有证据表明既有遗传因素(如人类白细胞抗原DRB1)，也有环境因素(如吸烟和暴露于外源性和自身抗原)。RA的特征是血清自身抗体，包括抗瓜氨酸多肽/蛋白抗体(ACPA)，临床上用抗环瓜氨酸肽(CCP)抗体测定。精氨酸残基的翻译后修饰为瓜氨酸残基是由称为肽基精氨酸脱亚胺酶(例如PAD4)的酶催化的，这种酶在人类和引起牙周病的细菌(P.gigivalis)中都有表达。类风湿性关节炎与牙周病有关，血清中PAD4抗体在类风湿性关节炎中已有报道。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，符合抗原驱动的克隆性扩增，但关键抗原尚不清楚。我们将解决有关类风湿性关节炎、牙周病和非裔美国人类风湿性关节炎中B细胞/自身抗体(Af-AMER)的关系的重要未回答的问题，非裔美国人是研究中代表性不足的少数群体。我们将测试假设，暴露于牙周源性细菌，通过与遗传因素(例如，HLA-DRB1)和环境因素(如吸烟)的相互作用，会导致血清ACPA和抗PAD4抗体以及高度的B细胞克隆性；这些因素可能影响临床表型，如发病年龄和Af-Amer中RA的放射学严重程度；来自RA抗原特异性ACPA/CCP/PAD B细胞的抗体与PAD发生交叉反应，这可能是因果关系。我们的目的是：1.检测抗CCP+RA患者血清ACPA和抗PAD4抗体与临床、遗传学和放射学特征的关系；2.检测抗CCP+和抗CCP-neg RA患者血清ACPA谱和抗PAD4抗体与牙周炎和牙周炎暴露的关系；3.比较Af-Amer中有无抗CCP、ACPA、抗PAD4抗体前后外周血B细胞的克隆度和突变模式；并评估来自瓜氨酸蛋白特异性和PAD4特异性B淋巴细胞的抗体在RA中的反应性。这项申请利用了三个正在进行的大型临床项目：Clear Region、非裔美国人RA网络和ACR REF赠款。我们有令人兴奋的、创新的初步数据显示，在CCP+RA患者中，从外周血中分离出抗原特异性的抗PAD4B细胞。这些新的研究将为Af-AME中RA的发病机制提供重要的新信息，并可能导致诊断、治疗或预防这种疾病的创新方法。

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.