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

描述（由申请人提供）：类风湿关节炎的病因尚不清楚，但有遗传（如HLA-DRB 1）和环境因素（如吸烟和暴露于外源性和自身抗原）的证据。RA的特征在于血清自身抗体，包括抗瓜氨酸肽/蛋白抗体（ACPA），临床上通过抗环瓜氨酸肽（CCP）抗体测定进行测量。精氨酸残基至瓜氨酸残基的翻译后修饰由称为肽基琥珀酰脱亚胺酶（例如PAD 4）的酶催化，所述酶在人类和引起牙周病的细菌（牙龈卟啉单胞菌）中表达。RA与牙周病有一定的相关性，并且已有RA患者血清中存在PAD 4抗体的报道。RA滑膜和外周血B细胞中的免疫球蛋白基因重排是高度突变的，与抗原驱动的克隆扩增一致，但关键抗原未知。我们将解决一些重要的悬而未决的问题，如非裔美国人（Af-Amer）中类风湿关节炎、牙周病和类风湿关节炎中B细胞/自身抗体之间的关系。我们将测试的假设，暴露于牙周致病菌，通过相互作用与遗传（如HLA-DRB 1）和环境因素（例如吸烟）导致血清ACPA和抗PAD 4抗体和高度的B细胞克隆性;这些因素可能影响临床表型，例如发病年龄和Af-Amer中RA的放射学严重程度; RA中来自抗原特异性ACPA/CCP/PAD B细胞的抗体与PAD交叉反应，暗示了因果关系。我们的目标是：1.在患有抗CCP+ RA的Af-Amer患者中，检查血清ACPA与多种特异性瓜氨酸化表位以及血清抗PAD 4抗体与临床、遗传和放射学特征的相关性; 2.在具有抗CCP+和抗CCP-阴性RA的Af-Amer中检查牙周炎和暴露于牙龈卟啉单胞菌与血清ACPA谱和抗PAD 4抗体的关联; 3.比较Af- Amer（含和不含抗CCP Ab、ACPA、抗PAD 4 Ab）的外周血B细胞的克隆性程度和突变模式;并评估瓜氨酸化蛋白特异性和PAD 4特异性B淋巴细胞抗体在RA中的反应性。该申请利用了三个正在进行的大型临床项目：CLEAR注册表;非洲裔美国人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，从CCP+ RA的外周血中分离抗原特异性抗PAD 4 B细胞。这些新的研究将提供重要的新信息的发病机制，类风湿关节炎在Af- Amer，并可能导致创新的方法来诊断，治疗，或预防这种疾病。

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.