Investigating Mucosal Breaks in the Initiation and Progression of Rheumatoid Arthritis

研究类风湿关节炎发生和进展过程中的粘膜破裂

• 批准号: 10615760
• 负责人: Dana Elizabeth Orange
• 金额: $ 62.42万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-23 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615760
• 关键词: Affect; Antibodies; Antibody Repertoire; Antigen Targeting; Antigen-Antibody Complex; Antigens; Arthritis; Autoimmune; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Bacteremia; Bacteria; Bacterial Antibodies; Bacterial DNA; Binding; Blood; Citrulline; Clinical; Collection; Cross Reactions; DNA; DNA sequencing; Data Set; Dental Care; Development; Disease; Environmental Exposure; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Exhibits; Family; Fingers; Flare; Genes; Gingival Pocket; Home; Human; Human Characteristics; IL6 gene; Immune response; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; In Vitro; Interleukin-6; Joints; Lead; Leukocyte Elastase; Lymphocyte Subset; Lymphocytic Infiltrate; Macrophage; Measurement; Measures; Mediating; Monitor; Mucous Membrane; Nucleotides; Oral; Oral cavity; Oral mucous membrane structure; Osteoclasts; PRTN3 gene; Patients; Peptide antibodies; Periodontal Diseases; Periodontal Pocket; Periodontitis; Plasmablast; Play; Population; Production; Protein Isoforms; Protocols documentation; Reaction; Recombinants; Rheumatoid Arthritis; Role; Sampling; Signal Transduction; Site; Specificity; Stains; Structure of germinal center of lymph node; Synovial Membrane; Synovitis; T cell response; T-Lymphocyte; TNF gene; Testing; Tissues; Venous; antibody test; cigarette smoking; citrullinated protein; cohort; cross reactivity; cyclic citrullinated peptide; member; neutrophil; novel diagnostics; novel strategies; novel therapeutic intervention; oral bacteria; osteoclastogenesis; pathogen; pre-clinical; prevent; response; sample collection; seropositive; single-cell RNA sequencing; success; transcriptome sequencing

Rheumatoid arthritis (RA) is an autoimmune synovitis that affects 0.5% of the world population. RA is characterized by intermittent flares of clinical arthritis that is thought to be mediated in part by anti- citrullinated protein autoimmune responses. The best established environmental risk factors for developing RA include cigarette smoking and periodontal disease, suggesting oral mucosa is a critical site for disease initiation. Nevertheless, the mechanisms by which these environmental exposures lead to RA development and progression remain poorly understood. We have established a clinical and technical protocol for repeated home finger stick blood collection in RA patients to allow for longitudinal RNA sequencing (RNAseq). Using this novel approach, we recently discovered bacteria characteristic of human oral mucosa in the blood of anti-CCP+ RA patients, followed by activation of a signature B cell immune response 3 weeks later, and then clinical flare of disease activity 2 weeks after that. We also investigated B cell responses to these pathogens. We demonstrated elevations in IgA blood plasmablasts both in pre-clinical RA as well as in established RA, with the continual re-activation of a distinct set of IgA/IgG plasmablast clonal families in established RA suggesting a persistent mucosally-driven germinal center reaction. We demonstrate that the recombinant Mabs encoded by the persistently reactivated IgA/G plamablast clonal families encode antibodies that react with both human citrullinated antigens and citrullinated isoforms of oral bacteria identified in the blood of patients antecedent to flares. We anticipate that RA plasmablast Mabs with distinct specificities, either alone or in immune complexes, mediate activation of distinct cellular responses that promote synovitis and tissue destruction in RA. This R01 proposal will test the hypothesis that mucosal breaks trigger plasmablast responses that encode anti-bacterial antibodies that cross-react with host citrullinated antigens. We further hypothesize that mucosal bacteria-induced ACPA activate cellular responses, including macrophage TNF production, NETosis and osteoclast activation, which promote synovitis and joint tissue destruction in RA. Aim 1 will identify the antibody repertoires responsive to pre-flare bacteremia in two independent cohorts of RA patients. Aim 2 will characterize RA plasmablast IgA/G Mabs and sera for reactivity to citrullinated isoforms of bacterial species derived from subgingival collections. Aim 3 will characterize periodontitis tissue for evidence of RA-related autoimmunity. Aim 4 will determine the mechanisms by which cross reactive Mabs, either alone or in immune complexes, mediate arthritis. Success of this proposal would demonstrate that citrullinated periodontal bacteria and mucosal breaks play a key role in mediating RA flare, findings that could lead to development of new diagnostic and therapeutic approaches.

类风湿性关节炎 (RA) 是一种自身免疫性滑膜炎，影响世界人口的 0.5%。 RA 是 其特征是临床关节炎的间歇性发作，被认为部分是由抗- 瓜氨酸蛋白自身免疫反应。最确定的发展环境风险因素 RA 包括吸烟和牙周病，表明口腔粘膜是疾病的关键部位 引发。然而，这些环境暴露导致 RA 发展的机制 和进展仍然知之甚少。我们已经建立了临床和技术方案 重复在家中对 RA 患者进行指尖采血，以进行纵向 RNA 测序 （RNA测序）。利用这种新方法，我们最近发现了人类口腔粘膜特征的细菌 在抗 CCP+ RA 患者的血液中，随后激活标志性 B 细胞免疫反应 3 周 随后，两周后临床出现疾病活动。我们还研究了 B 细胞对 这些病原体。我们证明了临床前 RA 和 RA 中 IgA 血浆母细胞的升高 在已建立的 RA 中，一组独特的 IgA/IgG 浆母细胞克隆家族不断重新激活 建立的 RA 表明存在持续的粘膜驱动的生发中心反应。我们证明了 由持续再激活的 IgA/G 浆母细胞克隆家族编码的重组 Mab 与人类瓜氨酸抗原和口腔细菌瓜氨酸亚型发生反应的抗体 在发作前患者的血液中发现。我们预计 RA 浆母细胞 Mab 具有独特的 特异性，无论是单独的还是在免疫复合物中，介导不同细胞反应的激活 促进 RA 中的滑膜炎和组织破坏。该 R01 提案将检验以下假设：粘膜 断裂触发浆母细胞反应，编码与宿主发生交叉反应的抗菌抗体 瓜氨酸抗原。我们进一步假设粘膜细菌诱导的 ACPA 激活细胞 反应，包括巨噬细胞 TNF 的产生、NETosis 和破骨细胞的激活，这些都会促进 RA 中的滑膜炎和关节组织破坏。目标 1 将确定对爆发前反应的抗体库 两组独立的 RA 患者出现菌血症。目标 2 将表征 RA 浆母细胞 IgA/G Mab 以及对来自龈下菌种的瓜氨酸亚型的反应性的血清。目标 3 将表征牙周炎组织以获得 RA 相关自身免疫的证据。目标 4 将确定 交叉反应性单克隆抗体（单独或在免疫复合物中）介导关节炎的机制。成功 该提案将证明瓜氨酸化的牙周细菌和粘膜破裂发挥着关键作用 在介导 RA 发作方面，这些发现可能会导致新的诊断和治疗方法的开发。

项目成果

Incidence of Interstitial Lung Disease in Patients With Rheumatoid Arthritis Treated With Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs.

使用生物和靶向合成疾病缓解抗风湿药物治疗的类风湿关节炎患者间质性肺疾病的发病率。

• 发表时间: 2023-03-01
• 影响因子: 13.8
• 作者: Baker, Matthew C;Liu, Yuhan;Lu, Rong;Lin, Janice;Melehani, Jason;Robinson, William H
• 通讯作者: Robinson, William H

The monocyte cell surface is a unique site of autoantigen generation in rheumatoid arthritis.

单核细胞表面是类风湿关节炎中自身抗原产生的独特位点。

• DOI: 10.1073/pnas.2304199121
• 发表时间: 2024-04-17
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Mekha A. Thomas;Pooja Naik;Hong Wang;Jon T Giles;Ale;er A. Girgis;er;Seok;Tory P Johnson;A. M. Curran;Jonathan D. Crawford;Shaghayegh Jahanbani;Clifton O Bingham;William H Robinson;Chan Hyun Na;E. Darrah
• 通讯作者: E. Darrah

Myeloablative autologous haematopoietic stem cell transplantation resets the B cell repertoire to a more naïve state in patients with systemic sclerosis.

清髓性自体造血干细胞移植可将系统性硬化症患者的 B 细胞库重置至更原始的状态。

• 发表时间: 2023-03
• 影响因子: 27.4
• 作者: Adamska, Julia Z;Zia, Amin;Bloom, Michelle S;Crofford, Leslie J;Furst, Daniel E;Goldmuntz, Ellen;Keyes;Mayes, Maureen D;McSweeney, Peter;Nash, Richard A;Pinckney, Ashley;Welch, Beverly;Love, Zelda Z;Sullivan, Keith M;Robinso
• 通讯作者: Robinso

Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis.

类风湿关节炎中细胞毒性 CD8 T 细胞靶向瓜氨酸抗原。

• 发表时间: 2023-01-19
• 影响因子: 16.6
• 作者: Moon, Jae;Younis, Shady;Ramadoss, Nitya S;Iyer, Radhika;Sheth, Khushboo;Sharpe, Orr;Rao, Navin L;Becart, Stephane;Carman, Julie A;James, Eddie A;Buckner, Jane H;Deane, Kevin D;Holers, V Michael;Goodman, Susan M;Donlin, Laura T;Davis
• 通讯作者: Davis