Anti–Citrullinated Protein Antibodies With Multiple Specificities Ameliorate Collagen Antibody–Induced Arthritis in a Time‐Dependent Manner

Author:

Gomez Alejandro M.1ORCID,Brewer R. Camille1,Moon Jae‐Seung1,Acharya Suman1,Kongpachith Sarah1,Wang Qian1ORCID,Jahanbani Shaghayegh1,Wong Heidi H.1,Lanz Tobias V.1,Love Zelda Z.1,Min‐Oo Gundula2,Niedziela‐Majka Anita2,Robinson William H.1ORCID

Affiliation:

1. Stanford University School of Medicine, Stanford, and VA Palo Alto Health Care System Palo Alto California

2. Gilead Sciences Inc. Foster City California

Abstract

ObjectiveAnti–citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and have long been regarded as pathogenic. Despite substantial in vitro evidence supporting this claim, reports investigating the proinflammatory effects of ACPAs in animal models of arthritis are rare and include mixed results. Here, we sequenced the plasmablast antibody repertoire of a patient with RA and functionally characterized the encoded ACPAs.MethodsWe expressed ACPAs from the antibody repertoire of a patient with RA and characterized their autoantigen specificities on antigen arrays and enzyme‐linked immunosorbent assays. Binding affinities were estimated by bio‐layer interferometry. Select ACPAs (n = 9) were tested in the collagen antibody–induced arthritis (CAIA) mouse model to evaluate their effects on joint inflammation.ResultsRecombinant ACPAs bound preferentially and with high affinity (nanomolar range) to citrullinated (cit) autoantigens (primarily histones and fibrinogen) and to auto‐cit peptidylarginine deiminase 4 (PAD4). ACPAs were grouped for in vivo testing based on their predominant cit‐antigen specificities. Unexpectedly, injections of recombinant ACPAs significantly reduced paw thickness and arthritis severity in CAIA mice as compared with isotype‐matched control antibodies (P ≤ 0.001). Bone erosion, synovitis, and cartilage damage were also significantly reduced (P ≤ 0.01). This amelioration of CAIA was observed for all the ACPAs tested and was independent of cit‐PAD4 and cit‐fibrinogen specificities. Furthermore, disease amelioration was more prominent when ACPAs were injected at earlier stages of CAIA than at later phases of the model.ConclusionRecombinant patient‐derived ACPAs ameliorated CAIA. Their antiinflammatory effects were more preventive than therapeutic. This study highlights a potential protective role for ACPAs in arthritis.image

Funder

Gilead Sciences

Publisher

Wiley

Subject

Immunology,Rheumatology,Immunology and Allergy

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3