期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 8, 页码 2946-2956出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI93450
关键词
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资金
- American College of Rheumatology Innovative Grant Program Within our Reach, Finding a Cure for RA
- Ounsworth-Fitzgerald Foundation
- Mathers Foundation
- English, Bonter, Mitchell Foundation
- Littauer Foundation
- Lillian B. Davey Foundation
- Eshe Fund
- NIH [P41 GM104603, S10 RR020946, S10 OD010724]
- Rheumatology Research Foundation
In rheumatoid arthritis (RA), immunological triggers at mucosal sites, such as the gut microbiota, may promote autoimmunity that affects joints. Here, we used discovery-based proteomics to detect HLA-DR-presented peptides in synovia or peripheral blood mononuclear cells and identified 2 autoantigens, N-acetylglucosamine-6-sulfatase (GNS) and filamin A (FLNA), as targets of T and B cell responses in 52% and 56% of RA patients, respectively. Both GNS and FLNA were highly expressed in synovia. GNS appeared to be citrullinated, and GNS antibody values correlated with anti-citrullinated protein antibody (ACPA) levels. FLNA did not show the same results. The HLA-DR-presented GNS peptide has marked sequence homology with epitopes from sulfatase proteins of the Prevotella sp. and Parabacteroides sp., whereas the HLA-DR-presented FLNA peptide has homology with epitopes from proteins of the Prevotella sp. and Butyricimonas sp., another gut commensal. Patients with T cell reactivity with each self-peptide also had responses to the corresponding microbial peptides, and the levels were directly correlated. Furthermore, HLA-DR molecules encoded by shared-epitope (SE) alleles were predicted to bind these self-and microbial peptides strongly, and these responses were more common in RA patients with SE alleles. Thus, sequence homology between T cell epitopes of 2 self-proteins and a related order of gut microbes may provide a link between mucosal and joint immunity in patients with RA.
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