Abstract
The objective of the study is to investigate potential citrullinated autoantigens as targets of anti-citrullinated protein antibodies (ACPAs) response in synovial fluids (SFs) of patients with rheumatoid arthritis (RA). SFs from six RA patients and six osteoarthritis (OA) patients as controls were collected. The citrullinated proteins in SFs were extracted by immunoprecipitation with rabbit anti-citrulline antibodies. Matrix-assisted laser desorption/ionization time of flight mass spectrometry/time of flight mass spectrometry (MALDI-TOF/TOF) mass spectrometry was subsequently performed to discover a characteristic neutral loss to finally determine citrullinated autoantigens. A total of 182 citrullinated peptides and 200 citrullinated sites were identified in RA SFs, while 3 citrullinated peptides and 4 citrullinated sites were identified in OA SFs. The 182 citrullinated peptides from RA SFs and the 3 citrullinated peptides from OA SFs were derived from 83 and 3 autoantigens, respectively. Eighty-three autoantigens except protein-arginine deiminase type-2 (PADI2) and protein-arginine deiminase type-2 (PADI4) were over-citrullinated compared with controls, and the citrullinated sites of PADI2 and PADI4 were different in two groups. Interestingly, citrullinated histone H3.3 (H3F3A) was found in OA controls, but not in RA groups. The differential citrullinated proteins identified in RA SFs suggested potential autoantigens were targeted for ACPAs response and might contribute to the induction and perpetuation of complement activation and joint inflammation in RA.Electronic supplementary materialThe online version of this article (doi:10.1007/s10067-016-3247-4) contains supplementary material, which is available to authorized users.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease characterized by the formation of inflammatory, invasive tissue, and rheumatoid pannus in synovial membranes, subsequently resulting in joint destruction and systemic complications
The 182 citrullinated peptides from the RA synovial fluids (SFs) were derived from 83 autoantigens, and the three citrullinated peptides from the OA SFs were derived from three autoantigens
26 citrullinated proteins identified here have been validated in previous studies (Table 4), which suggests that this strategy for identifying citrullinated peptides is highly effective
Summary
Rheumatoid arthritis (RA) is an autoimmune disease characterized by the formation of inflammatory, invasive tissue, and rheumatoid pannus in synovial membranes, subsequently resulting in joint destruction and systemic complications. The related autoimmunity is often associated with certain major histocompatibility complex (MHC) types and the presence of anti-citrullinated protein antibodies (ACPAs) [1]. ACPAs are important biomarkers of RA and can be detected even before the clinical onset of the disease; they are recognized as a predictive and diagnostic marker. ACPAs in the inflammatory synovium bind to citrullinated autoantigens to form immune complexes (ICs), which lead to the development of inflammation [2,3,4,5,6,7]. A simple and effective method is needed to detect citrullinated proteins in the joint fluid from RA patients
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