Abstract
IntroductionThe local production of pathogenic autoantibodies by plasma cells in synovium is one of the hallmarks of rheumatoid arthritis (RA). There may be a potential link between ectopic lymphoid neogenesis and the local autoimmunity in rheumatoid synovium. The unfolded protein response (UPR) has key roles in the development and maintenance of plasma cells secreting immunoglobulin. This study was designed to explore the potential links between the activation of the UPR of infiltrating plasma cells in inflamed peripheral joints and the histopathological variants of rheumatoid synovitis as well as the local production of pathogenic autoantibodies.MethodsThe variants of rheumatoid synovium were histopathologically classified into follicular and diffuse synovitis. Immunohistochemical and double-immunofluorescent stainings were performed to detect the expression of 78-kDa glucose-regulated protein (GRP78), a marker of activation of the UPR, in infiltrating plasma cells of synovium, and flow cytometry and immunoblotting analyses were performed to quantify GRP78 in plasma cells of synovial fluid in inflamed peripheral joints of RA. The detections were also taken in osteoarthritis (OA) as controls. The synovial fluid levels of anti-cyclic citrullinated peptide antibodies (anti-CCP) (IgG) were quantified with the enzyme-linked immunosorbent assay and corrected to those of total IgG in RA.ResultsExpressions of GRP78 were more intensive in infiltrating plasma cells in RA synovium relative to those in OA synovium (P < 0.001) and in synovium with follicular synovitis relative to that with diffuse synovitis (P < 0.001). Analyses by flow cytometry and immunoblotting showed that there was a significant upregulation of GRP78 of plasma cells from synovial fluid of RA compared with that of OA (P < 0.05) and from synovial fluid of follicular synovitis relative to that of diffuse synovitis (P < 0.05). Moreover, a positive relationship between the expression of GRP78 of plasma cells from synovial fluid and the corrected synovial levels of anti-CCP (IgG) was seen in RA (P < 0.001).ConclusionsThere may be a link between enhanced activation of the UPR of plasma cells and ectopic lymphoid neogenesis as well as the local production of anti-CCP (IgG) in inflamed peripheral joints of RA.
Highlights
The local production of pathogenic autoantibodies by plasma cells in synovium is one of the hallmarks of rheumatoid arthritis (RA)
Expressions of GRP78 were more intensive in infiltrating plasma cells in RA synovium relative to those in OA synovium (P < 0.001) and in synovium with follicular synovitis relative to that with diffuse synovitis (P < 0.001)
There may be a link between enhanced activation of the unfolded protein response (UPR) of plasma cells and ectopic lymphoid neogenesis as well as the local production of anti-CCP (IgG) in inflamed peripheral joints of RA
Summary
The local production of pathogenic autoantibodies by plasma cells in synovium is one of the hallmarks of rheumatoid arthritis (RA). This study was designed to explore the potential links between the activation of the UPR of infiltrating plasma cells in inflamed peripheral joints and the histopathological variants of rheumatoid synovitis as well as the local production of pathogenic autoantibodies. Anti-CCP: anti-cyclic citrullinated peptide antibodies; BiP: immunoglobulin heavy-chain-binding protein; BSA: bovine serum albumin; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; FACS: fluorescence-activated cell sorting; FITC: fluorescein isothiocyanate; GRP78: 78-kDa glucose-regulated protein; HE: hematoxylin and eosin; OA: osteoarthritis; PBS: phosphate-buffered saline; RA: rheumatoid arthritis; SP: streptavidin/ peroxidase; TBST: 1 mL of Tween 20 in 1 L of Tris-buffered saline; UPR: unfolded protein response. Genesis, which is characterized by the formation of lymphoid follicle with germinal center response and can facilitate the terminal differentiation of B cells into plasma cells in rheumatoid synovium [5], and the local production of high-affinity pathogenic autoantibodies [6,7]. The UPR can play key roles in the development and maintenance of the plasma cells secreting immunoglobulin [8,9] and may be essential to allow plasma cells to become secretary factories dedicated to high-level autoantibody production [11,12]
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