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Anticitrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts. | LitMetric

AI Article Synopsis

  • - The study investigates how anti-citrullinated protein/peptide antibodies (ACPAs) contribute to joint issues in rheumatoid arthritis (RA) before joint inflammation occurs, focusing on interactions with fibroblast-like synoviocytes (FLS).
  • - Researchers stimulated FLS with ACPAs and observed changes in cell behavior, including increased migration and cytokine production, particularly after stress or chemokine exposure, indicating that ACPAs can significantly affect FLS characteristics.
  • - The findings suggest that specific ACPAs may enhance FLS migration in the context of transient synovial stress, potentially contributing to the progression of RA, with different ACPA clones having unique impacts on disease mechanisms.

Article Abstract

Objectives: Rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) might contribute to bone loss and arthralgia before the onset of joint inflammation. We aimed to dissect additional mechanisms by which ACPAs might contribute to development of joint pathology.

Methods: Fibroblast-like synoviocytes (FLS) were isolated from the synovial membrane of patients with RA. The FLS cultures were stimulated with polyclonal ACPAs (anti-CCP-2 antibodies) purified from the peripheral blood of patients with RA or with monoclonal ACPAs derived from single synovial fluid B cells. We analysed how ACPAs modulate FLS by measuring cell adhesion and mobility as well as cytokine production. Expression of protein arginine deiminase (PAD) enzymes and protein citrullination were analysed by immunofluorescence, and signal transduction was studied using immunoblotting.

Results: Challenge of FLS by starvation-induced stress or by exposure to the chemokine interleukin-8 was essential to sensitise the cells to ACPAs. These challenges led to an increased PAD expression and protein citrullination and an ACPA-mediated induction of FLS migration through a mechanism involving phosphoinositide 3-kinase activation. Inhibition of the PAD enzymes or competition with soluble citrullinated proteins or peptides completely abolished the ACPA-induced FLS migration. Different monoclonal ACPAs triggered distinct cellular effects in either fibroblasts or osteoclasts, suggesting unique roles for individual ACPA clones in disease pathogenesis.

Conclusion: We propose that transient synovial insults in the presence of a certain pre-existing ACPA repertoire might result in an ACPA-mediated increase of FLS migration.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900251PMC
http://dx.doi.org/10.1136/annrheumdis-2018-214967DOI Listing

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