2017
DOI: 10.1126/sciimmunol.aag3358
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Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis

Abstract: Rheumatoid arthritis (RA) is characterized by synovial joint inflammation and by development of pathogenic humoral and cellular autoimmunity to citrullinated proteins. Neutrophil extracellular traps (NETs) are a source of citrullinated autoantigens and activate RA synovial fibroblasts (FLS), cells crucial in joint damage. We investigated the molecular mechanisms by which NETs promote proinflammatory phenotypes in FLS, and whether these interactions generate pathogenic anti-citrulline adaptive immune responses.… Show more

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Cited by 237 publications
(227 citation statements)
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“…In this study, we cannot determine whether immunogenic proteins on NETs triggered local autoantibody generation or if local autoantibodies triggered increased NETs. However, findings from several recent studies support the hypothesis that NETs could trigger ACPA, including that NETs can themselves trigger immune responses associated with autoimmunity(39), that NETs in lupus patients can alter the structure and function of proteins including apolipoproteins(40), and that the uptake of NET proteins by antigen presenting cells is associated with systemic ACPA(8). …”
Section: Discussionmentioning
confidence: 99%
“…In this study, we cannot determine whether immunogenic proteins on NETs triggered local autoantibody generation or if local autoantibodies triggered increased NETs. However, findings from several recent studies support the hypothesis that NETs could trigger ACPA, including that NETs can themselves trigger immune responses associated with autoimmunity(39), that NETs in lupus patients can alter the structure and function of proteins including apolipoproteins(40), and that the uptake of NET proteins by antigen presenting cells is associated with systemic ACPA(8). …”
Section: Discussionmentioning
confidence: 99%
“…We have previously reported that cytokines secreted by ex vivo cultures of activated SFs are enriched in the synovial fluids of RA patients (12). Activated SFs are also capable of presenting arthritogenic peptides to T cells, further promoting RA pathogenesis (57). Taken together, these observations support a complex relationship between SFs and their environment in RA, in which SFs are directly activated by the inflamed RA microenvironment and activated SFs further perpetuate this inflammation and autoimmunity.…”
Section: Discussionmentioning
confidence: 99%
“…Instead, the possible presence of citrullination in NETs was determined by the indirect analysis of a single protein (ie, vimentin) using antibodies . More recently, Carmona‐Rivera et al used MS to confirm the presence of citrullination in NETs induced by RF . Using trypsin to digest the NET cargo, the study found 28 citrullinated peptides from 20 proteins in NETs.…”
Section: Discovering the Origin Of The Intracellular Citrullinome In Ramentioning
confidence: 80%
“…Although further studies have questioned the role of citrullination in NET formation in humans, potential discrepancies in the study of NETs appear to be explained from the use of distinct artificial stimuli, such as phorbol 12‐myristate 13‐acetate (PMA) and calcium ionophores, which activate different pathways to induce NETs or neutrophil lysis . In this regard, although there is a large volume of publications linking NETs, citrullination, and RA, only few studies have explored autoantigen citrullination in NETs induced by stimuli relevant for RA pathogenesis …”
Section: Discovering the Origin Of The Intracellular Citrullinome In Ramentioning
confidence: 99%