Abstract
Objective. AS is a systemic inflammatory disease of the SpA family. Polymorphisms at loci including HLA-B27, IL-23R and ERAP-1 directly implicate immune mechanisms in AS pathogenesis. Previously, in an SpA model, we identified HLA-B27–mediated effects on dendritic cells that promoted disease-associated Th17 cells. Here we extend these studies to AS patients using deep immunophenotyping of candidate pathogenic cell populations. The aim of our study was to functionally characterize the immune populations mediating AS pathology.Methods. Using 11-parameter flow cytometry, we characterized the phenotype and functions of lymphocyte and myeloid cells from peripheral blood, and the synovial phenotype of AS patients and age-matched healthy controls.Results. Significantly fewer circulating CD1c-expressing dendritic cells were observed in AS patients, offset by an increase in CD14− CD16+ mononuclear cells. Ex vivo functional analysis revealed that this latter population induced CCR6 expression and promoted secretion of IL-1β and IL-6 when co-cultured with naive CD4+ T cells. Additionally, systemic inflammation in AS patients significantly correlated with increased proportions of activated CCR9+ CD4+ T cells.Conclusion. CD14− CD16+ mononuclear cells may contribute to AS by promoting Th17 responses, and antigen-presenting cells of mucosal origin are likely to contribute to systemic inflammation in AS.
Highlights
AS is a chronic arthropathy of the axial and peripheral skeleton, characterized by inflammation and abnormal bone and entheseal remodelling
Fewer circulating CD1c-expressing dendritic cells were observed in AS patients, offset by an increase in CD14À CD16+ mononuclear cells
Ex vivo functional analysis revealed that this latter population induced CCR6 expression and promoted secretion of IL-1b and IL-6 when co-cultured with naive CD4+ T cells
Summary
AS is a chronic arthropathy of the axial and peripheral skeleton, characterized by inflammation and abnormal bone and entheseal remodelling. AS is recognized as the prototypic disease of a larger SpA group of conditions that share genetic, pathophysiological and clinical features. TNF inhibitors a decade ago, current therapeutics remain inadequate for a substantial proportion of patients, offering a compelling case for improved pathophysiological discovery. Large genome-wide association studies have recently contributed several novel loci and novel candidate pathways in this regard. There is particular interest in the confirmed associations with IL23R, ERAP1 and STAT3 [13]. Taken together with the provisional clinical benefit accrued upon inhibition of the IL-17A pathway in clinical trials in AS patients [4], this suggests that novel immune-mediated pathways beyond TNF may be formally implicated in pathogenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
