Browse by author
Lookup NU author(s): Dr Amy AndersonORCiD, Christine Routledge, Phil Mawson, Professor John IsaacsORCiD, Dr Arthur PrattORCiD
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
0 0 1 417 2381 Newcastle University 19 5 2793 14.0 Normal 0 false false false EN-US JA X-NONE Background: Rheumatoid arthritis (RA) is a chronic, debilitating, inflammatory autoimmune disease, caused by a breakdown in self-tolerance. In order to effectively treat RA rapid and accurate diagnosis is needed, which will be greatly aided by the identification of robust biomarkers. We recently identified a transcriptional signature in circulating CD4+ T-cells which predicted RA progression amongst patients attending an early arthritis clinic. As well as appearing most prominently in a diagnostically challenging sub-group of individuals who were seronegative for anti-citrullinated peptide autoantibodies (ACPAs), the signature contained an over-representation of Stat3 regulated genes, whose expression in turn correlated with serum IL-6. We therefore sought an improved understanding of Stat3 signalling amongst immune cell subsets of an independent early arthritis patient cohort. Methods: 94 newly presenting patients, naïve to immunomodulatory treatment (including steroids), were recruited from an early arthritis clinic, and followed until diagnoses were confirmed. Basal and IL-6-induced expression levels of pY705Stat3 (pStat3) were determined in T-cell and B-cell subsets using Phosflow, a flow cytometry based method for measuring intracellular phospho-proteins. Contemporaneous serum IL-6, IL-6R and soluble gp130 levels were measured by immuno-assay. Results: Basal pStat3 levels were high in circulating CD4+ T-cells, but low in both CD8+ T-cells and B-cells. Basal pStat3 expression correlated with serum IL-6 levels most strongly in CD4+ T-cells and, to a lesser extent, CD8+ T-cells, but not B-cells. The expected pStat3 induction following IL-6 stimulation, observed in all subsets, was most pronounced in CD4+ T-cells, and this reflected significantly higher basal IL-6R surface expression in this cell population. Finally, when patients were categorised by diagnostic outcome, ACPA-negative RA patients had significantly higher basal pStat3 in CD4+ T-cells than ACPA-positive RA, inflammatory non-RA and non-inflammatory arthritis patients – a pattern that was not seen in CD8+ T-cells or B-cells, and which corroborates our previous observations in respect of Stat3 target gene expression. Conclusions. Our findings support a particular role for IL-6-driven CD4+ T cell activation, primarily via Stat3, during the induction of RA. Since CD4+ T-cells preferentially express surface IL-6R, a critical role in this setting for classical IL-6 signalling (as opposed to trans signalling, which is not dependent on IL-6R surface expression) is suggested. Expression of pStat3 in CD4+ T-cells may serve as a biomarker for predicting the evolution of RA in ACPA-negative patients and may also be a useful tool for predicting efficacy of therapies which target IL-6 signalling.
Author(s): Anderson AE, Routledge C, Mawson P, Isaacs JD, Pratt AG
Publication type: Conference Proceedings (inc. Abstract)
Publication status: In Press
Conference Name: American College of Rheumatology
Year of Conference: 2013
