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Interleukin-6 driven STAT3 phosphorylation in circulating lymphocytes is specific for CD4 T cells in early rheumatoid arthritis

Lookup NU author(s): Dr Amy Anderson, Christine Routledge, Philip Mawson, Professor John Isaacs, Dr Arthur Pratt

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Abstract

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.


Publication metadata

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


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