Background/Purpose: Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease, caused by a breakdown in self tolerance. Robust biomarkers are needed which, as well having diagnostic utility, enable its stratification into therapeutically relevant sub-sets.   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 signal transduction and activator of transcription-3 (STAT3) regulated genes, whose expression in turn correlated with serum interleukin (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 p_Y705STAT3 (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.

Conclusion: 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interleukin-6-driven-stat3-phosphorylation-in-circulating-lymphocytes-is-specific-for-cd4-t-cells-in-early-rheumatoid-arthritis/