High Dimensional Analyses of Circulating Immune Cells in Psoriatic Arthritis Detects Elevated Phosphorylated STAT3.

Claudia Macaubas,Elizabeth D Mellins,Deepanwita Sengupta,Idit Lavi,Amir Haddad,Devy Zisman,Muna Elias,Shamma S Rahman

doi:10.3389/fimmu.2021.758418

Claudia Macaubas, Elizabeth D Mellins + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2021.758418

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Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, affecting up to 40% of patients with psoriasis. Constitutive expression by CD4+ T cells of an active form of STAT3, a signal transducer and transcription factor, has been shown to induce many of the major features of PsA in an animal model. We used high dimensional mass cytometry (CyTOF) to probe ex-vivo levels of phosphorylated STAT3 (pSTAT3) in circulating immune cell subpopulations from PsA patients during active and inactive states. We evaluated the frequency of 16 immune cell populations and the levels of the activated forms of STAT3 (pSTAT3) and, for comparison, STAT1 (pSTAT1) and Src (pSrc) in whole blood fixed shortly after collection. In addition to PsA patients, we studied active rheumatoid arthritis (RA) patients. Increased levels of pSTAT3 were found in all the CD4+ T cell subsets analyzed, specifically, Th1, Th2, Th17, T follicular helper (Tfh) and T regulatory (Treg) as well as in CD14+CD16- (classical) monocytes from active PsA patients compared to inactive patients. After correcting for body mass index (BMI), smoking and conventional disease modifying antirheumatic drugs (c-DMARDs), levels of pSTAT3 levels remained increased in Th1 and Tfh CD4+ T cells, and in CD14+CD16- monocytes from active patients compared to inactive patients. No differences between the patient groups were observed for pSTAT1 or pSrc. No differences were found between the active PsA and active RA groups after correction for multiple testing. During active PsA, circulating Th1 and Tfh CD4+ T cells, and CD14+CD16- monocytes expressing high levels of pSTAT3 may play a role in PsA pathophysiology, perhaps by migration to inflamed sites.

Highlights

Psoriatic arthritis (PsA), a chronic inflammatory arthritis belonging to the group of spondyloarthropathies, affects 6-41% of patients with psoriasis [1]
We examined whether the levels of phosphorylated STAT3 (pSTAT3) in Th1 or T follicular helper (Tfh) cells CD4+ T cells or in CD14+CD16- monocytes were correlated with tender joints (TJ), swollen joints (SJ), enthesitis or C reactive protein (CRP)
We describe findings of elevated levels of phosphorylated STAT3 in CD4+ T cell subsets and CD14+CD16- monocytes in active PsA patients, in comparison to patients with inactive disease

Summary

INTRODUCTION

Psoriatic arthritis (PsA), a chronic inflammatory arthritis belonging to the group of spondyloarthropathies, affects 6-41% of patients with psoriasis [1]. Work by Yang et al described an animal model in which overexpression of STAT3C, a constitutively active form of STAT3, in CD4+ T cells led to expression of many of the major features of PsA, including psoriasis-like skin lesions, tendinitis/ enthesitis and arthritis [14, 15]. To analyze the contribution of variables that differed between active and inactive PsA patients, we performed linear regression model with bootstrapping for deriving robust estimates of standard errors and confidence intervals for estimates regression coefficients. This allowed estimation of the contribution of BMI, smoking and conventional disease-modifying anti-rheumatic drugs (c-DMARDS). Clustering was performed by hierarchical clustering using Euclidean distance with average linkage

RESULTS

DISCUSSION

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