Increased presence of FOXP3+ regulatory T cells in inflamed muscle of patients with active juvenile dermatomyositis compared to peripheral blood.

Rianne C. Scholman,Annet van Royen-Kerkhof,Valeria Ricotti,Yvonne Vercoulen,Maud Plantinga,Roel A. de Weger,Hemlata Varsani,Hans J. P. M. Koenen,Mette H. Bakker,Mark Klein,Christa van Schieveen,Elisabeth F. Elst,Wim Spliet,Felicitas Bellutti Enders,Lucy R. Wedderburn,Jenny Meerding,Berent J. Prakken

doi:10.1371/journal.pone.0105353

Abstract

Juvenile dermatomyositis (JDM) is an immune-mediated inflammatory disease affecting the microvasculature of skin and muscle. CD4+CD25+FOXP3+ regulatory T cells (Tregs) are key regulators of immune homeostasis. A role for Tregs in JDM pathogenesis has not yet been established. Here, we explored Treg presence and function in peripheral blood and muscle of JDM patients. We analyzed number, phenotype and function of Tregs in blood from JDM patients by flow cytometry and in vitro suppression assays, in comparison to healthy controls and disease controls (Duchenne’s Muscular Dystrophy). Presence of Tregs in muscle was analyzed by immunohistochemistry. Overall, Treg percentages in peripheral blood of JDM patients were similar compared to both control groups. Muscle biopsies of new onset JDM patients showed increased infiltration of numbers of T cells compared to Duchenne’s muscular dystrophy. Both in JDM and Duchenne’s muscular dystrophy the proportion of FOXP3+ T cells in muscles were increased compared to JDM peripheral blood. Interestingly, JDM is not a self-remitting disease, suggesting that the high proportion of Tregs in inflamed muscle do not suppress inflammation. In line with this, peripheral blood Tregs of active JDM patients were less capable of suppressing effector T cell activation in vitro, compared to Tregs of JDM in clinical remission. These data show a functional impairment of Tregs in a proportion of patients with active disease, and suggest a regulatory role for Tregs in JDM inflammation.

Highlights

Juvenile dermatomyositis (JDM) is a rare systemic immune mediated inflammatory disease in which the immune system targets skeletal muscles, skin and sometimes internal organs
JDM patients have normal expression of Treg markers in peripheral blood In order to establish Treg frequencies in peripheral blood from JDM patients, we analyzed expression of CD25hi according to published methods [9], and FOXP3 by CD4+ T cells
In a recently published study we show that chemokines involved in recruitment of inflammatory T cells are elevated in the plasma of patients with active disease onset [3]

Summary

Introduction

Juvenile dermatomyositis (JDM) is a rare systemic immune mediated inflammatory disease in which the immune system targets skeletal muscles, skin and sometimes internal organs. In muscle biopsies of new onset JDM patients activated CD4+ T cells are predominantly present, suggesting a pathogenic role for these cells [6]. CD4+CD25+FOXP3+ regulatory T cells (Tregs) are known to be potent regulators of T cell mediated autoimmune responses [7,8]. In patients with oligoarticular juvenile idiopathic arthritis (JIA), the presence of Tregs correlates with favorable disease outcome [9]. In studies describing Treg numbers in adults with systemic sclerosis or dermatomyositis, contrasting results have been found [10,11,12] and it remains unclear whether FOXP3 expressing Tregs are present and functional in JDM patients

Methods

Results

Conclusion