CD19+CD24hiCD38hi B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-α.

Christopher J M Piper,Claudia Mauri,Emiliano Marasco,Yiannis Ioannou,Lucy R Wedderburn,Claire T Deakin,Elizabeth C Rosser,Meredyth G Ll Wilkinson,Stuart Adams,Philip L Beales,Anna Radziszewska,Georg W Otto,David A Isenberg,Daniel Kelberman,Kiran Nistala,Stefanie Dowle,Chantal L Duurland,Rita Carsetti

doi:10.3389/fimmu.2018.01372

Abstract

Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry. The results identified that immature transitional B cells were significantly expanded in active JDM, actively dividing, and correlated positively with disease activity. Protein and RNAseq analysis revealed high interferon alpha (IFNα) and TLR7-pathway signatures pre-treatment. Stimulation of B cells through TLR7/8 promoted both IL-10 and IL-6 production in controls but failed to induce IL-10 in JDM patient cells. Interrogation of the CD40–CD40L pathway (known to induce B cell IL-10 and IL-6) revealed similar expression of IL-10 and IL-6 in B cells cultured with CD40L from both JDM patients and controls. In conclusion, JDM patients with active disease have a significantly expanded immature transitional B cell population which correlated with the type I IFN signature. Activation through TLR7 and IFNα may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype.

Highlights

Juvenile dermatomyositis (JDM), a systemic autoimmune disease, is the most common idiopathic inflammatory myopathy in childhood
In agreement with previously published data, there was a significant increase in the percentage of CD19+ B cells in pre-treatment JDM patients compared with age-matched child healthy controls (CHCs); a phenomenon that was normalized by 7–30 months on-treatment (Figure 1A)
We show that there is an expansion of immature transitional B cells in JDM patients pre-treatment and that the frequency of this population correlates with disease severity

Summary

Introduction

Juvenile dermatomyositis (JDM), a systemic autoimmune disease, is the most common idiopathic inflammatory myopathy in childhood. Symptoms include proximal muscle weakness and skin rash around the eyes (heliotrope), which are pathognomonic for JDM [1]. Disease pathology is thought to involve autoimmune tissue attack and complement-mediated vasculopathy [3]. Inflammatory infiltrate typically seen in affected muscle is composed of B cells, CD4+ and CD8+ T cells, macrophages, and dendritic cells (DCs) [4, 5]. DCs are not normally present in healthy muscle tissue; at the onset of myositis, patients’ muscle biopsies have an abundance of CD83+ plasmacytoid DCs (pDC) [6, 7], which are a major source of interferon alpha (IFNα)

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Conclusion