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

Frontiers in Immunology

Emiliano Marasco¹  Rita Carsetti¹  Meredyth G. Ll. Wilkinson²  Yiannis Ioannou²  Anna Radziszewska²  David A. Isenberg²  Kiran Nistala³  Christopher J. M. Piper³  Claudia Mauri³  Philip L. Beales⁴  Daniel Kelberman⁴  Georg W. Otto⁴  Stefanie Dowle⁴  Stuart Adams⁵  Elizabeth C. Rosser⁶  Chantal L. Duurland⁶  Lucy R. Wedderburn⁷  Claire T. Deakin⁷ 

[1] B Cell Physiopathology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy;Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom;Centre for Rheumatology, University College London, London, United Kingdom;Experimental and Personalised Medicine, Genetics and Genomic Medicine, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom;Haematology, Specialist Integrated Haematological Malignancy Diagnostic Service (SIHMDS), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom;Infection, Inflammation and Rheumatology Section, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom;NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom;

关键词: immature transitional B cells;    B cells;    juvenile dermatomyositis;    toll-like receptor 7;    interferon alpha;    interleukin-10;   

DOI  :  10.3389/fimmu.2018.01372

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown