Frontiers in Immunology (Jun 2018)
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,
- Meredyth G. Ll. Wilkinson,
- Meredyth G. Ll. Wilkinson,
- Claire T. Deakin,
- Claire T. Deakin,
- Claire T. Deakin,
- Georg W. Otto,
- Georg W. Otto,
- Stefanie Dowle,
- Stefanie Dowle,
- Chantal L. Duurland,
- Stuart Adams,
- Emiliano Marasco,
- Elizabeth C. Rosser,
- Anna Radziszewska,
- Anna Radziszewska,
- Rita Carsetti,
- Yiannis Ioannou,
- Yiannis Ioannou,
- Philip L. Beales,
- Philip L. Beales,
- Daniel Kelberman,
- Daniel Kelberman,
- David A. Isenberg,
- David A. Isenberg,
- Claudia Mauri,
- Kiran Nistala,
- Lucy R. Wedderburn,
- Lucy R. Wedderburn,
- Lucy R. Wedderburn
Affiliations
- Christopher J. M. Piper
- Centre for Rheumatology, University College London, London, United Kingdom
- Meredyth G. Ll. Wilkinson
- Centre for Rheumatology, University College London, London, United Kingdom
- Meredyth G. Ll. Wilkinson
- Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom
- Claire T. Deakin
- Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom
- Claire T. Deakin
- Infection, Inflammation and Rheumatology Section, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
- Claire T. Deakin
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
- Georg W. Otto
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
- Georg W. Otto
- Experimental and Personalised Medicine, Genetics and Genomic Medicine, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
- Stefanie Dowle
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
- Stefanie Dowle
- Experimental and Personalised Medicine, Genetics and Genomic Medicine, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
- Chantal L. Duurland
- Infection, Inflammation and Rheumatology Section, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
- Stuart Adams
- Haematology, Specialist Integrated Haematological Malignancy Diagnostic Service (SIHMDS), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
- Emiliano Marasco
- B Cell Physiopathology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy
- Elizabeth C. Rosser
- Infection, Inflammation and Rheumatology Section, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
- Anna Radziszewska
- Centre for Rheumatology, University College London, London, United Kingdom
- Anna Radziszewska
- Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom
- Rita Carsetti
- B Cell Physiopathology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy
- Yiannis Ioannou
- Centre for Rheumatology, University College London, London, United Kingdom
- Yiannis Ioannou
- Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom
- Philip L. Beales
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
- Philip L. Beales
- Experimental and Personalised Medicine, Genetics and Genomic Medicine, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
- Daniel Kelberman
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
- Daniel Kelberman
- Experimental and Personalised Medicine, Genetics and Genomic Medicine, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
- David A. Isenberg
- Centre for Rheumatology, University College London, London, United Kingdom
- David A. Isenberg
- Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom
- Claudia Mauri
- Centre for Rheumatology, University College London, London, United Kingdom
- Kiran Nistala
- Centre for Rheumatology, University College London, London, United Kingdom
- Lucy R. Wedderburn
- Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom
- Lucy R. Wedderburn
- Infection, Inflammation and Rheumatology Section, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
- Lucy R. Wedderburn
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
- DOI
- https://doi.org/10.3389/fimmu.2018.01372
- Journal volume & issue
-
Vol. 9
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.
Keywords
- immature transitional B cells
- B cells
- juvenile dermatomyositis
- toll-like receptor 7
- interferon alpha
- interleukin-10
