期刊
FRONTIERS IN IMMUNOLOGY
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2018.01372
关键词
immature transitional B cells; B cells; juvenile dermatomyositis; toll-like receptor 7; interferon alpha; interleukin-10
类别
资金
- Wellcome Trust UK [085860, 097259]
- Action Medical Research UK [SP4252]
- Myositis Support Group UK
- Arthritis Research UK [14518, 20164]
- Great Ormond Street Children's Charity [V1268]
- Myositis Association
- National Institute for Health Research (NIHR) Translational Research Collaboration (TRC) Rare Diseases
- NIHR's Rare Diseases Translational Research Collaboration
- NIHR Biomedical Research Centres of Great Ormond Street Hospital (GOSH)
- University College London Hospital (UCLH)
- National Institute of Health Research Biomedical Research Centre at Great Ormond Street Hospital (GOSH)
- University College London
- Great Ormond Street Children's Charity
- Rosetrees Trust [M536]
- Seventh Framework Programme of the EU, SP3-People, support for training and career development for researchers (Marie Curie), Network for Initial Training (ITN), FP7-PEOPLE-2011-ITN, under the Marie Sklodowska-Curie grant [289903]
- Henry Smith Charity
- Rosetrees Trust [M536] Funding Source: researchfish
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 (IFN alpha) 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 IFN alpha may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype.
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