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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1372
JournalFrontiers in Immunology
Volume9
DOIs
Publication statusPublished - 2018

Fingerprint

Toll-Like Receptor 7
Interferons
B-Lymphoid Precursor Cells
B-Lymphocytes
Phenotype
Interleukin-10
Interferon-alpha
Interleukin-6
CD40 Ligand
Lymphocytosis
Interferon Type I
Myositis
Juvenile dermatomyositis
Muscle Weakness
Exanthema
Blood Cells
Flow Cytometry
Cohort Studies
Biomarkers

Cite this

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

In: Frontiers in Immunology, Vol. 9, 2018, p. 1372.

Research output: Contribution to journalArticle

Piper, CJM, Wilkinson, MGL, Deakin, CT, Otto, GW, Dowle, S, Duurland, CL, Adams, S, Marasco, E, Rosser, EC, Radziszewska, A, Carsetti, R, Ioannou, Y, Beales, PL, Kelberman, D, Isenberg, DA, Mauri, C, Nistala, K & Wedderburn, LR 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', Frontiers in Immunology, vol. 9, pp. 1372. https://doi.org/10.3389/fimmu.2018.01372
Piper, Christopher J M ; Wilkinson, Meredyth G Ll ; Deakin, Claire T ; Otto, Georg W ; Dowle, Stefanie ; Duurland, Chantal L ; Adams, Stuart ; Marasco, Emiliano ; Rosser, Elizabeth C ; Radziszewska, Anna ; Carsetti, Rita ; Ioannou, Yiannis ; Beales, Philip L ; Kelberman, Daniel ; Isenberg, David A ; Mauri, Claudia ; Nistala, Kiran ; Wedderburn, Lucy R. / 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. In: Frontiers in Immunology. 2018 ; Vol. 9. pp. 1372.
@article{f062d046b3254af1bd47b0a73f27a5b3,
title = "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",
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.",
author = "Piper, {Christopher J M} and Wilkinson, {Meredyth G Ll} and Deakin, {Claire T} and Otto, {Georg W} and Stefanie Dowle and Duurland, {Chantal L} and Stuart Adams and Emiliano Marasco and Rosser, {Elizabeth C} and Anna Radziszewska and Rita Carsetti and Yiannis Ioannou and Beales, {Philip L} and Daniel Kelberman and Isenberg, {David A} and Claudia Mauri and Kiran Nistala and Wedderburn, {Lucy R}",
year = "2018",
doi = "10.3389/fimmu.2018.01372",
language = "English",
volume = "9",
pages = "1372",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S.A.",

}

TY - JOUR

T1 - 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

AU - Piper, Christopher J M

AU - Wilkinson, Meredyth G Ll

AU - Deakin, Claire T

AU - Otto, Georg W

AU - Dowle, Stefanie

AU - Duurland, Chantal L

AU - Adams, Stuart

AU - Marasco, Emiliano

AU - Rosser, Elizabeth C

AU - Radziszewska, Anna

AU - Carsetti, Rita

AU - Ioannou, Yiannis

AU - Beales, Philip L

AU - Kelberman, Daniel

AU - Isenberg, David A

AU - Mauri, Claudia

AU - Nistala, Kiran

AU - Wedderburn, Lucy R

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.3389/fimmu.2018.01372

DO - 10.3389/fimmu.2018.01372

M3 - Article

C2 - 29988398

VL - 9

SP - 1372

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

ER -