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Association of Defective Regulation of Autoreactive Interleukin‐6–Producing Transitional B Lymphocytes With Disease in Patients With Systemic Sclerosis

Taher, TE; Ong, VH; Bystrom, J; Hillion, S; Simon, Q; Denton, CP; Pers, JO; ... Mageed, RA; + view all (2018) Association of Defective Regulation of Autoreactive Interleukin‐6–Producing Transitional B Lymphocytes With Disease in Patients With Systemic Sclerosis. Arthritis and Rheumatology , 70 (3) pp. 450-461. 10.1002/art.40390. Green open access

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Abstract

BACKGROUND: Systemic Sclerosis (SSc) has the highest case-specific mortality of any rheumatic disease and has no effective therapy. A clear manifestation of SSc is the presence of auto-antibodies. However, the origin of autoantibody-producing B lymphocytes and mechanisms of their activation, auto-antibody production and role remain unclear. OBJECTIVE: To identify mechanisms that contribute to pathogenic B cell generation, involvement in SSc and assess the altered distribution and function of B cells in patients. METHODS: Multi-colour flow cytometry was used to determine B cell subset distribution, cytokine production and tolerance induction in SSc patients and healthy controls. Cytokine production following stimulation of the cells ex vivo was carried out by multiplex analysis. RESULTS: The study reveals a range of defects in B lymphocyte tolerance and cytokine production in SSc. Evidence is provided for altered distribution of transitional B cell subsets, increased production of IL-6 and IL-8 and defective tolerance induction in SSc B cells. In addition, the study reveals that B cells in SSc have a reduced ability to produce IL-10 when stimulated through innate immune pathways. In contrast to healthy individuals, tolerance checkpoints in SSc patients fail to suppress the emergence of B cells that produce autoantibodies with specificity to the Scl-70 antigen, a specificity strongly associated with SSc. These defects are paralleled by altered intracellular signalling and apoptosis following B cell receptor (BCR) engagement. CONCLUSION: The study provides new insights into mechanisms underlying defective B lymphocyte responses in patients with SSc and their contribution to pathology.

Type: Article
Title: Association of Defective Regulation of Autoreactive Interleukin‐6–Producing Transitional B Lymphocytes With Disease in Patients With Systemic Sclerosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/art.40390
Publisher version: http://doi.org/10.1002/art.40390
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10039272
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