dc.contributor.author | Taher, TE | en_US |
dc.contributor.author | Ong, VH | en_US |
dc.contributor.author | Bystrom, J | en_US |
dc.contributor.author | Hillion, S | en_US |
dc.contributor.author | Simon, Q | en_US |
dc.contributor.author | Denton, CP | en_US |
dc.contributor.author | Pers, J-O | en_US |
dc.contributor.author | Abraham, DJ | en_US |
dc.contributor.author | Mageed, RA | en_US |
dc.date.accessioned | 2018-02-08T14:53:59Z | |
dc.date.available | 2017-11-21 | en_US |
dc.date.issued | 2018-03 | en_US |
dc.date.submitted | 2017-12-07T12:10:36.979Z | |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/32152 | |
dc.description.abstract | OBJECTIVE: Systemic sclerosis (SSc) has the highest case-specific mortality of any rheumatic disease, and no effective therapy is available. A clear manifestation of SSc is the presence of autoantibodies. However, the origin of autoantibody-producing B lymphocytes, their mechanisms of activation and autoantibody production, and their role remain unclear. This study was undertaken to identify mechanisms that contribute to pathogenic B cell generation and involvement in SSc and to assess the altered distribution and function of B cells in SSc patients. METHODS: Multicolor flow cytometry was performed 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 determined by multiplex assay. RESULTS: A range of defects in B lymphocyte tolerance and cytokine production in SSc were noted. There was evidence of altered distribution of transitional B cell subsets, increased production of interleukin-6 (IL-6) and IL-8, and defective tolerance induction in SSc B cells. In addition, B cells from SSc patients had a reduced ability to produce IL-10 when stimulated through innate immune pathways. In contrast to healthy individuals, tolerance checkpoints in SSc patients failed to suppress the emergence of B cells that produce autoantibodies with specificity to the Scl-70 antigen, which is strongly associated with SSc. These defects were paralleled by altered intracellular signaling and apoptosis following B cell receptor engagement. CONCLUSION: Our findings provide new insights into mechanisms underlying defective B lymphocyte responses in patients with SSc and their contribution to disease. | en_US |
dc.description.sponsorship | Raynaud's and Scleroderma Association (now named Scleroderma Research UK). Grant Number: UC5
Arthritis Research UK | en_US |
dc.format.extent | 450 - 461 | en_US |
dc.language | eng | en_US |
dc.relation.ispartof | Arthritis Rheumatol | en_US |
dc.rights | This is the peer reviewed version of the following article: Taher, T. E., Ong, V. H., Bystrom, J., Hillion, S., Simon, Q., Denton, C. P., Pers, J.-O., Abraham, D. J. and Mageed, R. A. (2018), Association of Defective Regulation of Autoreactive Interleukin-6–Producing Transitional B Lymphocytes With Disease in Patients With Systemic Sclerosis. Arthritis Rheumatol. doi:10.1002/art.40390, which has been published in final form at http://dx.doi.org/10.1002/art.40390. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. | |
dc.subject | Adult | en_US |
dc.subject | Aged | en_US |
dc.subject | Autoantibodies | en_US |
dc.subject | B-Lymphocytes | en_US |
dc.subject | Cytokines | en_US |
dc.subject | Female | en_US |
dc.subject | Flow Cytometry | en_US |
dc.subject | Humans | en_US |
dc.subject | Male | en_US |
dc.subject | Middle Aged | en_US |
dc.subject | Scleroderma, Systemic | en_US |
dc.title | Association of Defective Regulation of Autoreactive Interleukin-6-Producing Transitional B Lymphocytes With Disease in Patients With Systemic Sclerosis. | en_US |
dc.type | Article | |
dc.rights.holder | © 2017, American College of Rheumatology | |
dc.identifier.doi | 10.1002/art.40390 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/29193892 | en_US |
pubs.issue | 3 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 70 | en_US |
dcterms.dateAccepted | 2017-11-21 | en_US |