Association of Defective Regulation of Autoreactive Interleukin-6-Producing Transitional B Lymphocytes With Disease in Patients With Systemic Sclerosis
| Autor: | Sophie Hillion, David Abraham, Voon H Ong, Taher E. Taher, Jacques-Olivier Pers, Jonas Bystrom, Quentin Simon, Christopher P. Denton, Rizgar A. Mageed |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Immunology Arthritis Disease Scleroderma 03 medical and health sciences 0302 clinical medicine Rheumatology Cytokines metabolism Immature B-Lymphocyte Humans Immunology and Allergy Medicine In patient skin and connective tissue diseases Interleukin 6 health care economics and organizations Aged Autoantibodies 030203 arthritis & rheumatology B-Lymphocytes Scleroderma Systemic integumentary system biology business.industry Autoantibody Middle Aged Flow Cytometry medicine.disease body regions stomatognathic diseases 030104 developmental biology biology.protein Cytokines Female business |
| Zdroj: | Arthritis & Rheumatology. 70:450-461 |
| ISSN: | 2326-5191 |
| DOI: | 10.1002/art.40390 |
| Popis: | 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.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.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.Our findings provide new insights into mechanisms underlying defective B lymphocyte responses in patients with SSc and their contribution to disease. |
| Databáze: | OpenAIRE |
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