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BAFF inhibition attenuates fibrosis in scleroderma by modulating the regulatory and effector B cell balance.
- Source :
-
Science advances [Sci Adv] 2018 Jul 11; Vol. 4 (7), pp. eaas9944. Date of Electronic Publication: 2018 Jul 11 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and lung fibrosis. More than 90% of patients with SSc are positive for autoantibodies. In addition, serum B cell activating factor (BAFF) level is correlated with SSc severity and activity. Thus, B cells are considered to play a pathogenic role in SSc. However, there are two opposing subsets: regulatory B cells (Bregs) and effector B cells (Beffs). Interleukin-10 (IL-10)-producing Bregs negatively regulate the immune response, while IL-6-producing Beffs positively regulate it. Therefore, a protocol that selectively depletes Beffs would represent a potent therapy for SSc. The aims of this study were to investigate the roles of Bregs and Beffs in SSc and to provide a scientific basis for developing a new treatment strategy targeting B cells. A bleomycin-induced scleroderma model was induced in mice with a B cell-specific deficiency in IL-6 or IL-10. We also examined whether BAFF regulates cytokine-producing B cells and its effects on the scleroderma model. IL-6-producing Beffs increased in number and infiltrated the inflamed skin in the scleroderma model. The skin and lung fibrosis was attenuated in B cell-specific IL-6-deficient mice, whereas B cell-specific IL-10-deficient mice showed more severe fibrosis. In addition, BAFF increased Beffs but suppressed Bregs. Furthermore, BAFF antagonist attenuated skin and lung fibrosis in the scleroderma model with reduction of Beffs but not of Bregs. The current study indicates that Beffs play a pathogenic role in the scleroderma model, while Bregs play a protective role. BAFF inhibition is a potential therapeutic strategy for SSc via alteration of B cell balance.
- Subjects :
- Animals
B-Cell Activating Factor antagonists & inhibitors
B-Lymphocyte Subsets cytology
B-Lymphocyte Subsets drug effects
B-Lymphocyte Subsets metabolism
B-Lymphocytes, Regulatory cytology
B-Lymphocytes, Regulatory drug effects
B-Lymphocytes, Regulatory metabolism
Bleomycin toxicity
Collagen metabolism
Disease Models, Animal
Female
Fibrosis
Interleukin-10 blood
Interleukin-10 deficiency
Interleukin-10 genetics
Interleukin-6 blood
Interleukin-6 deficiency
Interleukin-6 genetics
Lipopolysaccharides pharmacology
Lung Diseases pathology
Male
Mice
Mice, Inbred C57BL
Scleroderma, Systemic chemically induced
Scleroderma, Systemic metabolism
Scleroderma, Systemic pathology
Skin Diseases pathology
B-Cell Activating Factor metabolism
B-Lymphocyte Subsets immunology
B-Lymphocytes, Regulatory immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2375-2548
- Volume :
- 4
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Science advances
- Publication Type :
- Academic Journal
- Accession number :
- 30009261
- Full Text :
- https://doi.org/10.1126/sciadv.aas9944