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The bm12 Inducible Model of Systemic Lupus Erythematosus SLE in C57BL/6 Mice
Published on: November 1, 2015
Interferon-α-induced B-lymphocyte stimulator expression and mobilization in healthy and systemic lupus erthymatosus
Patricia López1, Dagmar Scheel-Toellner2, Javier Rodríguez-Carrio2
1Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain, Rheumatology Research Group, MRC Centre for Immune Regulation, Institute for Biomedical Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK and Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain. Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain, Rheumatology Research Group, MRC Centre for Immune Regulation, Institute for Biomedical Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK and Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain. lopezpatricia@uniovi.es.
Insights
Interferon-alpha and SLE immune complexes increase B-lymphocyte stimulator (BLyS) in monocytes. Active systemic lupus erythematosus (SLE) patients show higher BLyS mobilization and expression in immune cells.
Area of Science:
- Immunology
- Rheumatology
Background:
- Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune system dysregulation.
- B-lymphocyte stimulator (BLyS) plays a crucial role in B-cell survival and maturation, and its overexpression is implicated in SLE pathogenesis.
Purpose of the Study:
- To investigate the cellular sources and regulatory factors driving B-lymphocyte stimulator (BLyS) overexpression in SLE patients.
- To determine the impact of inflammatory cytokines and SLE-specific immune complexes on BLyS expression and mobilization.
Main Methods:
- Quantification of surface and intracellular BLyS by flow cytometry in healthy and SLE monocytes stimulated with TNF-α, IFN-α, IFN-γ, GM-CSF, and SLE immune complexes (SLE-ICs).
- Measurement of soluble BLyS by ELISA.
- Ex vivo analysis of BLyS expression in various immune cell subsets from SLE patients and healthy controls.
- Assessment of disease activity using the BILAG index.
Main Results:
- In vitro, IFN-α and SLE-ICs increased surface-bound BLyS in healthy monocytes.
- SLE monocytes from patients with high anti-dsDNA or disease activity showed enhanced intracellular BLyS, rapid mobilization to the membrane, and release upon IFN-α stimulation.
- Ex vivo, SLE patients exhibited upregulated BLyS in B cells, myeloid DCs, and plasmacytoid DCs.
- Active SLE patients displayed an increased surface:intracellular BLyS ratio in monocytes and myeloid DCs.
Conclusions:
- IFN-α and disease activity/anti-dsDNA levels influence monocyte BLyS induction and mobilization.
- Active SLE patients show elevated membrane-bound:intracellular BLyS ratios in monocytes and myeloid DCs, indicating increased BLyS release.
- Widespread BLyS expression in blood cells of SLE patients suggests generalized immune stimulation.
Objective:
The aim of this study was to investigate the cellular populations and regulatory factors responsible for B-lymphocyte stimulator (BLyS) overexpression in SLE patients.
Methods:
Surface and intracellular BLyS levels were quantified by flow cytometry in healthy and SLE monocytes cultured in the presence of TNF-α, IFN-α, IFN-γ, GM-CSF and SLE immune complexes (SLE-ICs), while soluble BLyS was measured by ELISA. Also, both surface and intracellular BLyS expression by different cell subsets was determined in 23 SLE patients and 16 healthy controls. Disease activity was assessed using classic BILAG index.
Results:
In vitro experiments using healthy monocytes showed that IFN-α and SLE-ICs induced a progressive increase in surface-bound BLyS with respect to the intracellular stores. IFN-α-treated SLE monocytes, especially from patients with high anti-dsDNA levels or disease activity, exhibited higher intracellular levels of BLyS that was mobilized to the membrane more rapidly and subsequently released. Furthermore, ex vivo analysis of SLE patients revealed up-regulated BLyS expression in B cells, myeloid and plasmacytoid dendritic cells (DCs), whereas active patients had an increased surface:intracellular BLyS ratio in monocytes and myeloid DCs.
Conclusion:
Monocyte BLyS induction and mobilization from intra- to extracellular compartments seems to be influenced by IFN-α and disease activity or anti-dsDNA levels. Accordingly, monocytes and myeloid DCs from active patients presented the highest membrane-bound:intracellular BLyS ratio. In addition, expression levels in several blood cells support the existence of generalized immune stimulation in SLE patients.
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