title: Interferon-α induces altered transitional B cell signaling and function in Systemic Lupus Erythematosus.
abstract: Previous studies suggest that the B cells of patients with Systemic Lupus Erythematosus (SLE) are hyper-responsive to BCR crosslinking; however, it has been unclear whether this is the result of altered B cell signaling or differences in various B cell subpopulations in SLE patients as compared to healthy controls. Here we have developed a novel Phosflow technique that permits examination of cell signaling in distinct B cell subpopulations stratified based upon developmental stage and cell surface IgM levels, which we use to show that the naïve B cells of SLE patients are hyper-responsive to IgM receptor crosslinking, resulting in increased SYK phosphorylation. We further demonstrate that this hyper-responsiveness is most marked in the transitional B cell subset and that it is associated with altered function, resulting in decreased apoptosis and increased proliferation of these cells. Examination of repeated samples from the same patients revealed that the hyper-responsiveness fluctuated over time, suggesting that it may be mediated by pro-inflammatory factors rather than genetic variations between patients. In support of this concept, incubation of healthy control B cells with IFN-α or SLE plasma induced the hyper-responsive phenotype, which was blocked by anti-IFN-α antibody. Furthermore, no obvious correlation was seen between genetic variants that are proposed to alter BCR signaling and the increased SYK phosphorylation. The findings suggest that pro-inflammatory factors, in particular Type I IFNs, modulate B cell function in SLE in a way that could contribute to the breach of tolerance in this condition.
authors: Arthritis Centre of Excellence, Toronto Western Hospital Research Institute, University of Toronto Faculty of Medicine, Toronto, Canada.
authors: Nan-Hua
authors: NH
authors: Chang
authors: Arthritis Centre of Excellence, Toronto Western Hospital Research Institute, University of Toronto Faculty of Medicine, Toronto, Canada.
authors: Timothy T
authors: TT
authors: Li
authors: University of Ottawa, Ottawa, Canada.
authors: Julie J
authors: JJ
authors: Kim
authors: Arthritis Centre of Excellence, Toronto Western Hospital Research Institute, University of Toronto Faculty of Medicine, Toronto, Canada.
authors: Carolina
authors: C
authors: Landolt-Marticorena
authors: CHU de Québec and Faculty of Medicine, Université Laval, Quebec City, Canada.
authors: Paul R
authors: PR
authors: Fortin
authors: Arthritis Centre of Excellence, Toronto Western Hospital Research Institute, University of Toronto Faculty of Medicine, Toronto, Canada.
authors: Dafna D
authors: DD
authors: Gladman
authors: Arthritis Centre of Excellence, Toronto Western Hospital Research Institute, University of Toronto Faculty of Medicine, Toronto, Canada.
authors: Murray B
authors: MB
authors: Urowitz
authors: Arthritis Centre of Excellence, Toronto Western Hospital Research Institute, University of Toronto Faculty of Medicine, Toronto, Canada. Electronic address: jwither@uhnres.utoronto.ca.
authors: Joan E
authors: JE
authors: Wither
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism*; D016898:Interferon-alpha / Q000276:immunology* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D055815:Young Adult
chemical_list: D007075:Immunoglobulin M; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: B cell; Hyper-responsive; Interferon-alpha; Lupus; SYK