1. IL-27 Directly Enhances Germinal Center B Cell Activity and Potentiates Lupus in Sanroque Mice
- Author
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Cindy S. Ma, Rushika C. Wirasinha, Cecile King, Stephen Adelstein, Nico Ghilardi, Melanie Wong, Dipti Vijayan, Robert Brink, Michael Elliott, Danielle T. Avery, Norhanani Mohd Redzwan, Carola G. Vinuesa, Masao Kobayashi, Paul W Gray, Stuart G. Tangye, Giles Walters, and Marcel Batten
- Subjects
CD4-Positive T-Lymphocytes ,STAT3 Transcription Factor ,0301 basic medicine ,Interleukin-27 ,Ubiquitin-Protein Ligases ,Cellular differentiation ,Immunology ,CD38 ,Biology ,Lymphocyte Activation ,medicine.disease_cause ,Autoimmunity ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Immunology and Allergy ,Receptors, Cytokine ,Receptor ,Cells, Cultured ,B cell ,Mice, Knockout ,CD20 ,B-Lymphocytes ,Systemic lupus erythematosus ,Germinal center ,Cell Differentiation ,Receptors, Interleukin ,Germinal Center ,medicine.disease ,Lupus Nephritis ,Molecular biology ,Mice, Inbred C57BL ,Disease Models, Animal ,STAT1 Transcription Factor ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,030215 immunology - Abstract
Germinal centers (GC) give rise to high-affinity and long-lived Abs and are critical in immunity and autoimmunity. IL-27 supports GCs by promoting survival and function of T follicular helper cells. We demonstrate that IL-27 also directly enhances GC B cell function. Exposure of naive human B cells to rIL-27 during in vitro activation enhanced their differentiation into CD20+CD38+CD27lowCD95+CD10+ cells, consistent with the surface marker phenotype of GC B cells. This effect was inhibited by loss-of-function mutations in STAT1 but not STAT3. To extend these findings, we studied the in vivo effects of IL-27 signals to B cells in the GC-driven Roquinsan/san lupus mouse model. Il27ra−/−Roquinsan/san mice exhibited significantly reduced GCs, IgG2a(c)+ autoantibodies, and nephritis. Mixed bone marrow chimeras confirmed that IL-27 acts through B cell– and CD4+ T cell–intrinsic mechanisms to support GCs and alter the production of pathogenic Ig isotypes. To our knowledge, our data provide the first evidence that IL-27 signals directly to B cells promote GCs and support the role of IL-27 in lupus.
- Published
- 2016
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