title: Semaphorin 4C Protects against Allergic Inflammation: Requirement of Regulatory CD138+ Plasma Cells.
abstract: The regulatory properties of B cells have been studied in autoimmune diseases; however, their role in allergic diseases is poorly understood. We demonstrate that Semaphorin 4C (Sema4C), an axonal guidance molecule, plays a crucial role in B cell regulatory function. Mice deficient in Sema4C exhibited increased airway inflammation after allergen exposure, with massive eosinophilic lung infiltrates and increased Th2 cytokines. This phenotype was reproduced by mixed bone marrow chimeric mice with Sema4C deficient only in B cells, indicating that B lymphocytes were the key cells affected by the absence of Sema4C expression in allergic inflammation. We determined that Sema4C-deficient CD19+CD138+cells exhibited decreased IL-10 and increased IL-4 expression in vivo and in vitro. Adoptive transfer of Sema4c-/-CD19+CD138+cells induced marked pulmonary inflammation, eosinophilia, and increased bronchoalveolar lavage fluid IL-4 and IL-5, whereas adoptive transfer of wild-type CD19+CD138+IL-10+cells dramatically decreased allergic airway inflammation in wild-type and Sema4c-/-mice. This study identifies a novel pathway by which Th2-mediated immune responses are regulated. It highlights the importance of plasma cells as regulatory cells in allergic inflammation and suggests that CD138+B cells contribute to cytokine balance and are important for maintenance of immune homeostasis in allergic airways disease. Furthermore, we demonstrate that Sema4C is critical for optimal regulatory cytokine production in CD138+B cells.
authors.affiliation: The Research Institute of the McGill University Health Centre, Translational Research in Respiratory Diseases Program, Meakins Christie Laboratories, Montreal, Quebec H4A 3J1, Canada.|Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Di
authors.initials: D
authors.lastname: Xue
authors.affiliation: The Research Institute of the McGill University Health Centre, Translational Research in Respiratory Diseases Program, Meakins Christie Laboratories, Montreal, Quebec H4A 3J1, Canada.|Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Gabriel N
authors.identifier: 0000-0003-4665-968X
authors.initials: GN
authors.lastname: Kaufman
authors.affiliation: The Research Institute of the McGill University Health Centre, Translational Research in Respiratory Diseases Program, Meakins Christie Laboratories, Montreal, Quebec H4A 3J1, Canada.|Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Marieme
authors.identifier: 0000-0002-4865-7998
authors.initials: M
authors.lastname: Dembele
authors.affiliation: The Research Institute of the McGill University Health Centre, Translational Research in Respiratory Diseases Program, Meakins Christie Laboratories, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Marianne
authors.identifier: 0000-0003-0264-8540
authors.initials: M
authors.lastname: Beland
authors.affiliation: The Research Institute of the McGill University Health Centre, Translational Research in Respiratory Diseases Program, Meakins Christie Laboratories, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Amir H
authors.initials: AH
authors.lastname: Massoud
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada.|Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Mindt
authors.affiliation: The Research Institute of the McGill University Health Centre, Translational Research in Respiratory Diseases Program, Meakins Christie Laboratories, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Ryan
authors.identifier: 0000-0003-0159-5352
authors.initials: R
authors.lastname: Fiter
authors.affiliation: The Research Institute of the McGill University Health Centre, Translational Research in Respiratory Diseases Program, Meakins Christie Laboratories, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Fixman
authors.affiliation: The Research Institute of the McGill University Health Centre, Translational Research in Respiratory Diseases Program, Meakins Christie Laboratories, Montreal, Quebec H4A 3J1, Canada.
authors.forename: James G
authors.initials: JG
authors.lastname: Martin
authors.affiliation: Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, NY 10029; and.
authors.forename: Roland H
authors.identifier: 0000-0002-7513-3604
authors.initials: RH
authors.lastname: Friedel
authors.affiliation: The Research Institute of the McGill University Health Centre, Translational Research in Respiratory Diseases Program, Meakins Christie Laboratories, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Maziar
authors.identifier: 0000-0002-1254-6110
authors.initials: M
authors.lastname: Divangahi
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada.|Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Fritz
authors.affiliation: The Research Institute of the McGill University Health Centre, Translational Research in Respiratory Diseases Program, Meakins Christie Laboratories, Montreal, Quebec H4A 3J1, Canada; bruce.mazer@mcgill.ca.|Department of Pediatrics, Montreal Children's Hospital, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Bruce D
authors.identifier: 0000-0003-4018-1419
authors.initials: BD
authors.lastname: Mazer
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D039961:Semaphorins / Q000276:immunology*; D053668:Syndecan-1 / Q000276:immunology
chemical_list: D016207:Cytokines; C508242:Sdc1 protein, mouse; C119353:Sema4c protein, mouse; D039961:Semaphorins; D053668:Syndecan-1