title: Nitric oxide regulates BAFF expression and T cell-independent antibody responses.
abstract: Whereas NO is known to regulate T cell responses, its role in regulating B cell responses remains unclear. Previous studies suggested that inducible NO synthase 2 (NOS2/iNOS) is required for normal IgA Ab responses but inhibits antiviral IgG2a Ab responses. In this study we used NOS2(-/-) mice to determine the role of NO in T cell-dependent and T cell-independent (TI)-2 Ab responses. Whereas T cell-dependent Ab responses were only modestly increased in NOS2(-/-) mice, IgM and IgG3 Ab responses as well as marginal zone B cell plasma cell numbers and peritoneal B1b B cells were significantly elevated after immunization with the TI-2 Ag 4-hydroxy-3-nitrophenyl acetyl (NP)-Ficoll. The elevated TI-2 responses in NOS2(-/-) mice were accompanied by significant increases in serum levels of BAFF/BLyS and by increases in BAFF-producing Ly6C(hi) inflammatory monocytes and monocyte-derived dendritic cells (DCs), suggesting that NO normally inhibits BAFF expression. Indeed, we found that NOS2(-/-) DCs produced more BAFF than did wild-type DCs, and addition of a NO donor to NOS2(-/-) DCs reduced BAFF production. Bone marrow chimeric mice that lack NOS2 in either nonhematopoietic or hematopoietic cells had intermediate IgM and IgG3 Ab responses after NP-Ficoll immunization, suggesting that NOS2 from both hematopoietic and nonhematopoietic sources regulates TI-2 Ab responses. Similar to NOS2(-/-) mice, depletion of Ly6C(hi) inflammatory monocytes and monocyte-derived DCs enhanced NP-specific IgM and IgG3 responses to NP-Ficoll. Thus, NO produced by inflammatory monocytes and their derivative DC subsets plays an important role in regulating BAFF production and TI-2 Ab responses.
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109; and giordano@u.washington.edu.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giordano
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109; and.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Draves
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109; and.
authors.forename: Chang
authors.initials: C
authors.lastname: Li
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109; and.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Clark
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D005362:Ficoll / Q000737:chemistry / Q000276:immunology; D006241:Haptens / Q000276:immunology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000737:chemistry* / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009596:Nitrophenols / Q000276:immunology; D010648:Phenylacetates / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*
chemical_list: D053264:B-Cell Activating Factor; D006241:Haptens; D009596:Nitrophenols; D010648:Phenylacetates; C505720:Tnfsf13b protein, mouse; C026242:4-hydroxy-5-nitrophenyl acetic acid; D005362:Ficoll; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse