title: B cell developmental requirement for the G alpha i2 gene.
abstract: Null mutation of the Galphai2 trimeric G protein results in a discrete and profound mucosal disorder, including inflammatory bowel disease (IBD), attenuation of IL-10 expression, and immune function polarized to Th1 activity. Genetic and adoptive transfer experiments have established a role for B cells and IL-10 in mucosal immunologic homeostasis and IBD resistance. In this study, we addressed the hypothesis that Galphai2 is required for the development of IL-10-producing B cells. Galphai2(-/-) mice were reduced in the relative abundance of marginal zone (MZ), transitional type 2 (T2), and B-1a B cells and significantly increased in follicular mature and B-1b B cells. Reconstitution of RAG2(-/-) mice with Galphai2(-/-) bone marrow induced an IBD-like colitis and a deficiency in absolute numbers of MZ, T2, and B-1 B cells. Thus, the Galphai2(-/-) genotype in colitis susceptibility and B cell development involved a cis effect within the hemopoietic compartment. In vitro, the B cell population of Galphai2(-/-) mice was functionally deficient in LPS-induced proliferation and IL-10 production, consistent with the exclusive capacity of T2 and MZ cell subpopulations for LPS responsiveness. In vivo, Galphai2(-/-) mice were selectively impaired for the IgM response to T-independent type II, consistent with the relative depletion of MZ and peritoneal B-1 subpopulations. Collectively, these results reveal a selective role for Galphai2 in MZ and B-1 B cell development. Disorders of this Galphai2-dependent process in B cell development may represent a mechanism for IBD susceptibility.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095-1732, USA.
authors.forename: Harnisha
authors.initials: H
authors.lastname: Dalwadi
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
authors.forename: Matthew
authors.initials: M
authors.lastname: Schrage
authors.forename: Karsten
authors.initials: K
authors.lastname: Spicher
authors.forename: Tom T
authors.initials: TT
authors.lastname: Su
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.forename: Jonathan
authors.initials: J
authors.lastname: Braun
mesh_terms: D000818:Animals; D000955:Antigens, T-Independent / Q000008:administration & dosage / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000473:pathology / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D005796:Genes / Q000276:immunology / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D016130:Immunophenotyping; D007274:Injections, Intraperitoneal; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010529:Peritoneal Cavity / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000473:pathology
chemical_list: D000955:Antigens, T-Independent; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse