title: G alpha q-containing G proteins regulate B cell selection and survival and are required to prevent B cell-dependent autoimmunity.
abstract: Survival of mature B cells is regulated by B cell receptor and BAFFR-dependent signals. We show that B cells from mice lacking the G(alphaq) subunit of trimeric G proteins (Gnaq(-/-) mice) have an intrinsic survival advantage over normal B cells, even in the absence of BAFF. Gnaq(-/-) B cells develop normally in the bone marrow but inappropriately survive peripheral tolerance checkpoints, leading to the accumulation of transitional, marginal zone, and follicular B cells, many of which are autoreactive. Gnaq(-/-) chimeric mice rapidly develop arthritis as well as other manifestations of systemic autoimmune disease. Importantly, we demonstrate that the development of the autoreactive B cell compartment is the result of an intrinsic defect in Gnaq(-/-) B cells, resulting in the aberrant activation of the prosurvival factor Akt. Together, these data show for the first time that signaling through trimeric G proteins is critically important for maintaining control of peripheral B cell tolerance induction and repressing autoimmunity.
authors.affiliation: Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Misra
authors.forename: Guixiu
authors.initials: G
authors.lastname: Shi
authors.forename: Miguel E
authors.initials: ME
authors.lastname: Moreno-Garcia
authors.forename: Anil
authors.initials: A
authors.lastname: Thankappan
authors.forename: Michael
authors.initials: M
authors.lastname: Tighe
authors.forename: Betty
authors.initials: B
authors.lastname: Mousseau
authors.forename: Kim
authors.initials: K
authors.lastname: Kusser
authors.forename: Shirly
authors.initials: S
authors.lastname: Becker-Herman
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudkins
authors.forename: Robert
authors.initials: R
authors.lastname: Dunn
authors.forename: Marilyn R
authors.initials: MR
authors.lastname: Kehry
authors.forename: Thi-Sau
authors.initials: TS
authors.lastname: Migone
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.forename: Melvin
authors.initials: M
authors.lastname: Simon
authors.forename: Troy D
authors.initials: TD
authors.lastname: Randall
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.forename: Denny
authors.initials: D
authors.lastname: Liggitt
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lund
mesh_terms: D000740:Anemia / Q000097:blood / Q000276:immunology; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001168:Arthritis / Q000276:immunology / Q000473:pathology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000276:immunology / Q000494:pharmacology; D016175:B-Lymphocyte Subsets / Q000166:cytology; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics*; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D006706:Homeostasis / Q000276:immunology; D007108:Immune Tolerance; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011828:Radiation Chimera / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D001324:Autoantigens; D053264:B-Cell Activating Factor; D011947:Receptors, Antigen, B-Cell; C505720:Tnfsf13b protein, mouse; C044203:anti-IgM; D051057:Proto-Oncogene Proteins c-akt; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins