title: Beta 2-microglobulin-deficient mice are protected from hypergammaglobulinemia and have defective antibody responses because of increased IgG catabolism.
abstract: The goal of this study was to determine whether class I proteins play an important role in the regulation of Ig and to elucidate the mechanism(s) involved. We analyzed the phenotype imposed by a null allele of beta 2-microglobulin (beta 2m). Serum Ig levels of several mouse strains showed a beta 2m dependence that was most evident in mice genetically predisposed to develop chronic systemic lupus erythematosus, was preferential to IgG isotypes, and was greatly exaggerated in aging mice that normally develop hypergammaglobulinemia. Beta 2m-deficient mice, regardless of genetic background, also displayed a substantial reduction of specific Ab in response to a prototypic T cell-dependent Ag and a prototypic T cell-independent 2 Ag. This reduction could be accounted for by a selective diminution of Abs of the IgG class. Therefore, class I proteins play a considerable role in the regulation of Ig. The beta 2m dependence could not be explained by class I-dependent immunoregulatory cells (CD8+ cells, NK1.1+ T cells, or conventional NK+ cells) or by the transfer of maternal IgG into the prenatal/neonatal mouse made possible by the beta 2m-dependent Fc receptor (FcRn). However, a beta 2m-dependent increase in the half-lives of IgG, presumably conferred by lifelong FcRn expression, was observed in all mice regardless of genetic background and age. We conclude that FcRn-mediated protection of IgG from catabolism is a generic mechanism that best explains the lifelong beta 2m dependence of Ig in both normal and pathologic situations.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Christianson
authors.forename: W
authors.initials: W
authors.lastname: Brooks
authors.forename: S
authors.initials: S
authors.lastname: Vekasi
authors.forename: E A
authors.initials: EA
authors.lastname: Manolfi
authors.forename: J
authors.initials: J
authors.lastname: Niles
authors.forename: S L
authors.initials: SL
authors.lastname: Roopenian
authors.forename: J B
authors.initials: JB
authors.lastname: Roths
authors.forename: R
authors.initials: R
authors.lastname: Rothlein
authors.forename: D C
authors.initials: DC
authors.lastname: Roopenian
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000276:immunology; D000375:Aging / Q000276:immunology; D000818:Animals; D000955:Antigens, T-Independent / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004198:Disease Susceptibility; D005260:Female; D005362:Ficoll / Q000031:analogs & derivatives / Q000276:immunology; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006942:Hypergammaglobulinemia / Q000235:genetics / Q000276:immunology*; D017099:IgG Deficiency / Q000235:genetics / Q000276:immunology; D007136:Immunoglobulins / Q000096:biosynthesis* / Q000097:blood / Q000172:deficiency*; D007371:Interferon-gamma / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008431:Maternal-Fetal Exchange / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD; D008814:Mice, Inbred NZB; D011247:Pregnancy; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology; D001613:beta 2-Microglobulin / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000955:Antigens, T-Independent; C031007:DNP-Ficoll; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; D001613:beta 2-Microglobulin; D015847:Interleukin-4; D005362:Ficoll; D007371:Interferon-gamma