title: The Yaa mutation promoting murine lupus causes defective development of marginal zone B cells.
abstract: The accelerated development of systemic lupus erythematosus (SLE) in BXSB male mice is associated with the presence of an as yet unidentified mutant gene, Yaa (Y-linked autoimmune acceleration). In view of a possible role of marginal zone (MZ) B cells in murine SLE, we have explored whether the expression of the Yaa mutation affects the differentiation of MZ and follicular B cells, thereby implicating the acceleration of the disease. In this study, we show that both BXSB and C57BL/6 Yaa mice, including two different substrains of BXSB Yaa males that are protected from SLE, displayed an impaired development of MZ B cells early in life. Studies in bone marrow chimeras revealed that the loss of MZ B cells resulted from a defect intrinsic to B cells expressing the Yaa mutation. The lack of selective expansion of MZ B cells in diseased BXSB Yaa males strongly argues against a major role of MZ B cells in the generation of pathogenic autoantibodies in the BXSB model of SLE. Furthermore, a comparative analysis with mice deficient in CD22 or expressing an IgM anti-trinitrophenyl/DNA transgene suggests that the hyperreactive phenotype of Yaa B cells, as judged by a markedly increased spontaneous IgM secretion, is likely to contribute to the enhanced maturation toward follicular B cells and the block in the MZ B cell generation.
authors.affiliation: Department of Pathology, University of Geneva, Geneva, Switzerland.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Amano
authors.forename: Eri
authors.initials: E
authors.lastname: Amano
authors.forename: Thomas
authors.initials: T
authors.lastname: Moll
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.forename: Nabila
authors.initials: N
authors.lastname: Ibnou-Zekri
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martinez-Soría
authors.forename: Isabelle
authors.initials: I
authors.lastname: Semac
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Lars
authors.initials: L
authors.lastname: Nitschke
authors.forename: Shozo
authors.initials: S
authors.lastname: Izui
mesh_terms: D000818:Animals; D000955:Antigens, T-Independent / Q000008:administration & dosage / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000235:genetics; D007275:Injections, Intravenous; D051741:Kruppel-Like Transcription Factors; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D017464:Receptors, Complement 3d / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D019076:Transgenes / Q000276:immunology; D014301:Trinitrobenzenes / Q000276:immunology; D014998:Y Chromosome / Q000235:genetics* / Q000276:immunology*
chemical_list: D000955:Antigens, T-Independent; D007075:Immunoglobulin M; D051741:Kruppel-Like Transcription Factors; D017464:Receptors, Complement 3d; C498818:Sp6 protein, mouse; D014157:Transcription Factors; D014301:Trinitrobenzenes; C033027:secretory IgM