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The Yaa mutation promoting murine lupus causes defective development of marginal zone B cells

Marinkovic, Dragan
Martinez-Soria, Eduardo
Wirth, Thomas
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Published in Journal of Immunology. 2003, vol. 170, no. 5, p. 2293-2301
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.
Keywords AnimalsAntigens, T-Independent/administration & dosage/immunologyB-Lymphocyte Subsets/ immunology/metabolism/ pathologyCell Differentiation/genetics/immunologyCells, CulturedDown-Regulation/genetics/immunologyGene Expression Regulation/immunologyImmunoglobulin M/biosynthesis/geneticsInjections, IntravenousKruppel-Like Transcription FactorsLupus Nephritis/ genetics/ immunology/pathologyLymphocyte CountLymphopenia/genetics/immunologyMaleMiceMice, Inbred C57BLMice, KnockoutMice, Mutant StrainsMice, TransgenicMutationReceptors, Complement 3d/biosynthesisSpleen/immunology/metabolism/pathologyStem Cells/immunology/pathologyTranscription Factors/biosynthesis/deficiency/geneticsTransgenes/immunologyTrinitrobenzenes/immunologyY Chromosome/ genetics/ immunology
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PMID: 12594250
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