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Differential role of three major New Zealand Black-derived loci linked with Yaa-induced murine lupus nephritis

Fossati-Jimack, Liliane
Laporte, Catherine
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Published in Journal of Immunology. 2005, vol. 174, no. 2, p. 1111-1117
Abstract By assessing the development of Y-linked autoimmune acceleration (Yaa) gene-induced systemic lupus erythematosus in C57BL/6 (B6) x (New Zealand Black (NZB) x B6.Yaa)F(1) backcross male mice, we mapped three major susceptibility loci derived from the NZB strain. These three quantitative trait loci (QTL) on NZB chromosomes 1, 7, and 13 differentially regulated three different autoimmune traits: anti-nuclear autoantibody production, gp70-anti-gp70 immune complex (gp70 IC) formation, and glomerulonephritis. Contributions to the disease traits were further confirmed by generating and analyzing three different B6.Yaa congenic mice, each carrying one individual NZB QTL. The chromosome 1 locus that overlapped with the previously identified Nba2 (NZB autoimmunity 2) locus regulated all three traits. A newly identified chromosome 7 locus, designated Nba5, selectively promoted anti-gp70 autoantibody production, hence the formation of gp70 IC and glomerulonephritis. B6.Yaa mice bearing the NZB chromosome 13 locus displayed increased serum gp70 production, but not gp70 IC formation and glomerulonephritis. This locus, called Sgp3 (serum gp70 production 3), selectively regulated the production of serum gp70, thereby contributing to the formation of nephritogenic gp70 IC and glomerulonephritis, in combination with Nba2 and Nba5 in NZB mice. Among these three loci, a major role of Nba2 was demonstrated, because B6.Yaa Nba2 congenic male mice developed the most severe disease. Finally, our analysis revealed the presence in B6 mice of an H2-linked QTL, which regulated autoantibody production. This locus had no apparent individual effect, but most likely modulated disease severity through interaction with NZB-derived susceptibility loci.
Keywords AnimalsAntibodies, Antinuclear/bloodAntigen-Antibody Complex/bloodAutoantigens/bloodChromatin/immunologyCrosses, GeneticGenetic Markers/immunologyGenetic Predisposition to DiseaseGlomerulonephritis/genetics/immunologyGlycoproteins/blood/geneticsImmunoglobulin G/bloodLinkage (Genetics)/*immunologyLupus Erythematosus, Systemic/genetics/immunologyLupus Nephritis/*genetics/*immunologyMaleMiceMice, CongenicMice, Inbred C57BLMice, Inbred NZB/*geneticsMolecular Chaperones/geneticsMutationQuantitative Trait Loci/*immunologySyndromeUp-Regulation/genetics/immunologyY Chromosome/*immunology
Stable URL http://archive-ouverte.unige.ch/unige:11375
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Other version: http://www.jimmunol.org/cgi/reprint/174/2/1111.pdf
PMID: 15634937
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