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The Sgp3 locus on mouse chromosome 13 regulates nephritogenic gp70 autoantigen expression and predisposes to autoimmunity

Laporte, Catherine
Ballester, Benoit
Mary, Charles
Reininger, Luc
Published in Journal of Immunology. 2003, vol. 171, no. 7, p. 3872-3877
Abstract By interval mapping of a backcross progeny between New Zealand White (NZW) and C57BL/6 (B6) mice bearing the Y chromosome-linked autoimmune acceleration gene Yaa, we previously identified a genetic locus on mid-chromosome 13, here designated as Sgp3, showing a major effect on the expression of a nephritogenic autoantigen, gp70. In this study, the NZW-derived Sgp3 region was transferred by backcross procedure and marker-assisted selection on the B6 background to produce three independent congenic strains B6.NZW-Sgp3/1, -Sgp3/2, and -Sgp3/3. We show that NZW homozygosity at a single 3 centiMorgans ( approximately 12 megabases (Mb)) interval between markers D13Mit142 and D13Mit254 mediates increased basal serum levels of gp70 in B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice and with a higher degree in males ( approximately 15 micro g/ml) than in females ( approximately 9 micro g/ml) as compared with B6 ( approximately 2 micro g/ml), revealing a gender effect. However, their gp70 levels are still lower than that of NZW mice ( approximately 60 micro g/ml). In addition, B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice showed a moderate 2- to 3-fold increase in serum gp70 in response to LPS, which contrasted with over a 10-fold increase in NZW mice. Although both B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice failed to produce significant amounts of gp70 anti-gp70 immune complexes, unexpectedly, aged B6.NZW-Sgp3/2 congenic males bearing the Yaa gene developed increased titers of IgG autoantibodies to DNA and chromatin. Our data indicate that Sgp3 is involved in a complex process of gp70 production under polygenic control and may provide a significant contribution to lupus susceptibility not only through up-regulation of gp70 autoantigen production but also predisposition to autoimmunity.
Keywords AnimalsAntibodies, Antinuclear/biosynthesis/bloodAutoantigens/ biosynthesis/blood/geneticsChromatin/immunologyChromosome Mapping/methodsClusterinCrosses, GeneticFemaleGenetic Markers/ immunologyGenetic Predisposition to DiseaseGlycoproteins/ biosynthesis/blood/ genetics/physiologyImmunoglobulin G/biosynthesis/bloodLipopolysaccharides/administration & dosageLupus Nephritis/ genetics/immunologyMaleMiceMice, CongenicMice, Inbred C57BLMice, Inbred NZBMolecular Chaperones/blood/ genetics/physiologyMutationSpecies SpecificityY Chromosome/genetics
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PMID: 14500689
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