The Sgp3 locus on mouse chromosome 13 regulates nephritogenic gp70 autoantigen expression and predisposes to autoimmunity.
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.
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000097:blood; D001324:Autoantigens / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D002843:Chromatin / Q000276:immunology; D002874:Chromosome Mapping / Q000379:methods; D051152:Clusterin; D003433:Crosses, Genetic; D005260:Female; D005819:Genetic Markers / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics* / Q000502:physiology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D018832:Molecular Chaperones / Q000097:blood / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D013045:Species Specificity; D014998:Y Chromosome / Q000235:genetics
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D002843:Chromatin; C495243:Clu protein, mouse; D051152:Clusterin; D005819:Genetic Markers; D006023:Glycoproteins; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D018832:Molecular Chaperones; C479954:Sgp3 protein, mouse; C033589:glycoprotein gp70, murine serum; C015382:nephritogenoside