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

被引:27
作者
Laporte, C
Ballester, B
Mary, C
Izui, S
Reininger, L
机构
[1] Fac Med Marseille, INSERM, U399, F-13385 Marseille 05, France
[2] Univ Geneva, Ctr Med, Dept Pathol, CH-1211 Geneva, Switzerland
关键词
D O I
10.4049/jimmunol.171.7.3872
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 (similar to12 megabases (Mb)) interval between markers 1)13Mit142 and D13Mit254 mediates increased basal serum levels of gp70 in B6.NZWSgp3/1 and B6.NZW-Sgp3/2 mice and with a higher degree in males (similar to15 mug/ml) than in females (similar to9 mug/ml) as compared with B6 (similar to2 mug/ml), revealing a gender effect. However, their gp70 levels are still lower than that of NZW mice ( mug/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.
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页码:3872 / 3877
页数:6
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共 27 条
[21]  
2-H
[22]   AN ANCIENT PROVIRUS HAS IMPOSED ANDROGEN REGULATION ON THE ADJACENT MOUSE SEX-LIMITED PROTEIN GENE [J].
STAVENHAGEN, JB ;
ROBINS, DM .
CELL, 1988, 55 (02) :247-254
[23]   Establishment of monoclonal anti-retroviral gp70 autoantibodies from MRL/lpr lupus mice and induction of glomerular gp70 deposition and pathology by transfer into non-autoimmune mice [J].
Tabata, N ;
Miyazawa, M ;
Fujisawa, R ;
Takei, YA ;
Abe, H ;
Hashimoto, K .
JOURNAL OF VIROLOGY, 2000, 74 (09) :4116-4126
[24]   Genetic control of glycoprotein 70 autoantigen production and its influence on immune complex levels and nephritis in murine lupus [J].
Tucker, RM ;
Vyse, TJ ;
Rozzo, S ;
Roark, CL ;
Izui, S ;
Kotzin, BL .
JOURNAL OF IMMUNOLOGY, 2000, 165 (03) :1665-1672
[25]   Control of separate pathogenic autoantibody responses marks MHC gene contributions to murine lupus [J].
Vyse, TJ ;
Halterman, RK ;
Rozzo, SJ ;
Izui, S ;
Kotzin, BL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (14) :8098-8103
[26]   Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice [J].
Vyse, TJ ;
Drake, CG ;
Rozzo, SJ ;
Roper, E ;
Izui, S ;
Kotzin, BL .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 98 (08) :1762-1772
[27]   Speed congenics: a classic technique in the fast lane (relatively speaking) [J].
Wakeland, E ;
Morel, L ;
Achey, K ;
Yui, M ;
Longmate, J .
IMMUNOLOGY TODAY, 1997, 18 (10) :472-477