Epistatic suppression of systemic lupus erythematosus: fine mapping of Sles1 to less than 1 mb.
Sle is a susceptibility locus for systemic autoimmunity derived from the lupus-prone NZM2410 mouse. The New Zealand White-derived suppressive modifier Sles1 was identified as a specific modifier of Sle1 and prevents the development of IgG anti-chromatin autoantibodies mediated by Sle1 on the C57BL/6 (B6) background. Fine mapping of Sles1 with truncated congenic intervals localizes it to a approximately 956-kb segment of mouse chromosome 17. Sles1 completely abrogates the development of activated T and B cell populations in B6.Sle1. Despite this suppression of the Sle1-mediated cell surface activation phenotypes, B6.Sle1 Sles1 splenic B cells still exhibit intrinsic ERK phosphorylation. Classic genetic complementation tests using the nonautoimmmune 129/SvJ mouse suggests that this strain possesses a Sles1 allele complementary to that of New Zealand White, as evidenced by the lack of glomerulonephritis, splenomegaly, and antinuclear autoantibody production seen in (129 x B6.Sle1 Sles1)F(1)s. These findings localize and characterize the suppressive properties of Sles1 and implicate 129 as a useful strain for aiding in the identification of this elusive epistatic modifier gene.
Center for Immunology and Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Srividya
S
Subramanian
Young-Sun
YS
Yim
Kui
K
Liu
Katalin
K
Tus
Xin J
XJ
Zhou
Edward K
EK
Wakeland
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004843:Epistasis, Genetic; D005260:Female; D005816:Genetic Complementation Test; D016130:Immunophenotyping; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D020161:Physical Chromosome Mapping / Q000379:methods*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013489:Suppression, Genetic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000954:Antigens, Surface; D014409:Tumor Necrosis Factor-alpha