This research program is focused on characterizing the genetic interactions that mediate fatal disease in the lupus-prone NZM2410 mouse model of SLE. During the previous grant period, we identified four suppressive modifiers and two epistatic susceptibility loci that impacted disease development in our B6-congenic model of lupus autoimmunity. We subsequently produced a collection of B6-congenic strains carrying these disease-enhancing or disease-suppressing genes and initiated a detailed characterization of their component phenotypes and epistatic interactions. These experiments have led to the development of a model proposing that severe disease is mediated by epistatic interactions among genes in three separate pathways, each impacting a distinct element of disease pathogenesis {Wakeland, Liu, et al. 2001 2262/id}. In this application, we are proposing to identify three of the genes that were detected in our genetic dissection of this epistatic disease model. The identification of these genes will provide insights into genetic mechanisms that can suppress the breach in tolerance mediated by Sle1, and will identify genes that exacerbate the severity of glomerulonephritis as a consequence of immune complex deposition. We have three specific aims: 1). To fine map and identify kidney-targeting genes in the Sle1 gene cluster. We have developed a nephrotoxic antisera assay that allows the rapid detection of genes that exacerbate the development of glomerulonephritis (GN) as a consequence of immune complex deposition in the kidney. We propose to utilize this assay to complete the fine mapping and identification of these two genes via positional cloning strategies. 2). To fine map and identify Sles1. Sles1 was the strongest suppressive locus detected in our linkage analysis of disease modifiers in the NZW genome. This gene specifically suppresses the breach in immune tolerance mediated by the Sle1 gene cluster. We have produced a series of congenic recombinants with truncated intervals that will allow the localization of Sles1 into a ~950 Kb genomic interval. We will complete this fine mapping analysis and identify Sles1 3). Characterize the component phenotypes and genetic interactions of Sles2, Sles3, Sles4, and Sle6. We propose to create a series of bi- and tri-congenic strains to assess their impact on disease pathogenesis. The long-term goal of these studies is to characterize the genetic interactions that enhance and suppress lupus pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI045196-09
Application #
7019170
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Johnson, David R
Project Start
1998-09-30
Project End
2008-02-29
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
9
Fiscal Year
2006
Total Cost
$380,835
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Dutta, Mala; Kraus, Zachary J; Gomez-Rodriguez, Julio et al. (2013) A role for Ly108 in the induction of promyelocytic zinc finger transcription factor in developing thymocytes. J Immunol 190:2121-8
Hwang, Sun-Hee; Lee, Huiyin; Yamamoto, Miwako et al. (2012) B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosus-prone mice. J Immunol 189:5786-96
Wang, Andrew; Batteux, Frederic; Wakeland, Edward K (2010) The role of SLAM/CD2 polymorphisms in systemic autoimmunity. Curr Opin Immunol 22:706-14
Fairhurst, Anna-Marie; Mathian, Alexis; Connolly, John E et al. (2008) Systemic IFN-alpha drives kidney nephritis in B6.Sle123 mice. Eur J Immunol 38:1948-60
Subramanian, Srividya; Yim, Young-Sun; Liu, Kui et al. (2005) Epistatic suppression of systemic lupus erythematosus: fine mapping of Sles1 to less than 1 mb. J Immunol 175:1062-72
Anderson, Porter; Treanor, John; Porcelli, Susan et al. (2003) Non-interference between two protein carriers when used with the same polysaccharide for pneumococcal conjugate vaccines in 2-year-old children. Vaccine 21:1554-9
Nahm, M H; Briles, D E; Yu, X (2000) Development of a multi-specificity opsonophagocytic killing assay. Vaccine 18:2768-71
Pichichero, M E; Porcelli, S; Treanor, J et al. (1998) Serum antibody responses of weanling mice and two-year-old children to pneumococcal-type 6A-protein conjugate vaccines of differing saccharide chain lengths. Vaccine 16:83-91
Claesson, B A; Trollfors, B; Anderson, P W et al. (1996) Serum antibodies in six-year-old children vaccinated in infancy with a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine. Pediatr Infect Dis J 15:170-2