Anti-nuclear autoantibodies (ANA) represent the hallmark of murine and human lupus. The precise cellular and molecular steps leading to the formation of pathogenic ANAs remain poorly understood. We plan to study this by taking advantage of studies that have recently mapped lupus susceptibility loci in the NZM2410 murine model. When the NZM210-derived chromosome 1 interval, l3l is introgressed onto the B6 background, these mice (B6.NZMc1) produce high titres of IgG anti-H2A/H2B/DNA subnucleosome-specific ANAs, that show little reactivity to other chromatin epitopes, and have no avidity for glomerular antigens. In contrast, when the NZM2410-derived chromosome 7 interval, Sle3 (which by itself leads to increased T-cell activation, and reduced activation-induced T-cell death), in introgressed onto the B6.NZMc1 background, these (B6.NZMc1/c7) bicongenic mice develop high titres of ANAs that react strongly with all chromatin epitopes, bind glomerular antigens (i.e., they are """"""""glomerulotrophic"""""""" or """"""""necrophilic""""""""), and precipitate nephritis. This proposal aims to: (1) To define the relative molecular contributions of Sle1 and Sle3 to the generation of necrophilic ANAs, by analyzing monoclonal nuclear- antigen specific -cell hybridomas rescued from B6NZMc7, and B6.NZMc1/c7 congenic strains. The molecular structures, fine-specifications, and necrophilic and pathogenic potential of these mAbs will be analyzed. (2) To define precisely how Sle3 impacts T-cell activation, expansion and tolerance, using a TCR Tg model. (3) To determine if other molecules that modulate T-cell activation, expansion and tolerance, using a TCR Tg model. (3) To determine if other molecules that modulate T-cell activation/tolerance can also collaborate with Sle1, to generate nephrophilic ANAs, by analyzing B6.NZMc1 mice that also bear the CD43++ knockout, or the lpr allele, for serological and clinical evidence of component lupus phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047460-03
Application #
6374495
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Johnson, David R
Project Start
1999-08-15
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$207,020
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Chang, Sooghee; Mohan, Chandra (2005) Identification of novel VH1/J558 immunoglobulin germline genes of C57BL/6 (Igh b) allotype. Mol Immunol 42:1293-301
Xie, Shangkui; Mohan, Chandra (2004) Divide and conquer--the power of congenic strains. Clin Immunol 110:109-11
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Sedrak, Peter; Hsu, Kelvin; Mohan, Chandra (2003) Molecular signatures of anti-nuclear antibodies--contribution of heavy chain framework residues. Mol Immunol 40:491-9
Liang, Zhiyan; Chen, Cui; Mohan, Chandra (2003) Molecular signatures of anti-nuclear antibodies: contributions of specific light chain residues and a novel New Zealand Black V kappa 1 germline gene. J Immunol 171:3886-94
Chen, Leian; Chang, Sooghee; Mohan, Chandra (2002) Molecular signatures of antinuclear antibodies-contributions of heavy chain CDR residues. Mol Immunol 39:333-47
Xie, S; Chang, S H; Sedrak, P et al. (2002) Dominant NZB contributions to lupus in the (SWR x NZB)F1 model. Genes Immun 3 Suppl 1:S13-20
Shi, Xiaoyan; Xie, Chun; Kreska, Desi et al. (2002) Genetic dissection of SLE: SLE1 and FAS impact alternate pathways leading to lymphoproliferative autoimmunity. J Exp Med 196:281-92
Xie, S; Chang, S; Yang, P et al. (2001) Genetic contributions of nonautoimmune SWR mice toward lupus nephritis. J Immunol 167:7141-9

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