FcgammaRIIB is a potent lupus susceptibility gene capable of interacting with a variety of other loci to modify both the induction and progression of autoimmune disease. Mice deficient in this molecule develop spontaneous anti-nuclear antibodies and fatal glomerulonephritis when on the C57BL/6 background. The same mutation on the BALB/c background is unremarkable, indicating the existence of suppressor loci on the BALB/c background which restrict the development of autoimmunity. To study the impact of these background genetic modifiers in the B6.FcRIIB-/- disease model, a cross between B6.FcRIIB -/- and BALB.FcRIIB -/- mice was performed and the resulting F1 and F2 generations evaluated for autoimmune phenotypes. Linkage analysis indicated that chromosomes 12, and 17 were likely to contain regions with positive linkage for ANA and glomerulonephritis. We have focused our attention to the Chromosome 12 region because far no obvious candidate genes have been found in that interval, thus increasing the likelihood that fine mapping of this locus will lead to the identification of novel genes that modify susceptibility of autoimmune disease. The generation of a new congenic strain has allowed us to determine that the presence of this region of chromosome 12 from the BALB/c genome is sufficient to render B6.R2-/- mice resistant to lupus disease.? ? We analyze the effect of the Yaa genetic modifier in the progression of autoimmune disease observed in B6.R2-/- mice. Mice bearing the Yaa locus provide a prime example of how important it is to control the expression of innate receptors. In Yaa mice, a hyperactive phenotype in B and dendritic cells correlates with a genomic translocation that results in duplication of at least 17 genes, one of which being TLR7. While initial reports about this genomic duplication focused on hyperresponsiveness to TLR7 ligands in this strain, the nature of how this allele accelerates systemic autoimmunity remained unclear because of the fact that multiple genes are duplicated. For example, TLR7 could function with one or more of the other duplicated genes to potentiate the acceleration in pathology, or the increase in TLR7 expression may be merely correlative with the development of autoimmunity. Thus, the precise importance of TLR7 gene duplication in the Yaa mouse was undetermined. We decided to use two approaches to answer this question, by either decreasing or increasing TLR7 gene dosage. When we lowered TLR7 gene dosage we were able to ablate the hyperresponsiveness caused by the Yaa allele, and when bred to FcgammaRIIB-deficient mice we were able to eliminate the nucleolar antibody response, enhancement in pathology and mortality that is seen in the Yaa mouse. These data unmistakably showed that an increase in TLR7 gene dosage can potentiate systemic autoimmunity, as the phenotype of the Yaa mouse was completely restored through lowering TLR7 gene dosage.? ? Increasing TLR7 gene dosage via the generation of TLR7 transgenic mice resulted in the development of acute systemic autoimmune disease characterized by anti-RNA autoantibody production, glomerulonephritis, dendritic cell expansion, anemia, and a pro-inflammatory interferon signature in the dendritic cells. The combination of these two techniques allows us to conclude that TLR7 gene dosage is both necessary and sufficient to promote autoantibody production and pathological disease associated with lupus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000912-06
Application #
7592275
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2007
Total Cost
$1,259,762
Indirect Cost
City
State
Country
United States
Zip Code
Tarasenko, Tatyana; Kole, Hemanta K; Bolland, Silvia (2008) A lupus-suppressor BALB/c locus restricts IgG2 autoantibodies without altering intrinsic B cell-tolerance mechanisms. J Immunol 180:3807-14
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Tarasenko, Tatyana; Dean, Jonathan A; Bolland, Silvia (2007) FcgammaRIIB as a modulator of autoimmune disease susceptibility. Autoimmunity 40:409-17
Deane, Jonathan A; Bolland, Silvia (2006) Nucleic acid-sensing TLRs as modifiers of autoimmunity. J Immunol 177:6573-8
Pisitkun, Prapaporn; Deane, Jonathan A; Difilippantonio, Michael J et al. (2006) Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312:1669-72
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