Systemic Lupus Erythematosus (SLE) is inherited as a complex polygenic trait, which is further complicated by genetic and phenotypic heterogeneity. To define the genetics of this disease, the investigators and others have taken advantage of the uniform genetic composition of inbred mouse strains, of which several spontaneously develop clinical and immunopathologic characteristics similar to human SLE. They have previously identified the chromosomal locations of autoimmune susceptibility loci for the four main lupus strains that include the NZB, NZW, BXSB, and MRL-Faslpr mice. These studies demonstrated a multiplicative threshold inheritance of disease traits with specific combinations of loci contributing to each immunopathologic stage. Among the loci identified, four (Lmb1 to 4) from the MRL-Faslpr x C57BL/6-Faslpr cross were significantly linked to diseased traits with the highest likelihoods. Further mapping studies have revealed additional Lmb loci linked to the production of specific autoantibodies. Reciprocal interval congenic lines for all four Lmb loci were subsequently generated and significant component phenotypes were found for Lmb3 (chromosome 7) and to a lesser extent Lmb11 (chromosome 4). This proposal will extend this work by more precisely mapping Lmb3 and cloning the specific underlying genetic alterations. Cell transfer studies will be performed to determine whether expression of Lmb3 in bone marrow cells, T lymphocytes and/or B cells is necessary for the development of autoimmunity. To define the interactions of the Lmb loci, additional derivative congenic mice with combinations of one to four Lmb loci will be generated and analyzed. Finally, further characterization of the Lmb1 congenic mice and fine mapping of the Lmb1 locus will be performed. These studies should yield significant new insights into the etiopathogenesis of systemic autoimmunity, and may lead to new diagnostic and therapeutic approaches for human SLE.
| Deshmukh, Vishal A; Tardif, Virginie; Lyssiotis, Costas A et al. (2013) A regenerative approach to the treatment of multiple sclerosis. Nature 502:327-332 |
| Koh, Yi Ting; Scatizzi, John C; Gahan, Jennifer D et al. (2013) Role of nucleic acid-sensing TLRs in diverse autoantibody specificities and anti-nuclear antibody-producing B cells. J Immunol 190:4982-90 |
| Kono, Dwight H; Baccala, Roberto; Theofilopoulos, Argyrios N (2013) TLRs and interferons: a central paradigm in autoimmunity. Curr Opin Immunol 25:720-7 |
| Baccala, Roberto; Gonzalez-Quintial, Rosana; Blasius, Amanda L et al. (2013) Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. Proc Natl Acad Sci U S A 110:2940-5 |
| Lawson, Brian R; Eleftheriadis, Theodoros; Tardif, Virginie et al. (2012) Transmethylation in immunity and autoimmunity. Clin Immunol 143:8-21 |
| Scatizzi, John C; Haraldsson, Maria K; Pollard, K Michael et al. (2012) The Lbw2 locus promotes autoimmune hemolytic anemia. J Immunol 188:3307-14 |
| Gonzalez-Quintial, Rosana; Lawson, Brian R; Scatizzi, John C et al. (2011) Systemic autoimmunity and lymphoproliferation are associated with excess IL-7 and inhibited by IL-7R? blockade. PLoS One 6:e27528 |
| Theofilopoulos, Argyrios N; Kono, Dwight H; Beutler, Bruce et al. (2011) Intracellular nucleic acid sensors and autoimmunity. J Interferon Cytokine Res 31:867-86 |
| Theofilopoulos, Argyrios N; Gonzalez-Quintial, Rosana; Lawson, Brian R et al. (2010) Sensors of the innate immune system: their link to rheumatic diseases. Nat Rev Rheumatol 6:146-56 |
| Aït-Azzouzene, Djemel; Kono, Dwight H; Gonzalez-Quintial, Rosana et al. (2010) Deletion of IgG-switched autoreactive B cells and defects in Fas(lpr) lupus mice. J Immunol 185:1015-27 |
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