The primary roles of MHC molecules, T cell antigen receptors (TCR) and certain lymphoaccumulation-inducing mutations (lpr,gld) in the pathogenesis of murine lupus have been firmly established. This continuation application on murine models of generalized autoimmunity will further address the molecular basis and biologic pathways by which these genes contribute to the pathogenesis of this complex disorder. The origin and mechanism of action of the autoimmunity promoting/inducing lpr and gld double-negative TCR-alpha beta+ cells will be pursued by assessing their thymic education, V-beta TCR gene expression profiles, and ability to stimulate normal helper T cells to produce T and B cell growth/differentiation-promoting lymphokines. H-2 congenic lines of lupus mice will be developed to further define the role of H-2 haplotypes in this disease, particularly of I-E and its reactive V-beta clonotypes. Our experiments to date of V-beta gene expression profiles in lupus mice indicate disease/age-associated expansions for T cell clones expressing certain V-betas, but their role in disease pathogenesis and means of induction need to be determined. Subtractive approaches with experimentally-induced tolerance-related clonal deletions by neonatal injection of self- or foreign-superantigens will be employed to address this issue. Once disease-associated V-beta clonotypes have been identified, attempts to develop new lupus immunotherapies based on the elimination of such clones in adult mice with anti-V-beta-specific antibodies, or their control by active immunization with synthetic V-beta peptide vaccines, will be undertaken, The recently established SCID mouse/human lupus model will also be used to define human lupus-associated V-beta clonotypes and their autoimmune potential.
| 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 |
| Baccala, Roberto; Gonzalez-Quintial, Rosana; Schreiber, Robert D et al. (2012) Anti-IFN-ýý/ýý receptor antibody treatment ameliorates disease in lupus-predisposed mice. J Immunol 189:5976-84 |
| 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; 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 |
| Berger, Michael; Krebs, Philippe; Crozat, Karine et al. (2010) An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence. Nat Immunol 11:335-43 |
| 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 |
| Wickramarachchi, Dilki C; Theofilopoulos, Argyrios N; Kono, Dwight H (2010) Immune pathology associated with altered actin cytoskeleton regulation. Autoimmunity 43:64-75 |
| Shvets, Anna; Chakrabarti, Rabindranath; Gonzalez-Quintial, Rosana et al. (2009) Impaired negative regulation of homeostatically proliferating T cells. Blood 113:622-5 |
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