title: Definition of IFN-γ-related pathways critical for chemically-induced systemic autoimmunity.
abstract: IFN-γ is essential for idiopathic and murine mercury-induced systemic autoimmunity (mHgIA), and heterozygous IFN-γ(+/-) mice also exhibit reduced disease. This suggests that blocking specific IFN-γ-related pathways that may only partially inhibit IFN-γ production or function will also suppress autoimmunity. To test this hypothesis, mice deficient in genes regulating IFN-γ expression (Casp1, Nlrp3, Il12a, Il12b, Stat4) or function (Ifngr1, Irf1) were examined for mHgIA susceptibility. Absence of either Ifngr1 or Irf1 resulted in a striking reduction of disease, while deficiency of genes promoting IFN-γ expression had modest to no effect. Furthermore, both Irf1- and Ifng-deficiency only modestly reduced the expansion of CD44(hi) and CD44(hi)CD55(lo) CD4(+) T cells, indicating that they are not absolutely required for T cell activation. Thus, there is substantial redundancy in genes that regulate IFN-γ expression in contrast to those that mediate later signaling events. These findings have implications for the therapeutic targeting of IFN-γ pathways in systemic autoimmunity.
authors.affiliation: Department of Molecular and Experimental Medicine, MEM125, Scripps Research Institute, La Jolla, CA 92037, USA. mpollard@scripps.edu
authors.forename: K Michael
authors.initials: KM
authors.lastname: Pollard
authors.forename: Per
authors.initials: P
authors.lastname: Hultman
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Toomey
authors.forename: David M
authors.initials: DM
authors.lastname: Cauvi
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.forename: John C
authors.initials: JC
authors.lastname: Hamel
authors.forename: Dwight H
authors.initials: DH
authors.lastname: Kono
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics*; D049109:Cell Proliferation; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000276:immunology*; D006579:Heterozygote; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008627:Mercuric Chloride; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D008627:Mercuric Chloride; D007371:Interferon-gamma