Definition of IFN-γ-related pathways critical for chemically-induced systemic autoimmunity

K. Michael Pollard, Per Hultman, Christopher B. Toomey, David M. Cauvi, Hal M. Hoffman, John C. Hamel, Dwight H. Kono

Research output: Contribution to journalArticlepeer-review

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 CD44hi and CD44hiCD55lo 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.

Original languageEnglish (US)
Pages (from-to)323-331
Number of pages9
JournalJournal of Autoimmunity
Volume39
Issue number4
DOIs
StatePublished - Dec 2012
Externally publishedYes

Keywords

  • Animal model
  • Interferon
  • Mercury

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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