title: A novel model for IFN-γ-mediated autoinflammatory syndromes.
abstract: Autoinflammatory disease and hyperinflammatory syndromes represent a growing number of diseases associated with inappropriately controlled inflammation in multiple organs. Systemic inflammation commonly results from dysregulated activation of innate immune cells, and therapeutic targeting of the IL-1β pathway has been used to ameliorate some of these diseases. Some hyperinflammatory syndromes, however, such as hemophagocytic lymphohistiocytosis and the newly classified proteasome disability syndromes, are refractory to such treatments, suggesting that other factors or environmental stressors may be contributing. In comparing two cytokine reporter mouse strains, we identify IFN-γ as a mediator of systemic autoinflammatory disease. Chronically elevated levels of IFN-γ resulted in progressive multiorgan inflammation and two copies of the mutant allele resulted in increased mortality accompanied by myeloproliferative disease. Disease was alleviated by genetic deletion of T-bet. These studies raise the possibility that therapeutics targeting the IFN-γ pathway might be effective in hyperinflammatory conditions refractory to IL-1β-targeted therapies.
authors: Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143; Department of Medicine, University of California San Francisco, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143; Department of Immunology, Duke University Medical Center, Durham, NC 27710;
authors: R Lee
authors: RL
authors: Reinhardt
authors: Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143; Department of Medicine, University of California San Francisco, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143;
authors: Hong-Erh
authors: HE
authors: Liang
authors: Department of Immunology, Duke University Medical Center, Durham, NC 27710;
authors: Katherine
authors: K
authors: Bao
authors: Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143; Department of Medicine, University of California San Francisco, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143;
authors: April E
authors: AE
authors: Price
authors: Trudeau Institute, Saranac Lake, NY 12983; and.
authors: Markus
authors: M
authors: Mohrs
authors: Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112.
authors: Ben L
authors: BL
authors: Kelly
authors: Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143; Department of Medicine, University of California San Francisco, San Francisco, CA 94143; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143; Richard.Locksley@ucsf.edu.
authors: Richard M
authors: RM
authors: Locksley
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D056660:Hereditary Autoinflammatory Diseases / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000276:immunology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000276:immunology; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D007155:Immunologic Factors; D053583:Interleukin-1beta; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma
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