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.
Copyright © 2015 by The American Association of Immunologists, Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Disease Models, Animal
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Female
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Gene Expression Regulation
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Hereditary Autoinflammatory Diseases / drug therapy*
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Hereditary Autoinflammatory Diseases / genetics
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Hereditary Autoinflammatory Diseases / immunology
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Hereditary Autoinflammatory Diseases / pathology
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Humans
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Immunologic Factors / pharmacology*
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Interferon-gamma / antagonists & inhibitors*
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Interferon-gamma / immunology
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Interleukin-1beta / antagonists & inhibitors
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Interleukin-1beta / immunology
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Leishmania major / immunology
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Leishmaniasis, Cutaneous / genetics
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Leishmaniasis, Cutaneous / immunology
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Leishmaniasis, Cutaneous / pathology
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Listeria monocytogenes / immunology
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Listeriosis / genetics
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Listeriosis / immunology
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Listeriosis / pathology
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Mice
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Mice, Transgenic
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Models, Immunological*
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Myeloproliferative Disorders / drug therapy*
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Myeloproliferative Disorders / genetics
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Myeloproliferative Disorders / immunology
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Myeloproliferative Disorders / pathology
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T-Box Domain Proteins / deficiency
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology
Substances
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Immunologic Factors
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Interleukin-1beta
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Interferon-gamma