Homozygous IL37 mutation associated with infantile inflammatory bowel disease.

Autor:	Zhang ZZ; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge CB2 0AW, United Kingdom., Zhang Y; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892., He T; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892., Sweeney CL; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892., Baris S; School of Medicine, Marmara University, 34722 Istanbul, Turkey., Karakoc-Aydiner E; School of Medicine, Marmara University, 34722 Istanbul, Turkey., Yao Y; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892., Ertem D; School of Medicine, Marmara University, 34722 Istanbul, Turkey., Matthews HF; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892., Gonzaga-Jauregui C; Regeneron Genetics Center, Tarrytown, NY 10591., Malech HL; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892., Su HC; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892., Ozen A; School of Medicine, Marmara University, 34722 Istanbul, Turkey., Smith KGC; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge CB2 0AW, United Kingdom., Lenardo MJ; National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892; lenardo@nih.gov.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Mar 09; Vol. 118 (10).
DOI:	10.1073/pnas.2009217118
Abstrakt:	Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell-derived macrophages from the patient revealed an activated macrophage phenotype, which is more prone to lipopolysaccharide and IL-1β stimulation, resulting in hyperinflammatory tumor necrosis factor production. Insights from this patient will not only shed light on monogenic contributions of I-IBD but may also reveal the significance of the IL-18 and IL-37 axis in colonic homeostasis. Competing Interests: Competing interest statement: C.G.-J. is a full-time employee of the Regeneron Genetics Center and receives stock options as part of compensation. (Copyright © 2021 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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