2. Academic Validation
  3. Homozygous IL37 mutation associated with infantile inflammatory bowel disease

Homozygous IL37 mutation associated with infantile inflammatory bowel disease

  • Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2009217118. doi: 10.1073/pnas.2009217118.
Zinan Z Zhang 1 2,  Yu Zhang 1,  Tingyan He 1,  Colin L Sweeney 1,  Safa Baris 3,  Elif Karakoc-Aydiner 3,  Yikun Yao 1,  Deniz Ertem 3,  Helen F Matthews 1,  Claudia Gonzaga-Jauregui 4,  Harry L Malech 1,  Helen C Su 1,  Ahmet Ozen 3,  Kenneth G C Smith 2,  Michael J Lenardo 5
Affiliations

Affiliations

  • 1 National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.
  • 2 Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge CB2 0AW, United Kingdom.
  • 3 School of Medicine, Marmara University, 34722 Istanbul, Turkey.
  • 4 Regeneron Genetics Center, Tarrytown, NY 10591.
  • 5 National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892; [email protected].
PMID: 33674380 DOI: 10.1073/pnas.2009217118
Abstract

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.

Keywords

IBD; IL37; VEO-IBD; immunodeficiency; inflammatory bowel disease.

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