Effect of exogenous IL-37 on immune cells from a patient carrying a potential IL37 loss-of-function variant: A case study.

Autor: Teufel LU; Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands., van der Made CI; Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands., Klück V; Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands., Simons A; Department of Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Hoischen A; Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Vernimmen V; Department of Genetics, Maastricht UMC+, Maastricht, the Netherlands., Joosten LAB; Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Strada Victor Babes 8, 400000 Cluj-Napoca, Romania., Arts RJW; Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address: rob.jw.arts@radboudumc.nl.
Jazyk: angličtina
Zdroj: Cytokine [Cytokine] 2023 Feb; Vol. 162, pp. 156102. Date of Electronic Publication: 2022 Dec 05.
DOI: 10.1016/j.cyto.2022.156102
Abstrakt: Introduction: Chronic inflammatory or autoimmune diseases are commonly treated with immunosuppressive medication such as NSAIDs, corticosteroids, or antibodies against specific cytokines (TNF, IL-1 IL-17, IL-23, etc.) or signalling cascades (e.g. JAK-STAT inhibitors). Using sequencing data to locate genetic mutations in relevant genes allows the identification of alternative targets in a patient-tailored therapy setting. Interleukin (IL)-37 is an anti-inflammatory cytokine with broad effects on innate and adaptive immune cell function. Dysfunctional IL-37 expression or signalling is linked to various autoinflammatory disorders. The administration of recombinant IL-37 to hyperinflammatory patients that are non-responsive to standard treatment bears the potential to alleviate symptoms.
Methods: In this case study, the (hyper)responsiveness of immune cell subsets was investigated in a single patient with a seronegative autoimmune disorder who carries a heterozygous stop-gain variant in IL37 (IL37 Chr2(GRCh37):g.113670640G > A NM_014439.3:c.51G > A p.(Trp17*)). As the patient has been non-responsive to blockage of TNF or IL-1 by Etanercept or Anakinra, respectively, additional in-vitro experiments were set out to elucidate whether treatment with recombinant IL-37 could normalise observed immune cell functions.
Findings: Characterisation of immune cell function showed no elevated overall production of acute-phase pro-inflammatory cytokines by patient PBMCs and neutrophils at baseline or upon stimulation. T-cell responses were elevated, as was the metabolic activity and IL-1Ra production of PBMCs at baseline. The identified stop-gain variant in IL37 does not result in the absence of the protein in circulation. In line with this, treatment with recombinant IL-37 did overall not dampen immune responses with the exception of the complete suppression of IL-17.
Conclusion: The heterozygous stop-gain variant in IL37 (IL37 NM_014439.3:c.51G > A p.(Trp17*)) is not of functional relevance as we observed no clear pro-inflammatory phenotype in immune cells of a patient carrying this variant.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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