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. 2018 Jan;141(1):339-349.e11.
doi: 10.1016/j.jaci.2017.04.013. Epub 2017 Jun 3.

Pluripotent Stem Cell Models of Blau Syndrome Reveal an IFN-γ-dependent Inflammatory Response in Macrophages

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Pluripotent Stem Cell Models of Blau Syndrome Reveal an IFN-γ-dependent Inflammatory Response in Macrophages

Sanami Takada et al. J Allergy Clin Immunol. .

Abstract

Background: Blau syndrome, or early-onset sarcoidosis, is a juvenile-onset systemic granulomatosis associated with a mutation in nucleotide-binding oligomerization domain 2 (NOD2). The underlying mechanisms of Blau syndrome leading to autoinflammation are still unclear, and there is currently no effective specific treatment for Blau syndrome.

Objectives: To elucidate the mechanisms of autoinflammation in patients with Blau syndrome, we sought to clarify the relation between disease-associated mutant NOD2 and the inflammatory response in human samples.

Methods: Blau syndrome-specific induced pluripotent stem cell (iPSC) lines were established. The disease-associated NOD2 mutation of iPSCs was corrected by using a CRISPR-Cas9 system to precisely evaluate the in vitro phenotype of iPSC-derived cells. We also introduced the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages, and the statuses of nuclear factor κB pathway and proinflammatory cytokine secretion were investigated.

Results: IFN-γ acted as a priming signal through upregulation of NOD2. In iPSC-derived macrophages with mutant NOD2, IFN-γ treatment induced ligand-independent nuclear factor κB activation and proinflammatory cytokine production. RNA sequencing analysis revealed distinct transcriptional profiles of mutant macrophages both before and after IFN-γ treatment. Patient-derived macrophages demonstrated a similar IFN-γ-dependent inflammatory response.

Conclusions: Our data support the significance of ligand-independent autoinflammation in the pathophysiology of Blau syndrome. Our comprehensive isogenic disease-specific iPSC panel provides a useful platform for probing therapeutic and diagnostic clues for the treatment of patients with Blau syndrome.

Keywords: Blau syndrome; IFN-γ; disease-specific induced pluripotent stem cells; nuclear factor κB; nucleotide-binding oligomerization domain 2.

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