Anti-TNF treatment corrects IFN-γ-dependent proinflammatory signatures in Blau syndrome patient-derived macrophages

J Allergy Clin Immunol. 2022 Jan;149(1):176-188.e7. doi: 10.1016/j.jaci.2021.05.030. Epub 2021 Jun 24.


Background: Blau syndrome (BS) is an autoinflammatory disease associated with mutations in nucleotide-binding oligomerization domain 2. Although treatments with anti-TNF agents have been reported to be effective, the underlying molecular mechanisms remain unclear.

Objective: We aimed to elucidate the mechanisms of autoinflammation in patients with BS and to clarify how anti-TNF treatment controls the disease phenotype at the cellular level in clinical samples.

Methods: Macrophages were differentiated from monocytes of 7 BS patients, and global transcriptional profiles of 5 patients were analyzed with or without IFN-γ stimulation. Macrophages were also generated from BS-specific induced pluripotent stem cells (iPSCs), and their transcriptome was examined for comparison.

Results: Aberrant inflammatory responses were observed upon IFN-γ stimulation in macrophages from untreated BS patients, but not in those from patients treated with anti-TNF. iPSC-derived macrophages carrying a disease-associated mutation also showed IFN-γ-dependent accelerated inflammatory responses. Comparisons of peripheral blood- and iPSC-derived macrophages revealed the upregulation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) targets in unstimulated macrophages as a common feature.

Conclusions: IFN-γ stimulation is one of the key signals driving aberrant inflammatory responses in BS-associated macrophages. However, long-term treatment with anti-TNF agents ameliorates such abnormalities even in the presence of IFN-γ stimulation. Our data thus suggest that preexposure to TNF or functionally similar cytokines inducing NF-κB-driven proinflammatory signaling during macrophage development is a prerequisite for accelerated inflammatory responses upon IFN-γ stimulation in BS.

Keywords: Blau syndrome; NF-κB; anti-TNF treatment; autoinflammatory loop; disease-specific iPS cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arthritis / drug therapy
  • Arthritis / genetics
  • Arthritis / immunology*
  • Cell Line
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Interferon-gamma / immunology*
  • Macrophages / immunology*
  • Male
  • NF-kappa B / immunology
  • Sarcoidosis / drug therapy
  • Sarcoidosis / genetics
  • Sarcoidosis / immunology*
  • Synovitis / drug therapy
  • Synovitis / genetics
  • Synovitis / immunology*
  • Transcriptome
  • Tumor Necrosis Factor Inhibitors / pharmacology*
  • Tumor Necrosis Factor Inhibitors / therapeutic use
  • Uveitis / drug therapy
  • Uveitis / genetics
  • Uveitis / immunology*
  • Young Adult


  • NF-kappa B
  • Tumor Necrosis Factor Inhibitors
  • Interferon-gamma

Supplementary concepts

  • Blau syndrome