The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1

N Engl J Med. 2024 May 30;390(20):1873-1884. doi: 10.1056/NEJMoa2312665.


Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood.

Methods: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses.

Results: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients.

Conclusions: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Publication types

  • Clinical Study
  • Evaluation Study

MeSH terms

  • AIRE Protein* / deficiency
  • AIRE Protein* / genetics
  • AIRE Protein* / immunology
  • Adolescent
  • Adult
  • Animals
  • Autoantibodies / blood
  • Autoantibodies / immunology
  • Chemokine CXCL9 / genetics
  • Child
  • Disease Models, Animal
  • Female
  • Humans
  • Interferon-gamma* / genetics
  • Interferon-gamma* / immunology
  • Janus Kinase Inhibitors* / therapeutic use
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Nitriles / therapeutic use
  • Pilot Projects
  • Polyendocrinopathies, Autoimmune* / drug therapy
  • Polyendocrinopathies, Autoimmune* / genetics
  • Polyendocrinopathies, Autoimmune* / immunology
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyrimidines / therapeutic use
  • T-Lymphocytes / immunology
  • Transcription Factors / genetics
  • Transcription Factors / immunology


  • AIRE Protein
  • Autoantibodies
  • Chemokine CXCL9
  • Interferon-gamma
  • Janus Kinase Inhibitors
  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • ruxolitinib
  • Transcription Factors

Supplementary concepts

  • Autoimmune polyendocrinopathy syndrome, type 1