Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

J Clin Invest. 2020 Apr 1;130(4):1669-1682. doi: 10.1172/JCI129301.


BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Keywords: Genetic diseases; Immunology; Inflammation; Innate immunity; Monogenic diseases.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Intramural

MeSH terms

  • Autoimmune Diseases* / genetics
  • Autoimmune Diseases* / immunology
  • Female
  • Humans
  • Interferon Type I* / genetics
  • Interferon Type I* / immunology
  • Interleukin-18* / genetics
  • Interleukin-18* / immunology
  • Macrophage Activation Syndrome* / genetics
  • Macrophage Activation Syndrome* / immunology
  • Male
  • Mutation*
  • Panniculitis* / genetics
  • Panniculitis* / immunology
  • Pulmonary Alveolar Proteinosis* / genetics
  • Pulmonary Alveolar Proteinosis* / immunology


  • IL18 protein, human
  • Interferon Type I
  • Interleukin-18

Supplementary concepts

  • Pulmonary Alveolar Proteinosis, Acquired

Associated data

  • ClinicalTrials.gov/NCT02974595