Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Adriana A de Jesus - , Translational Autoinflammatory Diseases Section (TADS) (Author)
  • Yangfeng Hou - , Shandong Provincial Qianfoshan Hospital (Author)
  • Stephen Brooks - , Biomining and Discovery Section (Author)
  • Louise Malle - , Icahn School of Medicine at Mount Sinai (Author)
  • Angelique Biancotto - , Sanofi-Aventis (Author)
  • Yan Huang - , Translational Autoinflammatory Diseases Section (TADS) (Author)
  • Katherine R Calvo - , National Institutes of Health (NIH) (Author)
  • Bernadette Marrero - , Computational Systems Biology Section (Author)
  • Susan Moir - , Laboratory of Immunoregulation (Author)
  • Andrew J Oler - , Bioinformatics and Computational Biosciences Branch (BCBB) (Author)
  • Zuoming Deng - , Biomining and Discovery Section (Author)
  • Gina A Montealegre Sanchez - , Translational Autoinflammatory Diseases Section (TADS) (Author)
  • Amina Ahmed - , The Autoinflammatory Diseases Consortium (Author)
  • Eric Allenspach - , The Autoinflammatory Diseases Consortium (Author)
  • Bita Arabshahi - , The Autoinflammatory Diseases Consortium (Author)
  • Edward Behrens - , The Autoinflammatory Diseases Consortium (Author)
  • Susanne Benseler - , The Autoinflammatory Diseases Consortium (Author)
  • Liliana Bezrodnik - , The Autoinflammatory Diseases Consortium (Author)
  • Sharon Bout-Tabaku - , The Autoinflammatory Diseases Consortium (Author)
  • AnneMarie C Brescia - , The Autoinflammatory Diseases Consortium (Author)
  • Diane Brown - , The Autoinflammatory Diseases Consortium (Author)
  • Jon M Burnham - , The Autoinflammatory Diseases Consortium (Author)
  • Maria Soledad Caldirola - , The Autoinflammatory Diseases Consortium (Author)
  • Ruy Carrasco - , The Autoinflammatory Diseases Consortium (Author)
  • Alice Y Chan - , The Autoinflammatory Diseases Consortium (Author)
  • Rolando Cimaz - , The Autoinflammatory Diseases Consortium (Author)
  • Paul Dancey - , The Autoinflammatory Diseases Consortium (Author)
  • Jason Dare - , The Autoinflammatory Diseases Consortium (Author)
  • Marietta DeGuzman - , The Autoinflammatory Diseases Consortium (Author)
  • Victoria Dimitriades - , The Autoinflammatory Diseases Consortium (Author)
  • Ian Ferguson - , The Autoinflammatory Diseases Consortium (Author)
  • Polly Ferguson - , The Autoinflammatory Diseases Consortium (Author)
  • Laura Finn - , The Autoinflammatory Diseases Consortium (Author)
  • Marco Gattorno - , The Autoinflammatory Diseases Consortium (Author)
  • Alexei A Grom - , The Autoinflammatory Diseases Consortium (Author)
  • Eric P Hanson - , The Autoinflammatory Diseases Consortium (Author)
  • Philip J Hashkes - , The Autoinflammatory Diseases Consortium (Author)
  • Christian M Hedrich - , The Autoinflammatory Diseases Consortium (Author)
  • Ronit Herzog - , The Autoinflammatory Diseases Consortium (Author)
  • Gerd Horneff - , The Autoinflammatory Diseases Consortium (Author)
  • Rita Jerath - , The Autoinflammatory Diseases Consortium (Author)
  • Elizabeth Kessler - , The Autoinflammatory Diseases Consortium (Author)
  • Hanna Kim - , The Autoinflammatory Diseases Consortium (Author)
  • Daniel J Kingsbury - , The Autoinflammatory Diseases Consortium (Author)
  • Ronald M Laxer - , The Autoinflammatory Diseases Consortium (Author)
  • Pui Y Lee - , The Autoinflammatory Diseases Consortium (Author)
  • Min Ae Lee-Kirsch - , Department of Paediatrics, The Autoinflammatory Diseases Consortium (Author)
  • Laura Lewandowski - , The Autoinflammatory Diseases Consortium (Author)
  • Suzanne Li - , The Autoinflammatory Diseases Consortium (Author)
  • Vibke Lilleby - , The Autoinflammatory Diseases Consortium (Author)
  • Vafa Mammadova - , The Autoinflammatory Diseases Consortium (Author)
  • Lakshmi N Moorthy - , The Autoinflammatory Diseases Consortium (Author)
  • Gulnara Nasrullayeva - , The Autoinflammatory Diseases Consortium (Author)
  • Kathleen M O'Neil - , The Autoinflammatory Diseases Consortium (Author)
  • Karen Onel - , The Autoinflammatory Diseases Consortium (Author)
  • Seza Ozen - , The Autoinflammatory Diseases Consortium (Author)
  • Nancy Pan - , The Autoinflammatory Diseases Consortium (Author)
  • Pascal Pillet - , The Autoinflammatory Diseases Consortium (Author)
  • Daniela Gp Piotto - , The Autoinflammatory Diseases Consortium (Author)
  • Marilynn G Punaro - , The Autoinflammatory Diseases Consortium (Author)
  • Andreas Reiff - , The Autoinflammatory Diseases Consortium (Author)
  • Adam Reinhardt - , The Autoinflammatory Diseases Consortium (Author)
  • Lisa G Rider - , The Autoinflammatory Diseases Consortium (Author)
  • Rafael Rivas-Chacon - , The Autoinflammatory Diseases Consortium (Author)
  • Tova Ronis - , The Autoinflammatory Diseases Consortium (Author)
  • Angela Rösen-Wolff - , Department of Paediatrics, The Autoinflammatory Diseases Consortium (Author)
  • Johannes Roth - , The Autoinflammatory Diseases Consortium (Author)
  • Natasha Mckerran Ruth - , The Autoinflammatory Diseases Consortium (Author)
  • Marite Rygg - , The Autoinflammatory Diseases Consortium (Author)
  • Heinrike Schmeling - , The Autoinflammatory Diseases Consortium (Author)
  • Grant Schulert - , The Autoinflammatory Diseases Consortium (Author)
  • Christiaan Scott - , The Autoinflammatory Diseases Consortium (Author)
  • Gisella Seminario - , The Autoinflammatory Diseases Consortium (Author)
  • Andrew Shulman - , The Autoinflammatory Diseases Consortium (Author)
  • Vidya Sivaraman - , The Autoinflammatory Diseases Consortium (Author)
  • Mary Beth Son - , The Autoinflammatory Diseases Consortium (Author)
  • Yuriy Stepanovskiy - , The Autoinflammatory Diseases Consortium (Author)
  • Elizabeth Stringer - , The Autoinflammatory Diseases Consortium (Author)
  • Sara Taber - , The Autoinflammatory Diseases Consortium (Author)
  • Maria Teresa Terreri - , The Autoinflammatory Diseases Consortium (Author)
  • Cynthia Tifft - , The Autoinflammatory Diseases Consortium (Author)
  • Troy Torgerson - , The Autoinflammatory Diseases Consortium (Author)
  • Laura Tosi - , The Autoinflammatory Diseases Consortium (Author)
  • Annet Van Royen-Kerkhof - , The Autoinflammatory Diseases Consortium (Author)
  • Theresa Wampler Muskardin - , The Autoinflammatory Diseases Consortium (Author)
  • Scott W Canna - , UPMC Children’s Hospital of Pittsburgh (Author)
  • Raphaela Goldbach-Mansky - , Translational Autoinflammatory Diseases Section (TADS) (Author)

Abstract

BACKGROUND. Undifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.

METHODS. Sixty-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.

RESULTS. Thirty-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.

CONCLUSIONS. In 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 REGISTRATION. ClinicalTrials.gov NCT02974595.

FUNDING. The Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Details

Original languageEnglish
Pages (from-to)1669-1682
Number of pages14
JournalThe Journal of clinical investigation
Volume130
Issue number4
Publication statusPublished - 1 Apr 2020
Peer-reviewedYes

External IDs

PubMedCentral PMC7108905
Scopus 85082865229

Keywords

Keywords

  • Genetic diseases, Immunology, Inflammation, Innate immunity, Monogenic diseases