Title

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Authors

Adriana A. de Jesus, National Institute of Allergy and Infectious Diseases (NIAID)
Yangfeng Hou, Shandong University
Stephen Brooks, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Louise Malle, Icahn School of Medicine at Mount Sinai
Angelique Biancotto, Immunology and Inflammation Research Therapeutic Area
Yan Huang, National Institute of Allergy and Infectious Diseases (NIAID)
Katherine R. Calvo, National Institutes of Health (NIH)
Bernadette Marrero, Computational Systems Biology Section
Susan Moir, Laboratory of Immunoregulation
Andrew J. Oler, National Institute of Allergy and Infectious Diseases (NIAID)
Zuoming Deng, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Gina A. Montealegre Sanchez, National Institute of Allergy and Infectious Diseases (NIAID)
Amina Ahmed, Autoinflammatory Diseases Consortium
Eric Allenspach, Autoinflammatory Diseases Consortium
Bita Arabshahi, Autoinflammatory Diseases Consortium
Edward Behrens, Autoinflammatory Diseases Consortium
Susanne Benseler, Autoinflammatory Diseases Consortium
Liliana Bezrodnik, Autoinflammatory Diseases Consortium
Sharon Bout-Tabaku, Autoinflammatory Diseases Consortium
Anne Marie C. Brescia, Autoinflammatory Diseases Consortium
Diane Brown, Autoinflammatory Diseases Consortium
Jon M. Burnham, Autoinflammatory Diseases Consortium
Maria Soledad Caldirola, Autoinflammatory Diseases Consortium
Ruy Carrasco, Autoinflammatory Diseases Consortium
Alice Y. Chan, Autoinflammatory Diseases Consortium
Rolando Cimaz, Autoinflammatory Diseases Consortium
Paul Dancey, Autoinflammatory Diseases Consortium
Jason Dare, Autoinflammatory Diseases Consortium
Marietta DeGuzman, Autoinflammatory Diseases Consortium
Victoria Dimitriades, Autoinflammatory Diseases Consortium
Ian Ferguson, Autoinflammatory Diseases Consortium
Polly Ferguson, Autoinflammatory Diseases Consortium
Laura Finn, Autoinflammatory Diseases Consortium

Document Type

Journal Article

Publication Date

4-1-2020

Journal

Journal of Clinical Investigation

Volume

130

Issue

4

DOI

10.1172/JCI129301

Abstract

© 2020, American Society for Clinical Investigation. 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.

This document is currently not available here.

Share

COinS