Journal article
Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases
The Journal of clinical investigation, Vol.130(4), pp.1669-1682
04/01/2020
DOI: 10.1172/JCI129301
PMCID: PMC7108905
PMID: 31874111
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.
Details
- Title: Subtitle
- Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases
- Creators
- Adriana A de Jesus - Translational Autoinflammatory Diseases Section (TADS), NIAID/NIH, Bethesda, Maryland, USAPolly Ferguson - The Autoinflammatory Diseases ConsortiumYangfeng Hou - Department of Rheumatology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong, ChinaStephen Brooks - Biomining and Discovery Section, NIAMS/NIH, Bethesda, Maryland, USALouise Malle - Icahn School of Medicine at Mount Sinai, New York, New York, USAAngelique Biancotto - Immunology & Inflammation Research Therapeutic Area, Sanofi, Boston, Massachusetts, USAYan Huang - Translational Autoinflammatory Diseases Section (TADS), NIAID/NIH, Bethesda, Maryland, USAKatherine R Calvo - Department of Laboratory Medicine (DLM), Clinical Center/NIH, Bethesda, Maryland, USABernadette Marrero - Computational Systems Biology SectionSusan Moir - Laboratory of Immunoregulation, andAndrew J Oler - Bioinformatics and Computational Biosciences Branch (BCBB), Office of Cyber Infrastructure and Computational Biology (OCICB), NIAID/NIH, Bethesda, Maryland, USAZuoming Deng - Biomining and Discovery Section, NIAMS/NIH, Bethesda, Maryland, USAGina A Montealegre Sanchez - Translational Autoinflammatory Diseases Section (TADS), NIAID/NIH, Bethesda, Maryland, USAAmina Ahmed - The Autoinflammatory Diseases ConsortiumEric Allenspach - The Autoinflammatory Diseases ConsortiumBita Arabshahi - The Autoinflammatory Diseases ConsortiumEdward Behrens - The Autoinflammatory Diseases ConsortiumSusanne Benseler - The Autoinflammatory Diseases ConsortiumLiliana Bezrodnik - The Autoinflammatory Diseases ConsortiumSharon Bout-Tabaku - The Autoinflammatory Diseases ConsortiumAnneMarie C Brescia - The Autoinflammatory Diseases ConsortiumDiane Brown - The Autoinflammatory Diseases ConsortiumJon M Burnham - The Autoinflammatory Diseases ConsortiumMaria Soledad Caldirola - The Autoinflammatory Diseases ConsortiumRuy Carrasco - The Autoinflammatory Diseases ConsortiumAlice Y Chan - The Autoinflammatory Diseases ConsortiumRolando Cimaz - The Autoinflammatory Diseases ConsortiumPaul Dancey - The Autoinflammatory Diseases ConsortiumJason Dare - The Autoinflammatory Diseases ConsortiumMarietta DeGuzman - The Autoinflammatory Diseases ConsortiumVictoria Dimitriades - The Autoinflammatory Diseases ConsortiumIan Ferguson - The Autoinflammatory Diseases ConsortiumLaura Finn - The Autoinflammatory Diseases ConsortiumMarco Gattorno - The Autoinflammatory Diseases ConsortiumAlexei A Grom - The Autoinflammatory Diseases ConsortiumEric P Hanson - The Autoinflammatory Diseases ConsortiumPhilip J Hashkes - The Autoinflammatory Diseases ConsortiumChristian M Hedrich - The Autoinflammatory Diseases ConsortiumRonit Herzog - The Autoinflammatory Diseases ConsortiumGerd Horneff - The Autoinflammatory Diseases ConsortiumRita Jerath - The Autoinflammatory Diseases ConsortiumElizabeth Kessler - The Autoinflammatory Diseases ConsortiumHanna Kim - The Autoinflammatory Diseases ConsortiumDaniel J Kingsbury - The Autoinflammatory Diseases ConsortiumRonald M Laxer - The Autoinflammatory Diseases ConsortiumPui Y Lee - The Autoinflammatory Diseases ConsortiumMin Ae Lee-Kirsch - The Autoinflammatory Diseases ConsortiumLaura Lewandowski - The Autoinflammatory Diseases ConsortiumSuzanne Li - The Autoinflammatory Diseases ConsortiumVibke Lilleby - The Autoinflammatory Diseases ConsortiumVafa Mammadova - The Autoinflammatory Diseases ConsortiumLakshmi N Moorthy - The Autoinflammatory Diseases ConsortiumGulnara Nasrullayeva - The Autoinflammatory Diseases ConsortiumKathleen M O’Neil - The Autoinflammatory Diseases ConsortiumKaren Onel - The Autoinflammatory Diseases ConsortiumSeza Ozen - The Autoinflammatory Diseases ConsortiumNancy Pan - The Autoinflammatory Diseases ConsortiumPascal Pillet - The Autoinflammatory Diseases ConsortiumDaniela G.P Piotto - The Autoinflammatory Diseases ConsortiumMarilynn G Punaro - The Autoinflammatory Diseases ConsortiumAndreas Reiff - The Autoinflammatory Diseases ConsortiumAdam Reinhardt - The Autoinflammatory Diseases ConsortiumLisa G Rider - The Autoinflammatory Diseases ConsortiumRafael Rivas-Chacon - The Autoinflammatory Diseases ConsortiumTova Ronis - The Autoinflammatory Diseases ConsortiumAngela Rösen-Wolff - The Autoinflammatory Diseases ConsortiumJohannes Roth - The Autoinflammatory Diseases ConsortiumNatasha Mckerran Ruth - The Autoinflammatory Diseases ConsortiumMarite Rygg - The Autoinflammatory Diseases ConsortiumHeinrike Schmeling - The Autoinflammatory Diseases ConsortiumGrant Schulert - The Autoinflammatory Diseases ConsortiumChristiaan Scott - The Autoinflammatory Diseases ConsortiumGisella Seminario - The Autoinflammatory Diseases ConsortiumAndrew Shulman - The Autoinflammatory Diseases ConsortiumVidya Sivaraman - The Autoinflammatory Diseases ConsortiumMary Beth Son - The Autoinflammatory Diseases ConsortiumYuriy Stepanovskiy - The Autoinflammatory Diseases ConsortiumElizabeth Stringer - The Autoinflammatory Diseases ConsortiumSara Taber - The Autoinflammatory Diseases ConsortiumMaria Teresa Terreri - The Autoinflammatory Diseases ConsortiumCynthia Tifft - The Autoinflammatory Diseases ConsortiumTroy Torgerson - The Autoinflammatory Diseases ConsortiumLaura Tosi - The Autoinflammatory Diseases ConsortiumAnnet Van Royen-Kerkhof - The Autoinflammatory Diseases ConsortiumTheresa Wampler Muskardin - The Autoinflammatory Diseases ConsortiumScott W Canna - Children’s Hospital Pittsburgh, Pittsburgh, Pennsylvania, USARaphaela Goldbach-Mansky - Translational Autoinflammatory Diseases Section (TADS), NIAID/NIH, Bethesda, Maryland, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.130(4), pp.1669-1682
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI129301
- PMID
- 31874111
- PMCID
- PMC7108905
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- NA / NIH
- Language
- English
- Date published
- 04/01/2020
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Rheumatology, Allergy, and Immunology
- Record Identifier
- 9984070302102771
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