| Literature DB >> 31874111 |
Adriana A de Jesus1, Yangfeng Hou2, Stephen Brooks3, Louise Malle4, Angelique Biancotto5, Yan Huang1, Katherine R Calvo6, Bernadette Marrero7, Susan Moir8, Andrew J Oler9, Zuoming Deng3, Gina A Montealegre Sanchez1, Amina Ahmed10,11, Eric Allenspach10,12, Bita Arabshahi10,13, Edward Behrens10,14, Susanne Benseler10,15, Liliana Bezrodnik10,16, Sharon Bout-Tabaku10,17, AnneMarie C Brescia10,18, Diane Brown10,19, Jon M Burnham10,14, Maria Soledad Caldirola10,16, Ruy Carrasco10,20, Alice Y Chan10,21, Rolando Cimaz10,22, Paul Dancey10,23, Jason Dare10,24, Marietta DeGuzman10,25, Victoria Dimitriades10,26, Ian Ferguson10,27, Polly Ferguson10,28, Laura Finn10,29, Marco Gattorno10,30, Alexei A Grom10,31, Eric P Hanson10,32, Philip J Hashkes10,33, Christian M Hedrich10,34, Ronit Herzog10,35, Gerd Horneff10,36, Rita Jerath10,37, Elizabeth Kessler10,38, Hanna Kim10,39, Daniel J Kingsbury10,40, Ronald M Laxer10,41, Pui Y Lee10,42, Min Ae Lee-Kirsch10,43, Laura Lewandowski10,44, Suzanne Li10,45, Vibke Lilleby10,46, Vafa Mammadova10,47, Lakshmi N Moorthy10,48, Gulnara Nasrullayeva10,47, Kathleen M O'Neil10,32, Karen Onel10,49, Seza Ozen10,50, Nancy Pan10,49, Pascal Pillet10,51, Daniela Gp Piotto10,52, Marilynn G Punaro10,53, Andreas Reiff10,54, Adam Reinhardt10,55, Lisa G Rider10,56, Rafael Rivas-Chacon10,57, Tova Ronis10,58, Angela Rösen-Wolff10,43, Johannes Roth10,59, Natasha Mckerran Ruth10,60, Marite Rygg10,61, Heinrike Schmeling10,15, Grant Schulert10,31, Christiaan Scott10,62, Gisella Seminario10,16, Andrew Shulman10,63, Vidya Sivaraman10,64, Mary Beth Son10,65, Yuriy Stepanovskiy10,66, Elizabeth Stringer10,67, Sara Taber10,68, Maria Teresa Terreri10,52, Cynthia Tifft10,69, Troy Torgerson10,12, Laura Tosi10,70, Annet Van Royen-Kerkhof10,71, Theresa Wampler Muskardin10,72, Scott W Canna73, Raphaela Goldbach-Mansky1.
Abstract
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.Entities:
Keywords: Genetic diseases; Immunology; Inflammation; Innate immunity; Monogenic diseases
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Year: 2020 PMID： 31874111 PMCID： PMC7108905 DOI： 10.1172/JCI129301
Source DB: PubMed Journal: J Clin Invest ISSN： 0021-9738 Impact factor: 14.808