Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

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 underwen...

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Published in:	The Journal of clinical investigation Vol. 130; no. 4; pp. 1669 - 1682
Main Authors:	de Jesus, Adriana A, Hou, Yangfeng, Brooks, Stephen, Malle, Louise, Biancotto, Angelique, Huang, Yan, Calvo, Katherine R, Marrero, Bernadette, Moir, Susan, Oler, Andrew J, Deng, Zuoming, Montealegre Sanchez, Gina A, Ahmed, Amina, Allenspach, Eric, Arabshahi, Bita, Behrens, Edward, Benseler, Susanne, Bezrodnik, Liliana, Bout-Tabaku, Sharon, Brescia, AnneMarie C, Brown, Diane, Burnham, Jon M, Caldirola, Maria Soledad, Carrasco, Ruy, Chan, Alice Y, Cimaz, Rolando, Dancey, Paul, Dare, Jason, DeGuzman, Marietta, Dimitriades, Victoria, Ferguson, Ian, Ferguson, Polly, Finn, Laura, Gattorno, Marco, Grom, Alexei A, Hanson, Eric P, Hashkes, Philip J, Hedrich, Christian M, Herzog, Ronit, Horneff, Gerd, Jerath, Rita, Kessler, Elizabeth, Kim, Hanna, Kingsbury, Daniel J, Laxer, Ronald M, Lee, Pui Y, Lee-Kirsch, Min Ae, Lewandowski, Laura, Li, Suzanne, Lilleby, Vibke, Mammadova, Vafa, Moorthy, Lakshmi N, Nasrullayeva, Gulnara, O'Neil, Kathleen M, Onel, Karen, Ozen, Seza, Pan, Nancy, Pillet, Pascal, Piotto, Daniela Gp, Punaro, Marilynn G, Reiff, Andreas, Reinhardt, Adam, Rider, Lisa G, Rivas-Chacon, Rafael, Ronis, Tova, Rösen-Wolff, Angela, Roth, Johannes, Ruth, Natasha Mckerran, Rygg, Marite, Schmeling, Heinrike, Schulert, Grant, Scott, Christiaan, Seminario, Gisella, Shulman, Andrew, Sivaraman, Vidya, Son, Mary Beth, Stepanovskiy, Yuriy, Stringer, Elizabeth, Taber, Sara, Terreri, Maria Teresa, Tifft, Cynthia, Torgerson, Troy, Tosi, Laura, Van Royen-Kerkhof, Annet, Wampler Muskardin, Theresa, Canna, Scott W, Goldbach-Mansky, Raphaela
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 01-04-2020
Subjects:	Alternative splicing Alveoli Antibodies Autoantibodies Autoimmune Diseases - genetics Autoimmune Diseases - immunology Autoimmunity Basal ganglia Binding sites Biological response modifiers Biomedical research Cell activation Clinical Medicine Criminal investigation Cytokines Dermatomyositis Diseases Epidemiology Female Frameshift mutation Genes Health aspects Humans Immunoglobulins Immunologic factors Inflammation Interferon Interferon Type I - genetics Interferon Type I - immunology Interleukin 18 Interleukin-18 - genetics Interleukin-18 - immunology Laboratories Leukocytes (neutrophilic) Lung diseases Lupus Macrophage Activation Syndrome - genetics Macrophage Activation Syndrome - immunology Macrophages Male Mutation Myositis NF-κB protein Novels Panniculitis - genetics Panniculitis - immunology Pathogenesis Pharmaceutical industry Phenotypes Pulmonary alveolar proteinosis Pulmonary Alveolar Proteinosis - genetics Pulmonary Alveolar Proteinosis - immunology Research funding Respiratory tract diseases New York Canada California Maryland Switzerland Innate immunity Inflammation Immunology Monogenic diseases Genetic diseases
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Summary:	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.
ISSN:	0021-9738 1558-8238
DOI:	10.1172/jci129301