de Jesus, Adriana A., Hou, Yangfeng, Brooks, Stephen, Malle, Louise, Biancotto, Angelique ORCID: 0000-0003-2271-009X, Huang, Yan, Calvo, Katherine R., Marrero, Bernadette, Moir, Susan, Oler, Andrew J., Deng, Zuoming, Sanchez, Gina A. Montealegre, Ahmed, Amina, Allenspach, Eric, Arabshahi, Bita, Behrens, Edward, Benseler, Susanne, Bezrodnik, Liliana, Bout-Tabaku, Sharon, Brescia, AnneMarie C., Brown, Diane, Burnham, Jon M., Soledad Caldirola, Maria, Carrasco, Ruy, Chan, Alice Y., Cimaz, Rolando, Dancey, Paul, Dare, Jason, DeGuzman, Marietta, Dimitriades, Victoria, Ferguson, Ian, Ferguson, Polly, Finn, Laura, Gattorno, Marco ORCID: 0000-0003-0704-1916, Grom, Alexei A., Hanson, Eric P., Hashkes, Philip J., Hedrich, Christian M., Herzog, Ronit, Horneff, Gerd, Jerath, Rita, Kessler, Elizabeth, Kim, Hanna ORCID: 0000-0002-0595-6533, 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 ORCID: 0000-0001-7884-3751, Pillet, Pascal, Piotto, Daniela G. P., Punaro, Marilynn G., Reiff, Andreas, Reinhardt, Adam, Rider, Lisa G., Rivas-Chacon, Rafael, Ronis, Tova, Roesen-Wolff, Angela, Roth, Johannes ORCID: 0000-0002-6109-1503, 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, Muskardin, Theresa Wampler, Canna, Scott W. and Goldbach-Mansky, Raphaela (2020). Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. J. Clin. Invest., 130 (4). S. 1669 - 1683. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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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-kappa B 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-Goutieres 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-kappa B 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
de Jesus, Adriana A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hou, YangfengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brooks, StephenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malle, LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biancotto, AngeliqueUNSPECIFIEDorcid.org/0000-0003-2271-009XUNSPECIFIED
Huang, YanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Calvo, Katherine R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marrero, BernadetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moir, SusanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oler, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deng, ZuomingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez, Gina A. MontealegreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahmed, AminaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allenspach, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arabshahi, BitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Behrens, EdwardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benseler, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bezrodnik, LilianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bout-Tabaku, SharonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brescia, AnneMarie C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brown, DianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burnham, Jon M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soledad Caldirola, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carrasco, RuyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chan, Alice Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cimaz, RolandoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dancey, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dare, JasonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DeGuzman, MariettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dimitriades, VictoriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferguson, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferguson, PollyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finn, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gattorno, MarcoUNSPECIFIEDorcid.org/0000-0003-0704-1916UNSPECIFIED
Grom, Alexei A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hanson, Eric P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hashkes, Philip J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hedrich, Christian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herzog, RonitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horneff, GerdUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jerath, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kessler, ElizabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, HannaUNSPECIFIEDorcid.org/0000-0002-0595-6533UNSPECIFIED
Kingsbury, Daniel J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laxer, Ronald M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Pui Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee-Kirsch, Min AeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lewandowski, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, SuzanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lilleby, VibkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mammadova, VafaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moorthy, Lakshmi N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nasrullayeva, GulnaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Neil, Kathleen M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Onel, KarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozen, SezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pan, NancyUNSPECIFIEDorcid.org/0000-0001-7884-3751UNSPECIFIED
Pillet, PascalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piotto, Daniela G. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Punaro, Marilynn G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiff, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, AdamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rider, Lisa G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rivas-Chacon, RafaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ronis, TovaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roesen-Wolff, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roth, JohannesUNSPECIFIEDorcid.org/0000-0002-6109-1503UNSPECIFIED
Ruth, Natasha MckerranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rygg, MariteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmeling, HeinrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulert, GrantUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scott, ChristiaanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seminario, GisellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shulman, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sivaraman, VidyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Son, Mary BethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stepanovskiy, YuriyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stringer, ElizabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taber, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Terreri, Maria TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tifft, CynthiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torgerson, TroyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tosi, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Royen-Kerkhof, AnnetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muskardin, Theresa WamplerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Canna, Scott W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldbach-Mansky, RaphaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-338492
DOI: 10.1172/JCI129301
Journal or Publication Title: J. Clin. Invest.
Volume: 130
Number: 4
Page Range: S. 1669 - 1683
Date: 2020
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 1558-8238
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MACROPHAGE ACTIVATION SYNDROME; INSULIN-RECEPTOR SUBSTRATE-1; SAMD9L MUTATIONS CAUSE; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; GAMMA; DEFICIENCY; LRBA; INTERLEUKIN-18; RUXOLITINIB; ASSOCIATIONMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33849

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