Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases PMID: 31874111

ADC Targets in Oncology

2026-04-10

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

J Clin Invest. 2020 Apr 1;130(4):1669-1682. doi: 10.1172/JCI129301.

Adriana A de Jesus ¹ , Yangfeng Hou ² , Stephen Brooks ³ , Louise Malle ⁴ , Angelique Biancotto ⁵ , Yan Huang ¹ , Katherine R Calvo ⁶ , Bernadette Marrero ⁷ , Susan Moir ⁸ , Andrew J Oler ⁹ , Zuoming Deng ³ , Gina A Montealegre Sanchez ¹ , Amina Ahmed ¹⁰ ¹¹ , Eric Allenspach ¹⁰ ¹² , Bita Arabshahi ¹⁰ ¹³ , Edward Behrens ¹⁰ ¹⁴ , Susanne Benseler ¹⁰ ¹⁵ , Liliana Bezrodnik ¹⁰ ¹⁶ , Sharon Bout-Tabaku ¹⁰ ¹⁷ , AnneMarie C Brescia ¹⁰ ¹⁸ , Diane Brown ¹⁰ ¹⁹ , Jon M Burnham ¹⁰ ¹⁴ , Maria Soledad Caldirola ¹⁰ ¹⁶ , Ruy Carrasco ¹⁰ ²⁰ , Alice Y Chan ¹⁰ ²¹ , Rolando Cimaz ¹⁰ ²² , Paul Dancey ¹⁰ ²³ , Jason Dare ¹⁰ ²⁴ , Marietta DeGuzman ¹⁰ ²⁵ , Victoria Dimitriades ¹⁰ ²⁶ , Ian Ferguson ¹⁰ ²⁷ , Polly Ferguson ¹⁰ ²⁸ , Laura Finn ¹⁰ ²⁹ , Marco Gattorno ¹⁰ ³⁰ , Alexei A Grom ¹⁰ ³¹ , Eric P Hanson ¹⁰ ³² , Philip J Hashkes ¹⁰ ³³ , Christian M Hedrich ¹⁰ ³⁴ , Ronit Herzog ¹⁰ ³⁵ , Gerd Horneff ¹⁰ ³⁶ , Rita Jerath ¹⁰ ³⁷ , Elizabeth Kessler ¹⁰ ³⁸ , Hanna Kim ¹⁰ ³⁹ , Daniel J Kingsbury ¹⁰ ⁴⁰ , Ronald M Laxer ¹⁰ ⁴¹ , Pui Y Lee ¹⁰ ⁴² , Min Ae Lee-Kirsch ¹⁰ ⁴³ , Laura Lewandowski ¹⁰ ⁴⁴ , Suzanne Li ¹⁰ ⁴⁵ , Vibke Lilleby ¹⁰ ⁴⁶ , Vafa Mammadova ¹⁰ ⁴⁷ , Lakshmi N Moorthy ¹⁰ ⁴⁸ , Gulnara Nasrullayeva ¹⁰ ⁴⁷ , Kathleen M O'Neil ¹⁰ ³² , Karen Onel ¹⁰ ⁴⁹ , Seza Ozen ¹⁰ ⁵⁰ , Nancy Pan ¹⁰ ⁴⁹ , Pascal Pillet ¹⁰ ⁵¹ , Daniela Gp Piotto ¹⁰ ⁵² , Marilynn G Punaro ¹⁰ ⁵³ , Andreas Reiff ¹⁰ ⁵⁴ , Adam Reinhardt ¹⁰ ⁵⁵ , Lisa G Rider ¹⁰ ⁵⁶ , Rafael Rivas-Chacon ¹⁰ ⁵⁷ , Tova Ronis ¹⁰ ⁵⁸ , Angela Rösen-Wolff ¹⁰ ⁴³ , Johannes Roth ¹⁰ ⁵⁹ , Natasha Mckerran Ruth ¹⁰ ⁶⁰ , Marite Rygg ¹⁰ ⁶¹ , Heinrike Schmeling ¹⁰ ¹⁵ , Grant Schulert ¹⁰ ³¹ , Christiaan Scott ¹⁰ ⁶² , Gisella Seminario ¹⁰ ¹⁶ , Andrew Shulman ¹⁰ ⁶³ , Vidya Sivaraman ¹⁰ ⁶⁴ , Mary Beth Son ¹⁰ ⁶⁵ , Yuriy Stepanovskiy ¹⁰ ⁶⁶ , Elizabeth Stringer ¹⁰ ⁶⁷ , Sara Taber ¹⁰ ⁶⁸ , Maria Teresa Terreri ¹⁰ ⁵² , Cynthia Tifft ¹⁰ ⁶⁹ , Troy Torgerson ¹⁰ ¹² , Laura Tosi ¹⁰ ⁷⁰ , Annet Van Royen-Kerkhof ¹⁰ ⁷¹ , Theresa Wampler Muskardin ¹⁰ ⁷² , Scott W Canna ⁷³ , Raphaela Goldbach-Mansky ¹

Affiliations

1. Translational Autoinflammatory Diseases Section (TADS), NIAID/NIH, Bethesda, Maryland, USA.
2. Department of Rheumatology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong, China.
3. Biomining and Discovery Section, NIAMS/NIH, Bethesda, Maryland, USA.
4. Icahn School of Medicine at Mount Sinai, New York, New York, USA.
5. Immunology & Inflammation Research Therapeutic Area, Sanofi, Boston, Massachusetts, USA.
6. Department of Laboratory Medicine (DLM), Clinical Center/NIH, Bethesda, Maryland, USA.
7. Computational Systems Biology Section.
8. Laboratory of Immunoregulation, and.
9. Bioinformatics and Computational Biosciences Branch (BCBB), Office of Cyber Infrastructure and Computational Biology (OCICB), NIAID/NIH, Bethesda, Maryland, USA.
10. The Autoinflammatory Diseases Consortium.
11. Levine Children's Hospital, Charlotte, North Carolina, USA.
12. Divisions of Immunology & Rheumatology, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, Washington, USA.
13. Virginia Commonwealth University & Pediatric Specialists of Virginia, Fairfax, Virginia, USA.
14. Division of Rheumatology, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
15. Department of Pediatrics, Pediatric Rheumatology Section, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.
16. Immunology Unit, Pediatric Hospital R. Gutierrez, Buenos Aires, Argentina.
17. Department of Pediatric Medicine, Sidra Medicine, Qatar Foundation, Doha, Qatar.
18. Nemours/Alfred I. DuPont Hospital for Children, Wilmington, Delaware, USA.
19. Division of Rheumatology, Children's Hospital Los Angeles & USC, Los Angeles, California, USA.
20. Pediatric Rheumatology, Dell Children's Medical Center of Central Texas, Austin, Texas, USA.
21. Divisions of Pediatric AIBMT & Rheumatology, UCSF, San Francisco, California, USA.
22. Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.
23. Division of Rheumatology, Janeway Children's Hospital & Rehabilitation Centre, Saint John's, Newfoundland and Labrador, Canada.
24. Division of Pediatric Rheumatology, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, Arkansas, USA.
25. Department of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, Texas, USA.
26. Division of Pediatric Allergy, Immunology & Rheumatology, UC Davis Health, Sacramento, California, USA.
27. Department of Pediatrics/Pediatric Rheumatology, Yale University School of Medicine, New Haven, Connecticut, USA.
28. Pediatrics Department, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
29. Pathology Department, University of Washington and Seattle Children's Hospital, Seattle, Washington, USA.
30. Center for Autoinflammatory Diseases and Immunedeficiencies, IRCCS Giannina Gaslini, Genoa, Italy.
31. Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio, USA.
32. Department of Pediatrics Indiana University School of Medicine and Riley Hospital for Children, Indianapolis, Indiana, USA.
33. Pediatric Rheumatology Unit, Shaare Zedek Medical Center, Jerusalem, Israel.
34. Department of Women's & Children's Health, Institute of Translational Medicine, University of Liverpool & Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, United Kingdom.
35. Department of Otolaryngology, Division of Allergy and Immunology, New York University, New York, New York, USA.
36. Asklepios Klinik Sankt, Augustin GmbH, St. Augustin, Germany and Department of Pediatric and Adolescents Medicine, University of Cologne, Cologne, Germany.
37. Augusta University Medical Center, Augusta, Georgia, USA.
38. Division of Rheumatology, Children's Mercy, Kansas City and University of Missouri, Kansas City, Missouri, USA.
39. Pediatric Translational Research Branch, NIAMS/NIH, Bethesda, Maryland, USA.
40. Randall Children's Hospital at Legacy Emanuel, Portland, Oregon, USA.
41. Division of Pediatric Rheumatology, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada.
42. Division of Allergy, Immunology and Rheumatology, Boston Children's Hospital, Boston, Massachusetts, USA.
43. Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
44. Systemic Autoimmunity Branch, NIAMS/NIH, Bethesda, Maryland, USA.
45. Hackensack University Medical Center, Hackensack Meridian School of Medicine at Seton Hall University, Hackensack, New Jersey, USA.
46. Department of Rheumatology, Pediatric Section, Oslo University Hospital, Oslo, Norway.
47. Azerbaijan Medical University, Baku, Azerbaijan.
48. Rutgers - Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
49. Division of Pediatric Rheumatology, Weill Cornell Medicine & Hospital for Special Surgery, New York, New York, USA.
50. Hacettepe University, Department of Pediatrics, Ankara, Turkey.
51. Children Hospital Pellegrin-Enfants, Bordeaux, France.
52. Department of Pediatric Rheumatology, Federal University of Sao Paulo, Sao Paulo, Brazil.
53. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
54. Division of Rheumatology, Children's Hospital Los Angeles, Keck School of Medicine, USC, Los Angeles, California, USA.
55. University of Nebraska Medical Center/Children's Hospital and Medical Center, Omaha, Nebraska, USA.
56. Environmental Autoimmunity Group, NIEHS/NIH, Bethesda, Maryland, USA.
57. Department of Pediatric Rheumatology, Nicklaus Children's Hospital, Miami, Florida, USA.
58. Division of Pediatric Rheumatology, Children's National Health System, Washington, DC, USA.
59. Division of Pediatric Dermatology and Rheumatology, Children's Hospital of Eastern Ontario, Ottawa, Canada.
60. Medical University of South Carolina, Charleston, South Carolina, USA.
61. Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, and Department of Pediatrics, St. Olavs Hospital, Trondheim, Norway.
62. University of Cape Town, Red Cross War Memorial Children's Hospital, Cape Town, South Africa.
63. Pediatric Rheumatology, Children's Hospital of Orange County, UC Irvine, Irvine, California, USA.
64. Section of Rheumatology, Nationwide Children's Hospital, Columbus, Ohio, USA.
65. Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
66. Department of Pediatric Infectious Diseases and Immunology, Shupyk National Medical Academy for Postgraduate Education, Kiev, Ukraine.
67. IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
68. Division of Pediatric Rheumatology, Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.
69. Undiagnosed Diseases Program, NHGRI/NIH, Bethesda, Maryland, USA.
70. Bone Health Program, Children's National Health System, Washington, DC, USA.
71. Department of Pediatric Immunology and Rheumatology, Wilhelmina Children's Hospital Utrecht, Utrecht, Netherlands.
72. New York University School of Medicine, New York, New York, USA.
73. Children's Hospital Pittsburgh, Pittsburgh, Pennsylvania, USA.

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.

Keywords

Genetic diseases; Immunology; Inflammation; Innate immunity; Monogenic diseases.