ACR Meeting Abstracts

ACR Meeting Abstracts

  • Home
  • Meetings Archive
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018 ACR/ARHP Annual Meeting
    • 2017-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • Meeting Resource Center

Abstract Number: 2023

Different Patterns of Interferon-Response-Gene Expression May Elucidate Different Pathomechanisms That Drive IFN-Response-Gene Activation in Patients with Presumed IFN-Mediated Autoinflammatory Diseases

Adriana Almeida de Jesus1, Yanfeng Hou2, Louise Malle3, Scott Canna4, Gina A. Montealegre Sanchez1, Hanna Kim5, Rachel VanTries1, Seza Ozen6, Samantha Dill7, Dawn C. Chapelle7, Bernadette Marrero1, Yan Huang1, Angelique Biancotto8 and Raphaela Goldbach-Mansky1, 1Translational Autoinflammatory Disease Section (TADS), Laboratory of Clinical Investigation and Microbiology (LCIM), NIAID/NIH, Bethesda, MD, 2Department of Rheumatology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong, China, 3Icahn School of Medicine at Mount Sinai, New York, NY, 4RK Mellon Institute for Pediatric Research, University of Pittsburgh/Children's Hospital of Pittsburgh of UPMC, Pittsburrgh, PA, 5Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, MD, 6Hacettepe University Vasculitis Center (HUVAC), Ankara, Turkey, 7Pediatric Translational Research Branch, NIAMS/NIH, Bethesda, MD, 8Center for Human Immunology Autoimmunity and Inflammation (CHI), NIAID, NIH, Bethesda, MD

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Autoinflammatory Disease, Biomarkers, cytokines and interferons, Gene Expression

  • Tweet
  • Email
  • Print
Session Information

Date: Tuesday, October 23, 2018

Session Title: Pediatric Rheumatology – Basic Science Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Many infants and children with early-onset autoinflammatory diseases are mutation-negative for genetically known autoinflammatory diseases. Recent data suggest a role for Type-I interferon dysregulation in causing autoinflammatory disease phenotypes with clinical features that are distinct from those found in patients with IL-1 mediated autoinflammatory diseases. We assessed an IFN–response-gene signature (IRS), characterized the clinical phenotypes, IFN-related biomarkers and genetic causes.

Methods: We assessed IFN-response gene signatures (IRS) from 63 consecutively evaluated patients who were negative for known autoinflammatory disease-causing mutations. Whole blood gene expression of 28 selected interferon response genes (IRG) was determined by Nanostring and an IFN-score was calculated. Serum levels of 48 cytokines were measured by a multiplex immunoassay.Patients underwent clinical assessments and genetic analyses were performed by whole exome/genome sequencing (WES/WGS).

Results: Of 63 patients tested, 36 had elevated IFN-signatures. Patients with high IRS had higher frequencies of panniculitis (58 vs 0%, p<0.0001), basal ganglia calcifications (45 vs 0%, p=0.0043), interstitial lung disease (ILD) (48 vs 4.8%, p=0.0013), myositis (65 vs 15%, p=0.0005), skin vasculitis (29 vs 7.4%, p=0.05), arterial hypertension (32 vs 3.7%, p=0.011) and liver disease (73 vs 22%, p=0.0002), than patients without an IRS. Of 8 distinct clinical patterns, one group with pulmonary alveolar proteinosis (PAP) and macrophage activation syndrome (MAS) had high IL-18 serum levels. Other groups included 2 patients with novel LRBA mutations, 3 patients with a novel NEMO splice site mutation, 5 with de novo truncating SAMD9L mutations, 2 with myositis and anti-MDA5 autoantibodies, 7 with CANDLE-like panniculitis of which 1 had a known PSMB8 mutations and 2 had novel proteasome mutations in PSMB8 and in PSMG2, respectively. Patients with PAP and MAS, LRBA, NEMO, SAMD9L mutations had overall lower IFN scores and significantly lower USP18 but higher SOCS1 transcript levels compared to CANDLE and SAVI, both negative regulators of IFN signaling. SOCS1 transcription is regulated through the NF-κB signaling pathway and SOCS1 expression dysregulation may point to a different origin of the IFN response gene signature compared to CANDLE and SAVI patients. Interestingly, many of these patients with high SOCS1 and lower USP18 levels responded to TNF inhibition. Additionally, patients with high IRS had significantly higher serum levels of IP-10, MIG, MIP1α, MIP1β, SCF and GROα than those with negative IFN scores.

Conclusion: The assessment of patients with IFN signatures revealed distinct clinical pathogenically defined disease subsets. In 3 subgroups of patients, novel monogenic disease-causing mutations were detected. The contribution of SOCS1 and USP18 may assist in delineating different intracellular pathways that lead to the activation of the IFN response gene signature.

Acknowledgements: This work was supported by the NIH IRP of NIAID. We would like to thank the autoinflammatory disease network of physicians for patient referral.


Disclosure: A. Almeida de Jesus, None; Y. Hou, None; L. Malle, None; S. Canna, AB2 Bio, Ltd, 5; G. A. Montealegre Sanchez, None; H. Kim, None; R. VanTries, None; S. Ozen, None; S. Dill, None; D. C. Chapelle, None; B. Marrero, None; Y. Huang, None; A. Biancotto, None; R. Goldbach-Mansky, None.

To cite this abstract in AMA style:

Almeida de Jesus A, Hou Y, Malle L, Canna S, Montealegre Sanchez GA, Kim H, VanTries R, Ozen S, Dill S, Chapelle DC, Marrero B, Huang Y, Biancotto A, Goldbach-Mansky R. Different Patterns of Interferon-Response-Gene Expression May Elucidate Different Pathomechanisms That Drive IFN-Response-Gene Activation in Patients with Presumed IFN-Mediated Autoinflammatory Diseases [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/different-patterns-of-interferon-response-gene-expression-may-elucidate-different-pathomechanisms-that-drive-ifn-response-gene-activation-in-patients-with-presumed-ifn-mediated-autoinflammatory-diseas/. Accessed January 31, 2023.
  • Tweet
  • Email
  • Print

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/different-patterns-of-interferon-response-gene-expression-may-elucidate-different-pathomechanisms-that-drive-ifn-response-gene-activation-in-patients-with-presumed-ifn-mediated-autoinflammatory-diseas/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

ACR Pediatric Rheumatology Symposium 2020

© COPYRIGHT 2023 AMERICAN COLLEGE OF RHEUMATOLOGY

Wiley

  • Home
  • Meetings Archive
  • Advanced Search
  • Meeting Resource Center
  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences