ACR Meeting Abstracts

ACR Meeting Abstracts

  • Meetings
    • ACR Convergence 2024
    • ACR Convergence 2023
    • 2023 ACR/ARP PRSYM
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • ACR Meetings

Abstract Number: 0176

Characterization and Molecular Mechanism Underlying NEMO Deleted Exon 5 Autoinflammatory Syndrome (NDAS)

Alex Wessel1, Younglang Lee2, Eries Lee3, Jiazhi Xu4, Somin Kim5, Amy Hsu6, Jevgenia Rudenko7, Clinton Enos8, Stephen Brooks3, Zuoming Deng9, Bin Lin10, Daniel Hupalo11, Adriana Almeida de Jesus12, Daniela Piotto13, Maria Teresa Terreri14, Victoria Dimitriades15, Dalgard Clifton11, Steven Holland16, Raphaela Goldbach-Mansky17, Richard Siegel18 and Eric Hanson19, 1Washington University St. Louis, St. Louis, 2PUsan National University, Pusan, Republic of Korea, 3NIAMS, NIH, Bethesda, 4Indiana University School of Medicine, Indianapolis, 5Emory University, Atlanta, 6NIAID, NIH, Bethesda, 7OHSU, Portland, 8Eastern Virginia Medical School, Norfolk, 9National Institute of Arthritis Musculoskeletal and Skin diseases, Bethesda, 10Translational Autoinflammatory Disease Section (TADS)/NIAID/NIH, Bethesda, MD, 116The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, 12Translational Autoinflammatory Disease Section (TADS)/NIAID/NIH, Bethesda, 137Escola Paulista de Medicina/Universidade Federal de São Paulo, Sao Paolo, Brazil, 14Federal University of São Paulo, São Paulo, Brazil, 15Division of Infectious Diseases, Immunology & Allergy University of California Davis Health, Sacramento, 16Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, Bethesda, 17NIH, Bethesda, 18Novartis Institutes for BioMedical Research, Basel, Switzerland, 19Riley Hospital for Children, IUSM, Indianapolis, IN

Meeting: ACR Convergence 2020

Keywords: Autoinflammatory diseases, genetics, innate immunity

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print
Session Information

Date: Friday, November 6, 2020

Title: Pediatric Rheumatology – Basic Science Poster

Session Type: Poster Session A

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

Background/Purpose: The NF-kB essential modulator (NEMO) is a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in IKBKG encoding NEMO typically present with immune deficiency. However, we previously showed that the absence of the NEMO C-terminus zinc finger domain (NEMO-ΔCT), encoded by exon 10, leads to impaired negative regulation of the canonical IKK kinase and additional inflammatory disease phenotypes. Other functional NEMO domains are likely important for the regulation of NF-κB activation and type I IFN induction.

Methods: Patients and healthy controls enrolled in an IRB-approved natural history protocol provided blood and skin samples that were used for genetic and functional analyses. These studies included WGS/WES, minigene cDNA analysis, primary cell line gene reconstitution and knockdown experiments, signal transduction by microscopy, Western blot (WB), and intracellular flow cytometry, transcriptome, cytokine release, co-immunoprecipitation and WB, and in vitro viral infection models.

Results: Here we describe the diagnosis, disease features and molecular mechanism underlying enhanced NF-κB and Interferon induction due to expression of the alternative NEMO isoform lacking the domain encoded by exon 5 (NEMO-Δex5). We demonstrate that the NEMO Deleted exon 5 Autoinflammatory Syndrome (NDAS) is distinct from the immunodeficiency syndrome resulting from loss-of-function IKBKG mutations clinically. Dermal fibroblasts from NDAS patients uniquely activate NF-κB in response to TNF, but not TLR3 or RLR stimulation, and type I IFN and antiviral responses are blunted in vitro. By contrast, T cells, monocytes and macrophages expressing NEMO-Δex5 express a strong Type I Interferon and NF-κB transcriptional signature that correlates highly with alternative isoform expression. We utilized these cell specific differences to dissect the roles of TNF and the atypical IKK kinases, TBK1 and IKKε, in altered NEMO-Δex5 signaling and antiviral cell function. NEMO-Δex5 expression in both immune cells and TNF-stimulated dermal fibroblasts specifically protected IKKε from stimulation-induced protein destabilization, promoting type I IFN induction and enhanced antiviral responses in vitro.

Conclusion: NEMO-NDAS represents a distinct disease phenotype with unique cellular gene expression and functional profiles. Ongoing work is directed at understanding the regulation and function of NEMO-Δex5 in host defense and in both monogenic and complex genetic rheumatic diseases.


Disclosure: A. Wessel, None; Y. Lee, None; E. Lee, None; J. Xu, None; S. Kim, None; A. Hsu, None; J. Rudenko, None; C. Enos, None; S. Brooks, None; Z. Deng, None; B. Lin, None; D. Hupalo, None; A. Almeida de Jesus, None; D. Piotto, None; M. Terreri, None; V. Dimitriades, None; D. Clifton, None; S. Holland, None; R. Goldbach-Mansky, None; R. Siegel, Novartis, 1, 3; E. Hanson, None.

To cite this abstract in AMA style:

Wessel A, Lee Y, Lee E, Xu J, Kim S, Hsu A, Rudenko J, Enos C, Brooks S, Deng Z, Lin B, Hupalo D, Almeida de Jesus A, Piotto D, Terreri M, Dimitriades V, Clifton D, Holland S, Goldbach-Mansky R, Siegel R, Hanson E. Characterization and Molecular Mechanism Underlying NEMO Deleted Exon 5 Autoinflammatory Syndrome (NDAS) [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/characterization-and-molecular-mechanism-underlying-nemo-deleted-exon-5-autoinflammatory-syndrome-ndas/. Accessed .
  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to ACR Convergence 2020

ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-and-molecular-mechanism-underlying-nemo-deleted-exon-5-autoinflammatory-syndrome-ndas/

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 »

All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

Accepted abstracts are made available to the public online in advance of the meeting and are published in a special online supplement of our scientific journal, Arthritis & Rheumatology. Information contained in those abstracts may not be released until the abstracts appear online. In an exception to the media embargo, academic institutions, private organizations, and companies with products whose value may be influenced by information contained in an abstract may issue a press release to coincide with the availability of an ACR abstract on the ACR website. However, the ACR continues to require that information that goes beyond that contained in the abstract (e.g., discussion of the abstract done as part of editorial news coverage) is under media embargo until 10:00 AM ET on November 14, 2024. Journalists with access to embargoed information cannot release articles or editorial news coverage before this time. Editorial news coverage is considered original articles/videos developed by employed journalists to report facts, commentary, and subject matter expert quotes in a narrative form using a variety of sources (e.g., research, announcements, press releases, events, etc.).

Violation of this policy may result in the abstract being withdrawn from the meeting and other measures deemed appropriate. Authors are responsible for notifying colleagues, institutions, communications firms, and all other stakeholders related to the development or promotion of the abstract about this policy. If you have questions about the ACR abstract embargo policy, please contact ACR abstracts staff at [email protected].

Wiley

  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences

© Copyright 2025 American College of Rheumatology