UNC93B1 variants underlie TLR7-dependent autoimmunity-Reference-Cited by-同舟云学术

UNC93B1 variants underlie TLR7-dependent autoimmunity

Published:2024-01-11 Issue: Volume: Page:
ISSN:2470-9468
Container-title:Science Immunology
language:en
Short-container-title:Sci. Immunol.

Author:

Wolf Christine¹^ORCID,Lim Ee Lyn²^ORCID,Mokhtari Mohammad³^ORCID,Kind Barbara¹^ORCID,Odainic Alexandru⁴⁵^ORCID,Lara-Villacanas Eusebia⁶,Koss Sarah¹,Mages Simon³^ORCID,Menzel Katharina¹^ORCID,Engel Kerstin¹,Dückers Gregor⁷,Bernbeck Benedikt⁶,Schneider Dominik T.⁶^ORCID,Siepermann Kathrin⁷,Niehues Tim⁷^ORCID,Goetzke Carl Christoph⁸⁹¹⁰^ORCID,Durek Pawel⁹^ORCID,Minden Kirsten⁸⁹,Dörner Thomas⁹¹¹^ORCID,Stittrich Anna¹²^ORCID,Szelinski Franziska⁹¹¹^ORCID,Guerra Gabriela Maria⁹^ORCID,Massoud Mona⁹,Bieringer Markus¹³^ORCID,de Oliveira Mann Carina C.¹⁴^ORCID,Beltrán Eduardo¹⁵^ORCID,Kallinich Tilmann⁸⁹¹⁰^ORCID,Mashreghi Mir-Farzin⁹^ORCID,Schmidt Susanne V.⁴^ORCID,Latz Eicke⁴¹⁶,Klughammer Johanna³^ORCID,Majer Olivia²^ORCID,Lee-Kirsch Min Ae¹¹⁷^ORCID

Affiliation:

1. Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden; Dresden, 01307, Germany.

2. Max Planck Institute for Infection Biology; Berlin, 10117, Germany.

3. Gene Center, Systems Immunology, Ludwig-Maximilians-Universität Munich; Munich, 81377, Germany.

4. Institute of Innate Immunity, University of Bonn; Bonn, 53127, Germany.

5. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection & Immunity, University of Melbourne; Melbourne, VIC 3010, Australia.

6. Department of Pediatrics, Klinikum Dortmund, University Witten/Herdecke; Dortmund, 44145, Germany.

7. Department of Pediatrics, Helios Klinik Krefeld; Krefeld, 47805, Germany.

8. Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin; Berlin, 10117, Germany.

9. Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; Berlin, 10117, Germany.

10. Berlin Institute of Health at Charité-Universitätsmedizin Berlin; Berlin, 10178, Germany.

11. Department of Medicine, Rheumatology and Clinical Immunology, Charite-Universitätsmedizin Berlin; Berlin, 10117, Germany.

12. Labor Berlin Charité-Vivantes GmbH, Department of Human Genetics; Berlin, 13353, Germany.

13. Department of Cardiology and Nephrology, HELIOS Klinikum Berlin-Buch; Berlin, 13125, Germany.

14. Institute of Virology, Technical University of Munich; Munich, 81675, Germany.

15. Institute for Clinical Neuroimmunology, BioMedizinisches Zentrum, Ludwig-Maximilians-Universität Munich; Munich, 82152, Germany.

16. German Center for Neurodegenerative Diseases (DZNE); Bonn, 53175, Germany.

17. University Center for Rare Diseases, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden; Dresden, 01307, Germany.

Abstract

UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLR) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G, R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role of UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine,Immunology

Link

https://www.science.org/doi/pdf/10.1126/sciimmunol.adi9769

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