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

UNC93B1 variants underlie TLR7-dependent autoimmunity

Published:2024-02-23 Issue:92 Volume:9 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, 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 (TLRs) 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 and 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 for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

Publisher

American Association for the Advancement of Science (AAAS)

Link

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

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