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UNC93B1 variants underlie TLR7-dependent autoimmunity.

Science immunology

Authors: Christine Wolf, Ee Lyn Lim, Mohammad Mokhtari, Barbara Kind, Alexandru Odainic, Eusebia Lara-Villacanas, Sarah Koss, Simon Mages, Katharina Menzel, Kerstin Engel, Gregor Dückers, Benedikt Bernbeck, Dominik T Schneider, Kathrin Siepermann, Tim Niehues, Carl Christoph Goetzke, Pawel Durek, Kirsten Minden, Thomas Dörner, Anna Stittrich, Franziska Szelinski, Gabriela Maria Guerra, Mona Massoud, Markus Bieringer, Carina C de Oliveira Mann, Eduardo Beltrán, Tilmann Kallinich, Mir-Farzin Mashreghi, Susanne V Schmidt, Eicke Latz, Johanna Klughammer, Olivia Majer, Min Ae Lee-Kirsch

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.

PMID: 38207055

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