UNC93B1 variants underlie TLR7-dependent autoimmunity

被引：13

作者：

Wolf, Christine ^{[1
]}

Lim, Ee Lyn ^{[2
]}

Mokhtari, Mohammad ^{[3
]}

Kind, Barbara ^{[1
]}

Odainic, Alexandru ^{[4
,5
]}

Lara-Villacanas, Eusebia ^{[6
]}

Koss, Sarah ^{[1
]}

Mages, Simon ^{[3
]}

Menzel, Katharina ^{[1
]}

Engel, Kerstin ^{[1
]}

Dueckers, Gregor ^{[7
]}

Bernbeck, Benedikt ^{[6
]}

Schneider, Dominik T. ^{[6
]}

Siepermann, Kathrin ^{[7
]}

Niehues, Tim ^{[7
]}

Goetzke, Carl Christoph ^{[8
,9
,10
]}

Durek, Pawel ^{[9
]}

Minden, Kirsten ^{[8
,9
]}

Doerner, Thomas ^{[9
,11
]}

Stittrich, Anna ^{[12
]}

Szelinski, Franziska ^{[9
,11
]}

Guerra, Gabriela Maria ^{[9
]}

Massoud, Mona ^{[9
]}

Bieringer, Markus ^{[13
]}

Mann, Carina C. de Oliveira ^{[14
]}

Beltran, Eduardo ^{[15
]}

Kallinich, Tilmann ^{[8
,9
,10
]}

Mashreghi, Mir-Farzin ^{[9
]}

Schmidt, Susanne V. ^{[4
]}

Latz, Eicke ^{[4
,16
]}

Klughammer, Johanna ^{[3
]}

Majer, Olivia ^{[2
]}

Lee-Kirsch, Min Ae ^{[1
,17
]}

机构：

[1] Tech Univ Dresden, Med Fak Carl Gustav Carus, Dept Pediat, D-01307 Dresden, Germany

[2] Max Planck Inst Infect Biol, D-10117 Berlin, Germany

[3] Ludwig Maximilians Univ Munchen, Gene Ctr, Syst Immunol, D-81377 Munich, Germany

[4] Univ Bonn, Inst Innate Immun, D-53127 Bonn, Germany

[5] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Melbourne, Vic 3010, Australia

[6] Univ Witten Herdecke, Dept Pediat, Klinikum Dortmund, D-44145 Dortmund, Germany

[7] Dept Pediat, Helios Klin Krefeld, D-47805 Krefeld, Germany

[8] Charite Univ Med Berlin, Dept Pediat Resp Med Immunol & Crit Care Med, D-10117 Berlin, Germany

[9] Deutsch Rheuma Forschungszentrum Julich DRFZ, Inst Leibniz Assoc, D-10117 Berlin, Germany

[10] Charite Univ Med Berlin, Berlin Inst Hlth, D-10178 Berlin, Germany

[11] Charite Univ Med Berlin, Dept Med Rheumatol & Clin Immunol, D-10117 Berlin, Germany

[12] Lab Berlin Charite Vivantes GmbH, Dept Human Genet, D-13353 Berlin, Germany

[13] Dept Cardiol & Nephrol, HELIOS Klinikum Berlin Buch, D-13125 Berlin, Germany

[14] Tech Univ Munich, Inst Virol, D-81675 Munich, Germany

[15] Ludwig Maximilians Univ Munchen, Inst Clin Neuroimmunol, Biomed Zentrum, D-82152 Munich, Germany

[16] German Ctr Neurodegenerat Dis DZNE, D-53175 Bonn, Germany

[17] Univ Ctr Rare Dis, Tech Univ Dresden, Med Fak Carl Gustav Carus, D-01307 Dresden, Germany

来源：

SCIENCE IMMUNOLOGY | 2024年 / 9卷 / 92期

关键词：

TOLL-LIKE RECEPTORS; SYSTEMIC AUTOIMMUNITY; DENDRITIC CELLS; NUCLEIC-ACID; RNASE T2; TLR7; RECOGNITION; TOLL-LIKE-RECEPTOR-7; SPECIFICITY; SENSITIVITY;

D O I：

10.1126/sciimmunol.adi9769

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-alpha 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.

引用

页数：13

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