Gain-of-function human UNC93B1 variants cause systemic lupus erythematosus and chilblain lupus.

IF 12.6 1区 医学 Q1 IMMUNOLOGY
Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-06-13 DOI:10.1084/jem.20232066
Clémence David, Carlos A Arango-Franco, Mihaly Badonyi, Julien Fouchet, Gillian I Rice, Blaise Didry-Barca, Lucie Maisonneuve, Luis Seabra, Robin Kechiche, Cécile Masson, Aurélie Cobat, Laurent Abel, Estelle Talouarn, Vivien Béziat, Caroline Deswarte, Katie Livingstone, Carle Paul, Gulshan Malik, Alison Ross, Jane Adam, Jo Walsh, Sathish Kumar, Damien Bonnet, Christine Bodemer, Brigitte Bader-Meunier, Joseph A Marsh, Jean-Laurent Casanova, Yanick J Crow, Bénédicte Manoury, Marie-Louise Frémond, Jonathan Bohlen, Alice Lepelley
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引用次数: 0

Abstract

UNC93B1 is a transmembrane domain protein mediating the signaling of endosomal Toll-like receptors (TLRs). We report five families harboring rare missense substitutions (I317M, G325C, L330R, R466S, and R525P) in UNC93B1 causing systemic lupus erythematosus (SLE) or chilblain lupus (CBL) as either autosomal dominant or autosomal recessive traits. As for a D34A mutation causing murine lupus, we recorded a gain of TLR7 and, to a lesser extent, TLR8 activity with the I317M (in vitro) and G325C (in vitro and ex vivo) variants in the context of SLE. Contrastingly, in three families segregating CBL, the L330R, R466S, and R525P variants were isomorphic with respect to TLR7 activity in vitro and, for R525P, ex vivo. Rather, these variants demonstrated a gain of TLR8 activity. We observed enhanced interaction of the G325C, L330R, and R466S variants with TLR8, but not the R525P substitution, indicating different disease mechanisms. Overall, these observations suggest that UNC93B1 mutations cause monogenic SLE or CBL due to differentially enhanced TLR7 and TLR8 signaling.

功能增益型人类 UNC93B1 变异可导致系统性红斑狼疮和瘃状狼疮。
UNC93B1 是一种跨膜结构域蛋白,介导内体 Toll 样受体(TLRs)的信号转导。我们报告了五个携带 UNC93B1 罕见错义置换(I317M、G325C、L330R、R466S 和 R525P)的家族,这些家族会引起系统性红斑狼疮(SLE)或软骨病狼疮(CBL),表现为常染色体显性或常染色体隐性遗传。至于导致小鼠狼疮的 D34A 突变,我们发现在系统性红斑狼疮的情况下,I317M(体外)和 G325C(体外和体外)变体的 TLR7 活性增强,其次是 TLR8 活性增强。相反,在三个遗传 CBL 的家族中,L330R、R466S 和 R525P 变体在体外的 TLR7 活性是同构的,R525P 的体外活性也是同构的。相反,这些变体显示出 TLR8 活性的增强。我们观察到 G325C、L330R 和 R466S 变体与 TLR8 的相互作用增强了,但 R525P 的作用却没有增强,这表明它们的致病机制不同。总之,这些观察结果表明,UNC93B1 突变导致单基因系统性红斑狼疮或 CBL 的原因是 TLR7 和 TLR8 信号传导的不同增强。
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来源期刊
CiteScore
26.60
自引率
1.30%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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