治療法を個別化するためにループスの遺伝的原因を突き止める(Tracking down the genetic causes of lupus to personalize treatment)

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2024-05-23 カリフォルニア大学バークレー校(UCB)

ループスは生涯にわたる痛みを伴う自己免疫疾患で、治療法は限られています。現在、個々の遺伝的変異に応じた高度に個別化された治療が必要とされています。カリフォルニア大学バークレー校の研究者は、新しい論文で、マウスや細胞ラインで自己免疫疾患に関連する2つの遺伝的変異を特定し、それが人間のループス患者にも見られることを発見しました。これらの変異は、免疫細胞が外来DNAやRNAを認識するトール様受容体(TLR)の過敏反応に関連しています。この研究により、特定のTLR7受容体を標的とする薬が臨床試験中であり、個別化医療が進展する可能性があります。

<関連情報>

大規模な変異解析により、マウスとヒトにおいてTLRを介した自己免疫を促進するUNC93B1変異体が同定される
Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans

Victoria E. Rael,Julian A. Yano,John P. Huizar,Leianna C. Slayden,Madeleine A. Weiss,Elizabeth A. Turcotte,Jacob M. Terry,Wenqi Zuo,Isabelle Thiffault,Tomi Pastinen,Emily G. Farrow,Janda L. Jenkins,Mara L. Becker,Stephen C. Wong,Anne M. Stevens,Catherine Otten,Eric J. Allenspach,Devon E. Bonner,Jonathan A. Bernstein,Matthew T. Wheeler,Robert A. Saxton,Undiagnosed Diseases Network,Bo Liu,Olivia Majer,Gregory M. Barton
Journal of Experimental Medicine  Published:May 23 2024
DOI:https://doi.org/10.1084/jem.20232005

A scanning-alanine mutagenesis screen reveals distinct domains of UNC93B1 that regulate endosomal TLR signaling. (A) Schematic of UNC93B1 depicting the membrane topology, transmembrane domains (1–12), connecting loops, and N- and C-terminal cytosolic tails. Helices within loops 1 and 6 are labeled as H1, H2, and H3, in accordance with the recent structures of UNC93B1 (Ishida et al., 2021). (B) Overview of UNC93B1 scanning–alanine mutagenesis screen workflow. (C) Heatmap summarizing the effect of each UNC93B1 mutant on signaling by TLR3, TLR7, and TLR9. Unstim, unstimulated; TLR3, stimulation with Poly(I:C) (20 µg ml-1); TLR7, stimulation with R848 (10 ng ml-1); TLR9, stimulation with CpG-B (45 nM). Data are shown as log2FC of the average TNF gMFI of triplicate wells for a given mutant/stimulation condition compared to corresponding wild-type controls. Data are representative of at least two independent experiments. (D) Quantification of UNC93B1 mutants that signal equivalently to wild-type (neutral) or confer a twofold or greater increase or decrease in signaling by the indicated TLR. (E) Spearman’s rank correlation coefficient between changes in signaling capacity of indicated TLR pairs.

Nucleic acid–sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.

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医療・健康
個別化治療ループス自己免疫疾患トール様受容体（TLR）
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