Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus.
Mahmoud Al-AzabElina IdiiatullinaZiyang LiuMeng LinKatja Hrovat-SchaaleHuifang XianJianheng ZhuMandy YangBingtai LuZhiyao ZhaoYiyi LiuJingjie ChangXiaotian LiCaiqin GuoYunfeng LiuQi WuJiazhang ChenChaoting LanPing ZengJun CuiXia GaoWenhao ZhouYan ZhangYuxia ZhangSeth L MastersPublished in: Nature immunology (2024)
Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1 V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.
Keyphrases
- toll like receptor
- systemic lupus erythematosus
- inflammatory response
- nuclear factor
- immune response
- disease activity
- lps induced
- oxidative stress
- rheumatoid arthritis
- type diabetes
- induced apoptosis
- signaling pathway
- cell proliferation
- case report
- early onset
- young adults
- genome wide
- small molecule
- binding protein
- copy number
- gene expression
- adipose tissue
- drug induced