Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus PMID: 38831104

ADC Targets in Oncology

2026-04-10

Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus

Nat Immunol. 2024 Jun;25(6):969-980. doi: 10.1038/s41590-024-01846-5.

Mahmoud Al-Azab ^# ¹ ² , Elina Idiiatullina ^# ¹ ³ , Ziyang Liu ¹ , Meng Lin ¹ , Katja Hrovat-Schaale ⁴ ⁵ , Huifang Xian ¹ , Jianheng Zhu ¹ , Mandy Yang ⁶ , Bingtai Lu ¹ , Zhiyao Zhao ¹ ⁷ , Yiyi Liu ¹ , Jingjie Chang ¹ , Xiaotian Li ¹ , Caiqin Guo ¹ , Yunfeng Liu ⁸ , Qi Wu ¹ ⁹ , Jiazhang Chen ¹ , Chaoting Lan ¹ , Ping Zeng ¹ , Jun Cui ¹⁰ , Xia Gao ¹ , Wenhao Zhou ¹ , Yan Zhang ¹ , Yuxia Zhang ¹¹ , Seth L Masters ¹² ¹³ ¹⁴ ¹⁵ ¹⁶

Affiliations

1. Department of Immunology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, and State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China.
2. Department of Medical Microbiology, Faculty of Medicine, University of Science and Technology, Aden, Yemen.
3. Department of Therapy and Nursing, Bashkir State Medical University, Ufa, Russia.
4. Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
5. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
6. State Key Laboratory of Respiratory Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
7. Center for Mitochondrial Genetics and Health, Greater Bay Area Institute of Precision Medicine (Guangzhou), Guangzhou, China.
8. Clinical Laboratory, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China.
9. National Children Medical Center, Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai, China.
10. School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
11. Department of Immunology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, and State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China. [email protected].
12. Department of Immunology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, and State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China. [email protected].
13. Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [email protected].
14. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia. [email protected].
15. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. [email protected].
16. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia. [email protected].
# Contributed equally.

Abstract

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.