On September 30th, the reporter learned from the Liangzhu Laboratory of Zhejiang University that the research team of the laboratory has confirmed for the first time that a defect in a single human gene PLD4 can lead to systemic lupus erythematosus, and elucidated its pathogenic mechanism, providing important theoretical basis for the precise diagnosis and treatment of systemic lupus erythematosus. The relevant research was recently published in the international journal Nature. The exact pathogenesis of systemic lupus erythematosus is not fully understood, and genetic factors and immune abnormalities play a key role in its occurrence and development. This study has discovered a single gene that can cause systemic lupus erythematosus, providing a new perspective for a deeper understanding of the molecular mechanisms underlying the onset of systemic lupus erythematosus and the development of targeted treatment strategies. At present, the scientific community has identified more than 30 types of systemic lupus erythematosus caused by single gene mutations. The research team identified 5 patients with systemic lupus nephritis with PLD4 gene defects through whole exome sequencing. This discovery confirms for the first time the relationship between human PLD4 gene defects and systemic lupus erythematosus. The PLD4 gene is highly expressed in dendritic cells, B cells, and monocytes, encoding a "single stranded exonuclease" protein. This protein is like a pair of scissors, capable of cutting and degrading single stranded nucleic acids that appear in cell lysates. Research has found that in dendritic cells of patients with PLD4 gene defects, the TLR7/TLR9 signaling pathway and its downstream type I interferon have significantly enhanced immune response, accompanied by increased expression levels of various inflammatory factors. In order to reveal the pathogenic mechanism of PLD4 gene deficiency in systemic lupus erythematosus and its main effector immune cell population, the research team constructed a mouse model with the same gene deficiency. The results showed that the defective mice exhibited a typical lupus like phenotype. Multi tissue inflammation analysis shows that the kidneys are the most significantly affected organ in defective mice, which is highly consistent with the clinical kidney phenotype of human patients. The research team intervened with JAK inhibitor baritinib in deficient mice and found that baritinib significantly alleviated lupus like phenotype in deficient mice. Baritinib effectively inhibited the overactivation of type I interferon pathway in inflammatory cells derived from patients, providing a potential strategy for the treatment of systemic lupus erythematosus caused by PLD4 gene deficiency. (New Society)