Recently, the field of lupus erythematosus research has received great news.Chinese scientists have successfully confirmed that defects in a single human gene (PLD4) can cause systemic lupus erythematosus.This result was published in the journal Nature on September 10, laying an important theoretical foundation for the precise diagnosis and treatment of lupus erythematosus.
Lupus erythematosus, as a chronic autoimmune disease, has a complex pathogenesis. Systemic lupus erythematosus is extremely heterogeneous. There are great individual differences in both clinical symptoms and genetic mechanisms, which makes it difficult to explore the root cause of its pathogenesis.
Although the scientific community has previously identified more than 30 types of lupus caused by single gene mutations, its in-depth understanding is still subject to many limitations.
This time, a research team composed of the Liangzhu Laboratory of Zhejiang University, the National Kidney Disease Clinical Research Center of the Eastern Theater Command General Hospital, and the Institute of Life Sciences of Zhejiang University discovered PLD4 gene mutations in 5 patients with lupus nephritis through whole-exome sequencing.
Loss of PLD4 causes pDCs and B cells to continuously activate the TLR7/9 signaling pathway, triggering autoimmunity
This mutation is recessively inherited, and both PLD4 alleles of the patient are mutated, but his parents, who are mutation carriers, do not develop the disease. This discovery clarifies for the first time a direct link between human PLD4 gene defects and the onset of lupus.
In-depth research has found that the activity of PLD4 protein in patients with PLD4 deficiency is greatly reduced, causing the body's immune response to be excessive. The study also further explored the reason why PLD4 deficiency leads to long-term inflammation in the body, and the inflammation mostly occurs in the kidneys.
In order to find a treatment solution, the research team used mice as experimental subjects and used the JAK inhibitor baricitinib for intervention. The results were encouraging. The inhibitor significantly alleviated symptoms such as weight loss, autoantibody production and tissue inflammation in the defective mice.
also,Baricitinib also effectively inhibits the overactivation of the type I interferon pathway in patient-derived inflammatory cells, providing a potential precision treatment strategy for SLE patients carrying PLD4 mutations.