The Role of Programmed Cell Death 1 in Autoimmune Diseases: Mechanisms and Therapeutic Implications

Zhenyu Liu^1,2Zipeng Hu²Huilin Lao²Lemin Chen²Yue Wen²Yuqiang Liang²Chong Zhang²Jiang Wu^1*Xianliang Hou^2,3*

• ¹Department of nuclear, Nanjing General Hospital of Nanjing Military Command, nanjing, China
• ²Department of Central Laboratory, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
• ³Department of Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, China

Abstract Autoimmune diseases are complex disorders caused by the interaction between the immune system and self-antigens, involving genetic, environmental triggers, and other cellular factors. The programmed cell death receptor-1 (PD-1) gene, as a critical factor in immune regulation, has garnered significant attention in the study of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis. Although the pathogenesis of these diseases varies, they all manifest as a breakdown in immune tolerance and an imbalance in immune homeostasis. Research has shown that in the development of autoimmune diseases, changes in PD-1 gene expression, its binding with PD-L1 and PD-L2, and signal transduction pathways are often abnormal. These abnormalities may lead to the overactivation of T cells and B cells, resulting in the attack on self-tissues. Consequently, therapeutic strategies targeting the PD-1/PD-L1 signaling pathway hold promising potential. Gene therapy approaches or small-molecule drugs that enhance PD-L1 transcription could strengthen PD-1/PD-L1 binding and restore inhibitory signaling, thereby rebalancing immune responses and improving patients' quality of life. Additionally, recent studies suggest that targeting Vγ4γδT cells to monitor disease progression and prognosis represents another potential PD-1-based therapeutic strategy. This review focuses on the role of the PD-1 gene in autoimmune diseases, systematically elaborating on the structure, molecular functions, and regulatory mechanisms of PD-1 and its ligands, while providing an in-depth analysis of PD-1's mechanistic involvement in autoimmune diseases and its therapeutic prospects.