Li Jiaxun, Lv Luyu, Wei Qingqing, Pang Wenpeng, He Chunjuan, Wu Hao, Guo Liping
Department of Microbiology, School of Basic Medicine, Guangxi Medical University, Nanning, Guangxi, China.
Guangxi Key Laboratory of Thalassemia Research, Guangxi Medical University, Nanning, Guangxi, China.
Front Immunol. 2025 Jun 12;16:1620327. doi: 10.3389/fimmu.2025.1620327. eCollection 2025.
X-linked lymphoproliferative disease (XLP), also known as Duncan's disease, is a primary immunodeficiency disorder linked to the X chromosome. In 1998, SH2D1A, which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), was identified as the first pathogenic gene associated with XLP. To date, more than 100 mutation sites in this gene have been documented. The disease is associated with infection with Epstein-Barr virus (EBV) and characterized by hemophagocytic lymphohistiocytosis (HLH), hypogammaglobulinemia, and lymphomas. Pathogenesis is intricately associated with cell type-specific SAP-SLAM signaling pathways. Particularly, the immune cell defects involve impaired T cell-B cell interactions, reduced cytotoxicity of Natural Killer (NK) cells, and abnormal development of Natural Killer T (NKT) cells. These factors collectively increase susceptibility to EBV and drive clinical manifestations in XLP type 1 (XLP1) patients. Although establishing a definitive correlation between specific genotypes and clinical phenotypes remains challenging, emerging evidence suggests a potential association. This underscores the critical need for further large-scale studies to elucidate this relationship. Given the current understanding of the pathophysiological mechanisms associated with XLP1, specific treatments to normalize SAP expression and restore immune tolerance in XLP1 patients play an important role. In addition to the necessity for long-term studies to verify the efficacy and safety of hematopoietic stem cell transplantation (HSCT), gene therapies currently under development, along with other emerging treatments, exhibit substantial promise for future clinical applications.
X连锁淋巴增殖性疾病（XLP），也称为邓肯氏病，是一种与X染色体相关的原发性免疫缺陷疾病。1998年，编码信号淋巴细胞激活分子（SLAM）相关蛋白（SAP）的SH2D1A被确定为与XLP相关的首个致病基因。迄今为止，该基因已记录了100多个突变位点。该疾病与EB病毒（EBV）感染有关，其特征为噬血细胞性淋巴组织细胞增生症（HLH）、低丙种球蛋白血症和淋巴瘤。发病机制与细胞类型特异性的SAP-SLAM信号通路密切相关。特别是，免疫细胞缺陷涉及T细胞与B细胞相互作用受损、自然杀伤（NK）细胞的细胞毒性降低以及自然杀伤T（NKT）细胞发育异常。这些因素共同增加了对EBV的易感性，并导致1型XLP（XLP1）患者出现临床表现。尽管确定特定基因型与临床表型之间的确切关联仍然具有挑战性，但新出现的证据表明存在潜在关联。这突出了进一步开展大规模研究以阐明这种关系的迫切需求。鉴于目前对与XLP1相关的病理生理机制的了解，使XLP1患者的SAP表达正常化并恢复免疫耐受的特异性治疗发挥着重要作用。除了需要进行长期研究以验证造血干细胞移植（HSCT）的疗效和安全性外，目前正在开发的基因疗法以及其他新兴疗法在未来临床应用中显示出巨大前景。
