REVIEW article
Front. Immunol.
Sec. Primary Immunodeficiencies
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1620327
X-Linked Lymphoproliferative Disease Type 1 (XLP1): A clinical and genetic update
Provisionally accepted- 1Department of Microbiology, School of Basic Medicine, Guangxi Medical University,Guangxi, 530021, China, Nanning, Guangxi Zhuang Region, China
- 2Guangxi Key Laboratory of Thalassemia Research, Guangxi Medical University, Nanning, Guangxi Zhuang Region, China
- 3First Peoples Hospital of NingYang, Taian 271000, Shandong, China
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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.
Keywords: X-linked lymphoproliferative disease 1, SH2D1A gene, Epstein-Barr virus, SAP (signaling lymphocyte activation molecule-associated protein), Hematopoietic Stem Cell Transplantation, Treatment
Received: 29 Apr 2025; Accepted: 26 May 2025.
Copyright: © 2025 Li, Lv, Wei, Pang, He, Wu and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Liping Guo, Department of Microbiology, School of Basic Medicine, Guangxi Medical University,Guangxi, 530021, China, Nanning, Guangxi Zhuang Region, China
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