Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon.
Clin Immunol. 2023 Dec;257:109813. doi: 10.1016/j.clim.2023.109813. Epub 2023 Oct 26.
RASGRP1-deficiency results in an immune dysregulation and immunodeficiency that manifest as autoimmunity, lymphoproliferation, lymphopenia, defective T cell function, and increased incidence of Epstein-Bar Virus infections and lymphomas.
To investigate the mechanism of autoimmune hemolytic anemia and infections in a male patient of consanguineous parents from Lebanon.
Genetic diagnosis was obtained using next generation and Sanger sequencing. Protein expression and phosphorylation were determined by immunoblotting. T and B cell development and function were studied by flow cytometry. Cytokine and immunoglobulin secretions were quantified by enzyme-linked immunosorbent assay.
The patient suffered from severe lymphopenia especially affecting the T cell compartment. Genetic analysis revealed a homozygous insertion of adenine at position 1396_1397 in RASGRP1 that abolished protein expression and downstream Ras signaling. T cells from the patient showed severe activation defects resulting in uncontrolled Epstein-Bar Virus-induced B cell proliferation. B cells from the patient were normal.
This report expands the spectrum of mutations in patients with RasGRP1 deficiency, and provides evidence for the important role RasGRP1 plays in the ability of T cells to control Epstein-Bar Virus-induced B cell proliferation.
Following diagnosis, the patient will be maintained on oral valganciclovir and monitored regularly for Epstein-Bar Virus infections to avoid the development of Epstein-Bar Virus- induced B cell lymphoma. He is also candidate for hematopoietic stem cell transplantation.
RASGRP1 缺陷导致免疫失调和免疫缺陷，表现为自身免疫、淋巴增生、淋巴细胞减少、T 细胞功能缺陷、爱泼斯坦-巴尔病毒感染和淋巴瘤发生率增加。
研究一对黎巴嫩近亲父母的男性患者发生自身免疫性溶血性贫血和感染的机制。
采用下一代测序和 Sanger 测序进行遗传诊断。通过免疫印迹法测定蛋白表达和磷酸化。通过流式细胞术研究 T 和 B 细胞发育和功能。通过酶联免疫吸附试验定量细胞因子和免疫球蛋白分泌。
患者患有严重的淋巴细胞减少症，特别是 T 细胞减少。基因分析显示 RASGRP1 第 1396_1397 位的腺嘌呤纯合插入，导致蛋白表达和下游 Ras 信号缺失。患者的 T 细胞表现出严重的激活缺陷，导致无法控制爱泼斯坦-巴尔病毒诱导的 B 细胞增殖。患者的 B 细胞正常。
本报告扩展了 RasGRP1 缺陷患者突变谱，并为 RasGRP1 在 T 细胞控制爱泼斯坦-巴尔病毒诱导的 B 细胞增殖能力中的重要作用提供了证据。
诊断后，患者将口服缬更昔洛韦维持治疗，并定期监测爱泼斯坦-巴尔病毒感染，以避免爱泼斯坦-巴尔病毒诱导的 B 细胞淋巴瘤的发生。他也是造血干细胞移植的候选者。
