Mertowska Paulina, Mertowski Sebastian, Grywalska Ewelina
Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a St., Lublin, 20-093, Poland.
Sci Rep. 2025 May 12;15(1):16446. doi: 10.1038/s41598-025-01572-4.
Chronic lymphocytic leukemia (CLL) is characterized by immune dysfunctions driven by miRNA deregulation and the activation of immune checkpoint pathways, which contribute to disease progression and secondary immunodeficiency (SID). This study examines the interplay between miRNA expression profiles, Epstein-Barr virus (EBV) reactivation, and immune checkpoint pathways in the context of small intestine disease (SID) development in chronic lymphocytic leukemia (CLL). Patients were stratified into groups based on the presence of SID and EBV reactivation. Comprehensive analyses included miRNA profiling, EBV infection markers, and the expression of PD-1, PD-L1, CTLA-4, CD200, and CD86 on CD4 + and CD8 + T cells, as well as CD19 + B cells. The results revealed significant suppression of tumor-suppressive miRNAs (e.g., miR-15a, miR-181a, and miR-29a) in the SID EBV + group, correlating with enhanced immunosuppression. The highest expression of exhaustion markers (PD-1, PD-L1, CTLA-4) and immunosuppressive molecules (CD200/CD200R) was observed in the SID EBV⁺ group compared to all other groups, including SID EBV⁻, which may reflect the enhanced mechanisms of immunosuppression and lymphocyte exhaustion accompanying EBV reactivation in the course of secondary immunodeficiencies. Correlation analyses underscored significant associations between miRNA levels, EBV reactivation markers, and immune checkpoint activation. These findings highlight the dual role of miRNA deregulation and immune checkpoint activation in the immunosuppressive microenvironment of CLL. The study underscores the diagnostic and therapeutic potential of miRNAs and immune checkpoints in managing SID and EBV-associated immune dysregulation in CLL.
慢性淋巴细胞白血病（CLL）的特征是由微小RNA（miRNA）失调和免疫检查点通路激活所驱动的免疫功能障碍，这会促进疾病进展和继发性免疫缺陷（SID）。本研究探讨了在慢性淋巴细胞白血病（CLL）的小肠疾病（SID）发展背景下，miRNA表达谱、爱泼斯坦-巴尔病毒（EBV）再激活和免疫检查点通路之间的相互作用。根据SID和EBV再激活的情况将患者分层。综合分析包括miRNA谱分析、EBV感染标志物，以及CD4⁺和CD8⁺T细胞以及CD19⁺B细胞上PD-1、PD-L1、CTLA-4、CD200和CD86的表达。结果显示，在SID EBV⁺组中肿瘤抑制性miRNA（如miR-15a、miR-181a和miR-29a）受到显著抑制，这与免疫抑制增强相关。与所有其他组（包括SID EBV⁻组）相比，在SID EBV⁺组中观察到耗竭标志物（PD-1、PD-L1、CTLA-4）和免疫抑制分子（CD200/CD200R）的表达最高，这可能反映了在继发性免疫缺陷过程中伴随EBV再激活的免疫抑制和淋巴细胞耗竭机制增强。相关性分析强调了miRNA水平、EBV再激活标志物和免疫检查点激活之间的显著关联。这些发现突出了miRNA失调和免疫检查点激活在CLL免疫抑制微环境中的双重作用。该研究强调了miRNA和免疫检查点在管理CLL中的SID和EBV相关免疫失调方面的诊断和治疗潜力。
