Cell Therapy, Stem Cells and Tissues Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
Research Unit, Basque Center for Blood Transfusion and Human Tissues, Osakidetza, Galdakao, Spain.
Stem Cell Res Ther. 2020 Oct 27;11(1):453. doi: 10.1186/s13287-020-01964-5.
Primary immunodeficiency diseases (PIDs) are rare diseases that are characterized by genetic mutations that damage immunological function, defense, or both. Some of these rare diseases are caused by aberrations in the normal development of natural killer cells (NKs) or affect their lytic synapse. The pathogenesis of these types of diseases as well as the processes underlying target recognition by human NK cells is not well understood. Utilizing induced pluripotent stem cells (iPSCs) will aid in the study of human disorders, especially in the PIDs with defects in NK cells for PID disease modeling. This, together with genome editing technology, makes it possible for us to facilitate the discovery of future therapeutics and/or cell therapy treatments for these patients, because, to date, the only curative treatment available in the most severe cases is hematopoietic stem cell transplantation (HSCT). Recent progress in gene editing technology using CRISPR/Cas9 has significantly increased our capability to precisely modify target sites in the human genome. Among the many tools available for us to study human PIDs, disease- and patient-specific iPSCs together with gene editing offer unique and exceptional methodologies to gain deeper and more thorough understanding of these diseases as well as develop possible alternative treatment strategies. In this review, we will discuss some immunodeficiency disorders affecting NK cell function, such as classical NK deficiencies (CNKD), functional NK deficiencies (FNKD), and PIDs with involving NK cells as well as strategies to model and correct these diseases for further study and possible avenues for future therapies.
原发性免疫缺陷病（PIDs）是一种罕见疾病，其特征为免疫功能、防御功能或两者均因遗传突变而受损。这些罕见疾病中的一些是由自然杀伤细胞（NK 细胞）正常发育的异常引起的，或者影响其裂解突触。这些疾病的发病机制以及人类 NK 细胞的靶标识别过程尚未得到很好的理解。利用诱导多能干细胞（iPSCs）将有助于研究人类疾病，特别是在 NK 细胞缺陷的 PID 中，用于 PID 疾病建模。这与基因组编辑技术一起，使我们有可能为这些患者发现未来的治疗方法和/或细胞治疗方法，因为迄今为止，在大多数严重病例中，唯一可行的治疗方法是造血干细胞移植（HSCT）。利用 CRISPR/Cas9 的基因编辑技术的最新进展显著提高了我们精确修饰人类基因组靶位点的能力。在我们用于研究人类 PID 的许多工具中，疾病特异性和患者特异性 iPSCs 与基因编辑一起提供了独特而卓越的方法，可以更深入和更全面地了解这些疾病，并开发可能的替代治疗策略。在这篇综述中，我们将讨论一些影响 NK 细胞功能的免疫缺陷疾病，如经典 NK 缺陷（CNKD）、功能性 NK 缺陷（FNKD）以及涉及 NK 细胞的 PID 疾病，以及建模和纠正这些疾病的策略，以进行进一步研究和可能的未来治疗途径。
