与多核苷酸激酶3′-磷酸酶（PNKP）缺乏相关的b细胞免疫缺陷

The journal of allergy and clinical immunology. Global Pub Date : 2025-06-11 DOI:10.1016/j.jacig.2025.100514

Sanami Takada MD, PhD , Tsubasa Okano MD, PhD , Kay Tanita MD, PhD , Kaima Tsukada PhD , Masato Watanabe MD , Atsushi Hijikata PhD , Takuya Naruto PhD , Tzu-Wen Yeh PhD , Saki Kasuga MD, PhD , Sadao Tokimasa MD, PhD , Mariko Taniguchi-Ikeda MD, PhD , Reina Ogata MD , Azusa Ikeda MD, PhD , Tomohide Goto MD, PhD , Hitoshi Osaka MD, PhD , Masatoshi Takagi MD, PhD , Kohsuke Imai MD, PhD , Tomohiro Morio MD, PhD , Mirjam van der Burg PhD , Mikio Shimada PhD , Hirokazu Kanegane MD, PhD

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引用次数: 0

摘要

dna修复对于维持基因组完整性至关重要，并且在免疫系统中起着重要作用。DNA修复途径中的缺陷通常与免疫缺陷有关，包括b细胞缺陷，这与b细胞成熟过程中V(D)J重组、类转换和体细胞超突变过程中DNA修复的需要是一致的。多核苷酸激酶3′-磷酸酶（PNKP）在DNA修复中起着重要作用。PNKP缺乏的特征是神经发育异常；然而，免疫缺陷尚未报道。我们研究了一对pnkp缺陷的兄弟姐妹，他们表现为小头畸形、眼睛异常和低γ -球蛋白血症。我们的目的是分析PNKP缺乏对b细胞发育的影响。方法采用全外显子组测序方法鉴定低γ球蛋白血症的遗传原因。利用患者来源的成纤维细胞分析DNA修复效率。利用患者外周血和其他无严重免疫缺陷的PNKP缺乏症患者分析免疫表型和b细胞受体库。结果全外显子组测序结果显示PNKP存在复合杂合变异。在辐射诱导的双/单链DNA断裂中，成纤维细胞显示出DNA修复缺陷。流式细胞术显示总b细胞和类别转换记忆b细胞计数减少。b细胞受体库分析表明，这些患者的体细胞超突变频率降低，而其他PNKP缺乏症患者的b细胞受体库模式正常。结论本病例提示PNKP变异诱导的DNA修复异常可能与免疫缺陷有关。

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B-cell immunodeficiency associated with polynucleotide kinase 3′-phosphatase (PNKP) deficiency

Background

DNA repair is crucial for maintaining genomic integrity and plays a significant role in the immune system. Defects in DNA repair pathways are often associated with immunodeficiency, including B-cell defects, which are consistent with the need for DNA repair during V(D)J recombination, class switching, and somatic hypermutation during B-cell maturation. Polynucleotide kinase 3′-phosphatase (PNKP) plays a significant role in DNA repair. PNKP deficiency is characterized by neurologic developmental abnormalities; however, immunodeficiency has not yet been reported.

Objective

We focused on a pair of PNKP-deficient siblings who presented with microcephaly, eye abnormalities, and hypogammaglobulinemia. We aimed to analyze the effect of PNKP deficiency on B-cell development.

Methods

Whole-exome sequencing was performed to identify the genetic cause of hypogammaglobulinemia. DNA repair efficiency was analyzed using patient-derived fibroblasts. The immune phenotype and B-cell receptor repertoire were analyzed using the patient’s peripheral blood, alongside other patients with PNKP deficiency without severe immunodeficiency.

Results

Whole-exome sequencing revealed compound heterozygous PNKP variants. Fibroblasts revealed defects in DNA repair in response to radiation-induced double/single-stranded DNA breaks. Flow cytometry revealed reduced total B-cell and class-switched memory B-cell counts. The B-cell receptor repertoire analysis demonstrated reduced frequencies of somatic hypermutations in these patients, whereas other patients with PNKP deficiency exhibited normal B-cell receptor repertoire patterns.