Purpose

Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls.

Methods

The genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing.

Results

The patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein–Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient’s whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens.

Conclusion

Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.

中文翻译：

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一种新的 STK4 突变通过细胞因子诱导的粘附和趋化基因的失调损害 T 细胞免疫

目的

人类丝氨酸/苏氨酸激酶 4 (STK4) 缺乏症是一种罕见的常染色体隐性遗传疾病，可导致联合免疫缺陷；然而，免疫信号和宿主防御受损的程度尚不清楚。我们通过比较一名儿科患者的先天性和适应性细胞介导和体液免疫反应与三个杂合子亲属和不相关的对照。

方法

通过全基因组和Sanger测序验证遗传病因。STK4 基因和蛋白质表达分别通过定量 RT-PCR 和免疫印迹测量。通过高通量 RT-RCR、RNA-Seq、ELISA 和流式细胞术评估细胞异常。通过ELISA和噬菌体免疫沉淀测序评估抗体反应。

结果

该患者表现出部分 STK4 表达丧失和 STK4 功能完全丧失，并伴有反复的病毒和细菌感染，特别是持续的 Epstein-Barr 病毒血症和肺结核。细胞和分子分析揭示了 T 细胞亚群、浆细胞样树突状细胞和 NK 细胞的异常部分。患者全血和 PBMC 样本的转录反应表明干扰素信号传导失调、T 细胞免疫受损、T 细胞凋亡增加以及细胞因子诱导的粘附和白细胞趋化基因的调节受损。尽管如此，该患者对各种病原体具有可检测到的疫苗特异性抗体和 IgG 反应，与正常的 CD19 + B 细胞部分一致，尽管具有独特的抗体库，主要由疱疹病毒抗原驱动。

结论

STK4 缺乏症患者的免疫功能受损可能会超出淋巴细胞。