Abstract：
BACKGROUND: Human tapasin deficiency is reported to cause an autosomal-recessive inborn error of immunity characterized by substantially reduced cell surface expression of major histocompatibility complex class I (MHC-I).
OBJECTIVE: We evaluated the immunologic and clinical consequences of tapasin deficiency.
METHODS: A novel homozygous variant in TAPBP was identified by means of whole genome sequencing. The expression of tapasin and both subunits of the transporter associated with antigen presentation (TAP) were evaluated by Western blot analysis. Cell surface and intracellular expression of MHC-I were evaluated by flow cytometry. Small interfering RNAs were used for silencing TAPBP expression in HEK293T cells.
RESULTS: We identified a deletion in TAPBP (c.312del, p.(K104Nfs∗6)) causing tapasin deficiency in a patient with bronchiectasis and recurrent respiratory tract infections as well as herpes zoster. Besides substantial reduction in TAP1 and TAP2 expression, peripheral blood mononuclear cells from this patient and TAPBP-knockdown HEK293T cells, displayed reduced cell surface expression of MHC-I, while reduction in intracellular expression of MHC-I was less prominent, suggesting a defect in MHC-I trafficking to the plasma membrane. IFN-α improved cell surface expression of MHC-I in tapasin deficient lymphocytes and TAPBP-knockdown HEK293T cells, representing a possible therapeutic approach for tapasin deficiency.
CONCLUSIONS: Tapasin deficiency is a very rare inborn error of immunity, the pathomechanism and clinical spectrum of which overlaps with TAP deficiencies.
OBJECTIVE: We evaluated the immunologic and clinical consequences of tapasin deficiency.
METHODS: A novel homozygous variant in TAPBP was identified by means of whole genome sequencing. The expression of tapasin and both subunits of the transporter associated with antigen presentation (TAP) were evaluated by Western blot analysis. Cell surface and intracellular expression of MHC-I were evaluated by flow cytometry. Small interfering RNAs were used for silencing TAPBP expression in HEK293T cells.
RESULTS: We identified a deletion in TAPBP (c.312del, p.(K104Nfs∗6)) causing tapasin deficiency in a patient with bronchiectasis and recurrent respiratory tract infections as well as herpes zoster. Besides substantial reduction in TAP1 and TAP2 expression, peripheral blood mononuclear cells from this patient and TAPBP-knockdown HEK293T cells, displayed reduced cell surface expression of MHC-I, while reduction in intracellular expression of MHC-I was less prominent, suggesting a defect in MHC-I trafficking to the plasma membrane. IFN-α improved cell surface expression of MHC-I in tapasin deficient lymphocytes and TAPBP-knockdown HEK293T cells, representing a possible therapeutic approach for tapasin deficiency.
CONCLUSIONS: Tapasin deficiency is a very rare inborn error of immunity, the pathomechanism and clinical spectrum of which overlaps with TAP deficiencies.
摘要：
背景：据报道，人类tapasin缺乏症会导致常染色体隐性遗传先天性免疫错误（IEI），其特征在于主要组织相容性复合体I类(MHC-I)的细胞表面表达显著降低。
目的：评估他汀缺乏的免疫学和临床后果。
方法：通过全基因组测序（WGS）鉴定了TAPBP中的一种新的纯合变体。通过蛋白质印迹法评估了tapasin和与抗原呈递（TAP）相关的转运蛋白的两个亚基的表达。已经通过流式细胞术评估了MHCI类的细胞表面和细胞内表达。小干扰RNA(siRNA)用于沉默HEK293T细胞中的TAPBP表达。
结果：我们在TAPBP中发现了一个缺失（c.312del，p。（K104Nfs*6））导致支气管扩张和反复呼吸道感染以及带状疱疹患者的他汀缺乏症。除了TAP1和TAP2表达的大幅减少，来自该患者的PBMC和TAPBP敲除HEK293T细胞，显示MHC-I的细胞表面表达减少，虽然细胞内MHC-I表达的减少不太明显，提示MHC-I向质膜运输的缺陷。干扰素-α（IFN-α）改善了Tapasin缺陷淋巴细胞中MHC-I的细胞表面表达和TAPBP敲低HEK293T，代表了一种可能的治疗他汀缺乏症的方法。
结论：Tapasin缺乏症是一种非常罕见的IEI，其病理机制和临床谱与TAP缺陷重叠。
目的：评估他汀缺乏的免疫学和临床后果。
方法：通过全基因组测序（WGS）鉴定了TAPBP中的一种新的纯合变体。通过蛋白质印迹法评估了tapasin和与抗原呈递（TAP）相关的转运蛋白的两个亚基的表达。已经通过流式细胞术评估了MHCI类的细胞表面和细胞内表达。小干扰RNA(siRNA)用于沉默HEK293T细胞中的TAPBP表达。
结果：我们在TAPBP中发现了一个缺失（c.312del，p。（K104Nfs*6））导致支气管扩张和反复呼吸道感染以及带状疱疹患者的他汀缺乏症。除了TAP1和TAP2表达的大幅减少，来自该患者的PBMC和TAPBP敲除HEK293T细胞，显示MHC-I的细胞表面表达减少，虽然细胞内MHC-I表达的减少不太明显，提示MHC-I向质膜运输的缺陷。干扰素-α（IFN-α）改善了Tapasin缺陷淋巴细胞中MHC-I的细胞表面表达和TAPBP敲低HEK293T，代表了一种可能的治疗他汀缺乏症的方法。
结论：Tapasin缺乏症是一种非常罕见的IEI，其病理机制和临床谱与TAP缺陷重叠。
