PI3Kδ基因缺陷会影响B细胞的分化和成熟，导致低丙种球蛋白血症和反复感染。
Genetic defects in PI3Kδ affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections.
作者信息
Wentink Marjolein, Dalm Virgil, Lankester Arjan C, van Schouwenburg Pauline A, Schölvinck Liesbeth, Kalina Tomas, Zachova Radana, Sediva Anna, Lambeck Annechien, Pico-Knijnenburg Ingrid, van Dongen Jacques J M, Pac Malgorzata, Bernatowska Ewa, van Hagen Martin, Driessen Gertjan, van der Burg Mirjam
机构信息
Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Dept. of Internal Medicine, Division of Clinical Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
出版信息
Clin Immunol. 2017 Mar;176:77-86. doi: 10.1016/j.clim.2017.01.004. Epub 2017 Jan 17.
BACKGROUND
Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway.
METHODS
We studied precursor and peripheral B-cell differentiation and apoptosis via flowcytometry. Furthermore, we performed AKT-phosphorylation assays and somatic hypermutations (SHM) and class switch recombination (CSR) analysis.
RESULTS
We identified 13 patients of whom 3 had new mutations in PIK3CD or PIK3R1. Patients had low total B-cell numbers with increased frequencies of transitional B cells and plasmablasts, while the precursor B-cell compartment in bone marrow was relatively normal. Basal AKT phosphorylation was increased in lymphocytes from APDS patients and natural effector B cells where most affected. PI3K mutations resulted in altered SHM and CSR and increased apoptosis.
CONCLUSIONS
The B-cell compartment in APDS patients is affected by the mutations in PI3K. There is reduced differentiation beyond the transitional stage, increased AKT phosphorylation and increased apoptosis. This B-cell phenotype contributes to the clinical phenotype.
背景
PIK3CD和PIK3R1的突变通过PI3K-AKT信号通路失调导致活化PI3K-δ综合征（APDS）。
方法
我们通过流式细胞术研究前体B细胞和外周B细胞的分化及凋亡。此外，我们进行了AKT磷酸化检测、体细胞高频突变（SHM）和类别转换重组（CSR）分析。
结果
我们鉴定出13例患者，其中3例在PIK3CD或PIK3R1中有新突变。患者的总B细胞数量较低，过渡性B细胞和浆母细胞频率增加，而骨髓中的前体B细胞区室相对正常。APDS患者淋巴细胞和受影响最严重的天然效应B细胞中的基础AKT磷酸化增加。PI3K突变导致SHM和CSR改变以及凋亡增加。
结论
APDS患者的B细胞区室受PI3K突变影响。过渡阶段后的分化减少，AKT磷酸化增加，凋亡增加。这种B细胞表型促成了临床表型。
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