Cellular Mechanisms Underlying B Cell Abnormalities in Patients With Gain-of-Function Mutations in the PIK3CD Gene.
Cellular Mechanisms Underlying B Cell Abnormalities in Patients With Gain-of-Function Mutations in the PIK3CD Gene.
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PIK3CD 基因功能获得性突变患者 B 细胞异常的细胞机制
DOI：
10.3389/fimmu.2022.890073
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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活化磷脂酰肌醇3激酶（PI 3 K）-δ综合征（APDS）是一种先天性免疫缺陷，具有免疫缺陷和免疫失调的可变临床表型，由PIK 3CD的功能获得性突变引起。免疫表型的标志是移行B细胞和浆母细胞（PB）比例增加、进行性B细胞丢失和血清IgM水平升高。探讨独特的B细胞亚群和驱动B细胞失调超过过渡B细胞阶段的APDS的病理机制。收集了24例APDS患者的临床和免疫学资料。在5例病例中，我们对B细胞表型进行了深入分析，并培养纯化的幼稚B细胞，以评估其存活、活化、IG基因类别转换重组（CSR）、PB分化和抗体分泌。我们还分析了分选的CD 27-IgD-双阴性B（DNB）细胞的PB分化能力。与健康对照组（HC）相比，患者的B细胞大小增加，IgM+ DNB细胞比例更高。他们的幼稚B细胞表现出增加的死亡，受损的CSR，但相对正常的PB分化。在刺激后，患者的DNB细胞分泌类似水平的IgG，但比HC的DNB细胞分泌更高水平的IgM。PI 3 K抑制的靶向治疗部分恢复了B细胞表型。目前的研究表明，对APDS的B细胞病理学的其他机制的见解：（1）外周B细胞数量减少可能是由于幼稚B细胞死亡增加;（2）较大的B细胞大小和扩增的DNB群体表明幼稚B细胞活化和分化为DNB细胞增强;（3）CSR受损但PB分化正常的细胞主要产生IgM分泌细胞，导致IgM水平升高。
Activated phosphoinositide 3 kinase (PI3K) -delta syndrome (APDS) is an inborn error of immunity with variable clinical phenotype of immunodeficiency and immune dysregulation and caused by gain-of-function mutations in PIK3CD. The hallmark of immune phenotype is increased proportions of transitional B cells and plasmablasts (PB), progressive B cell loss, and elevated levels of serum IgM. To explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS. Clinical and immunological data was collected from 24 patients with APDS. In five cases, we performed an in-depth analysis of B cell phenotypes and cultured purified naïve B cells to evaluate their survival, activation, Ig gene class switch recombination (CSR), PB differentiation and antibody secretion. We also analyzed PB differentiation capacity of sorted CD27-IgD- double-negative B (DNB) cells. The patients had increased B cell sizes and higher proportions of IgM+ DNB cells than healthy controls (HC). Their naïve B cells exhibited increased death, impaired CSR but relatively normal PB differentiation. Upon stimulation, patient’s DNB cells secreted a similar level of IgG but a higher level of IgM than DNB cells from HC. Targeted therapy of PI3K inhibition partially restored B cell phenotypes. The present study suggests additional mechanistic insight into B cell pathology of APDS: (1) decreased peripheral B cell numbers may be due to the increased death of naïve B cells; (2) larger B cell sizes and expanded DNB population suggest enhanced activation and differentiation of naïve B cells into DNB cells; (3) the impaired CSR yet normal PB differentiation can predominantly generate IgM-secreting cells, resulting in elevated IgM levels.