Department of Dermatology and Allergology, Helsinki University Hospital and University of Helsinki, P.O.Box 160, FI-00029 HUS, Helsinki, Finland.
Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, P.O.Box 700, FI-00029 HUS, Helsinki, Finland.
Orphanet J Rare Dis. 2018 Nov 26;13(1):213. doi: 10.1186/s13023-018-0956-6.
Netherton syndrome (NS) is a rare life-threatening syndrome caused by SPINK5 mutations leading to a skin barrier defect and a severe atopic diathesis. NS patients are prone to bacterial infections, but the understanding of the underlying immune deficiency is incomplete.
We analyzed blood lymphocyte phenotypes and function in relation to clinical infections in 11 Finnish NS patients, aged 3 to 17 years, and healthy age-matched controls. The proportion of B cells (CD19) and naïve B cells (CD27, IgD) were high while memory B cells (CD27) and switched memory B cells (CD27IgMIgD), crucial for the secondary response to pathogens, was below or in the lowest quartile of the reference values in 8/11 (73%) and 9/11 (82%) patients, respectively. The proportion of activated non-differentiated B cells (CD21, CD38l) was below or in the lowest quartile of the reference values in 10/11 (91%) patients. Despite normal T cell counts, the proportion of naïve CD4 T cells was reduced significantly and the proportion of CD8 T central memory significantly elevated. An increased proportion of CD57 CD8 T cells indicated increased differentiation potential of the T cells. The proportion of cytotoxic NK cells was elevated in NS patients in phenotypic analysis based on CD56DIM, CD16 and CD27 NK cells but in functional analysis, decreased expression of CD107a/b indicated impaired cytotoxicity. The T and NK cell phenotype seen in NS patients also significantly differed from that of age-matched atopic dermatitis (AD) patients, indicating a distinctive profile in NS. The frequency of skin infections correlated with the proportion of CD62L T cells, naïve CD4 and CD27 CD8 T cells and with activated B cells. Clinically beneficial intravenous immunoglobulin therapy (IVIG) increased naïve T cells and terminal differentiated effector memory CD8 cells and decreased the proportion of activated B cells and plasmablasts in three patients studied.
This study shows novel quantitative and functional aberrations in several lymphocyte subpopulations, which correlate with the frequency of infections in patients with Netherton syndrome. IVIG therapy normalized some dysbalancies and was clinically beneficial.
Netherton 综合征（NS）是一种罕见的危及生命的综合征，由 SPINK5 突变引起，导致皮肤屏障缺陷和严重的特应性素质。NS 患者易发生细菌感染，但对潜在免疫缺陷的理解尚不完全。
我们分析了 11 名芬兰 NS 患者（3 至 17 岁）和年龄匹配的健康对照者的血液淋巴细胞表型和功能与临床感染的关系。B 细胞（CD19）和幼稚 B 细胞（CD27、IgD）的比例较高，而对病原体的二次反应至关重要的记忆 B 细胞（CD27）和转换记忆 B 细胞（CD27IgMIgD）分别低于或处于参考值的最低四分位数在 8/11（73%）和 9/11（82%）患者中。激活的未分化 B 细胞（CD21、CD38l）的比例低于或处于参考值的最低四分位数在 10/11（91%）患者中。尽管 T 细胞计数正常，但幼稚 CD4 T 细胞的比例显著降低，CD8 T 中央记忆细胞的比例显著升高。CD57 CD8 T 细胞比例的增加表明 T 细胞的分化潜能增加。基于 CD56DIM、CD16 和 CD27 NK 细胞的表型分析，NS 患者中 NK 细胞的比例升高，但在功能分析中，CD107a/b 的表达减少表明细胞毒性受损。NS 患者的 T 和 NK 细胞表型也与年龄匹配的特应性皮炎（AD）患者明显不同，表明 NS 存在独特的表型。皮肤感染的频率与 CD62L T 细胞、幼稚 CD4 和 CD27 CD8 T 细胞以及激活的 B 细胞的比例相关。在研究的 3 名患者中，临床有益的静脉注射免疫球蛋白治疗（IVIG）增加了幼稚 T 细胞和终末分化的效应记忆 CD8 细胞，并降低了激活的 B 细胞和浆母细胞的比例。
本研究显示，几种淋巴细胞亚群存在新的定量和功能异常，与 Netherton 综合征患者感染的频率相关。IVIG 治疗使一些失衡正常化，并具有临床益处。
