■原发性肾上腺功能不全(PAI)患者感染风险增加,肾上腺危象,死亡率较高。由于非生理性皮质醇替代,这种令人沮丧的结果已被推断为免疫细胞失调。由于不同类型PAI患者的免疫状况尚未得到系统的探讨,我们研究了不同原因的糖皮质激素(GC)缺乏的PAI患者的免疫表型.
■这项横断面单中心研究包括28例先天性肾上腺增生(CAH)患者,27库欣综合征(BADx)引起的双侧肾上腺切除术后,21例患有Addison病(AD)和52例健康对照。所有PAI患者均采用稳定的GC替代方案,中位剂量为每天25mg氢化可的松。从肝素化血液样品中分离外周血单核细胞。在用佛波醇肉豆蔻酸酯乙酸酯和离子霉素刺激4小时后,使用多色流式细胞术分析免疫细胞亚群。研究了自然杀伤(NK-)细胞的细胞毒性和时钟基因表达。
■与对照组相比,AD患者的T辅助细胞亚群百分比下调(Th1p=0.0024,Th2p=0.0157,Th17p<0.0001)。与对照组相比,AD(Tc1p=0.0075,Tc2p=0.0154)和CAH(Tc1p=0.0055,Tc2p=0.0012)患者的细胞毒性T细胞亚群减少。所有PAI患者亚群的NKCC均降低,CAH变化最小。脱颗粒标志物CD107a在BADx和AD中表达上调,与对照组相比,CAH患者没有(BADxp<0.0001;ADp=0.0002)。与NK细胞激活受体相反,NK细胞抑制受体CD94在BADx和AD中表达上调,但不是在CAH患者(p<0.0001)。尽管在我们的患者亚组中可以证实时钟基因表达的调节,未检测到个体间-群体间的主要差异。
■在不同病因的PAI患者中,尽管使用了相同的GC制剂和剂量,但T细胞和NK细胞表型的显著差异变得明显.我们的结果强调了不同原因的PAI患者在免疫细胞组成和功能方面的意外差异,并暗示了可能需要疾病特异性治疗的疾病特异性改变。
Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency.
This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing\'s syndrome (BADx), 21 with Addison\'s disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated.
The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected.
In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.