Bancos Irina, Hazeldine Jon, Chortis Vasileios, Hampson Peter, Taylor Angela E, Lord Janet M, Arlt Wiebke
Institute of Metabolism and Systems ResearchUniversity of Birmingham, Birmingham, UK.
Division of EndocrinologyDiabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Eur J Endocrinol. 2017 Apr;176(4):471-480. doi: 10.1530/EJE-16-0969.
Mortality in patients with primary adrenal insufficiency (PAI) is significantly increased, with respiratory infections as a major cause of death. Moreover, patients with PAI report an increased rate of non-fatal infections. Neutrophils and natural killer (NK) cells are innate immune cells that provide frontline protection against invading pathogens. Thus, we compared the function and phenotype of NK cells and neutrophils isolated from PAI patients and healthy controls to ascertain whether altered innate immune responses could be a contributory factor for the increased susceptibility of PAI patients to infection.
We undertook a cross-sectional study of 42 patients with PAI due to autoimmune adrenalitis (37) or bilateral adrenalectomy (5) and 58 sex- and age-matched controls. A comprehensive screen of innate immune function, consisting of measurements of neutrophil phagocytosis, reactive oxygen species production, NK cell cytotoxicity (NKCC) and NK cell surface receptor expression, was performed on all subjects.
Neutrophil function did not differ between PAI and controls. However, NKCC was significantly reduced in PAI (12.0 ± 1.5% vs 21.1 ± 2.6%, < 0.0001). Phenotypically, the percentage of NK cells expressing the activating receptors NKG2D and NKp46 was significantly lower in PAI, as was the surface density of NKG2D (all < 0.0001). Intracellular granzyme B expression was significantly increased in NK cells from PAI patients ( < 0.01).
Adrenal insufficiency is associated with significantly decreased NKCC, thereby potentially compromising early recognition and elimination of virally infected cells. This potential impairment in anti-viral immune defense may contribute to the increased rate of respiratory infections and ultimately mortality in PAI.
原发性肾上腺皮质功能减退症（PAI）患者的死亡率显著升高，呼吸道感染是主要死因。此外，PAI患者报告非致命性感染率增加。中性粒细胞和自然杀伤（NK）细胞是先天性免疫细胞，为抵御入侵病原体提供一线保护。因此，我们比较了从PAI患者和健康对照中分离出的NK细胞和中性粒细胞的功能和表型，以确定先天性免疫反应改变是否可能是PAI患者感染易感性增加的一个促成因素。
我们对42例因自身免疫性肾上腺炎（37例）或双侧肾上腺切除术（5例）导致PAI的患者以及58例性别和年龄匹配的对照进行了横断面研究。对所有受试者进行了先天性免疫功能的全面筛查，包括中性粒细胞吞噬作用、活性氧生成、NK细胞细胞毒性（NKCC）和NK细胞表面受体表达的测量。
PAI患者和对照组之间中性粒细胞功能无差异。然而，PAI患者的NKCC显著降低（12.0±1.5%对21.1±2.6%，<0.0001）。在表型上，PAI患者中表达激活受体NKG2D和NKp46的NK细胞百分比显著降低，NKG2D的表面密度也是如此（均<0.0001）。PAI患者NK细胞内颗粒酶B表达显著增加（<0.01）。
肾上腺皮质功能减退与NKCC显著降低有关，从而可能损害对病毒感染细胞的早期识别和清除。抗病毒免疫防御的这种潜在损害可能导致PAI患者呼吸道感染率增加，并最终导致死亡率上升。
