Department of Translational Medicine, Center for Basic and Clinical Immunology Research (CISI), World Allergy Organization (WAO) Center of Excellence, University of Naples Federico II, Naples, Italy.
Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Laboratory of Molecular Medicine and Genomics and Genomix4Life s.r.l, University of Salerno, Baronissi, Italy.
Allergy. 2020 Jan;75(1):158-168. doi: 10.1111/all.14002. Epub 2019 Oct 23.
Several factors may contribute to the circadian variability of clinical manifestations in asthma and allergy. Basophils play a pivotal role in allergic inflammation. However, evidence for a functional clock governing the effector function of these cells is sparse and contradictory. We have systematically sampled the 24-hour response of basophils to IgE- and non-IgE-dependent ligands in asthma to understand their possible contribution to the diurnal variations of allergic symptoms.
Leukocytes were collected every 4 hours for 24 hours from 10 patients with moderate, persistent asthma and 10 matched, nonallergic controls, and then incubated with concentrations of anti-IgE, formyl-methionyl-leucylphenylalanine (fMLP), or the Ca ionophore, A23187. Histamine release (HR) was tested for time-of-day- or disease-related variability by conventional statistics and for 24-hour rhythmicity by the cosinor method.
HR induced by anti-IgE was significantly increased at 08:00 vs. 20:00 in basophils from asthmatics but not controls. No significant differences were seen at any time in the response to A23187, while the response to fMLP was significantly higher at 08:00 vs. 20:00 in controls but not asthmatics. The basophil response to anti-IgE, but not fMLP or A23187, varied significantly across the 24 hours in asthma, and its amplitude, percent rhythm, and acrophase were comparable to those of peak expiratory flow or serum cortisol.
Using an integrated statistical approach, we show that basophil responsiveness undergoes significant circadian variability and that distinct patterns of rhythmicity can be recognized depending on the signal delivered, the activation parameters assessed, and the disease status.
多种因素可能导致哮喘和过敏的临床表现呈昼夜节律变化。嗜碱性粒细胞在过敏炎症中发挥关键作用。然而，关于调节这些细胞效应功能的功能性时钟的证据很少且相互矛盾。我们系统地采样了哮喘患者中嗜碱性粒细胞对 IgE 和非 IgE 依赖性配体的 24 小时反应，以了解它们对过敏症状昼夜变化的可能贡献。
从 10 名中度持续性哮喘患者和 10 名匹配的非过敏性对照者中每 4 小时采集白细胞一次，共 24 小时，然后用不同浓度的抗 IgE、甲酰基-甲硫氨酸-亮氨酸-苯丙氨酸 (fMLP) 或钙离子载体 A23187 孵育。通过传统统计学测试和余弦分析测试时间或疾病相关的嗜碱性粒细胞组胺释放 (HR) 变异性，以测试 24 小时节律性。
哮喘患者的嗜碱性粒细胞对 IgE 的反应在 08:00 时显著高于 20:00，而非对照者则无明显差异。在任何时间点，对 A23187 的反应均无显著差异，而对照组的嗜碱性粒细胞对 fMLP 的反应在 08:00 时显著高于 20:00，而非哮喘患者则无明显差异。哮喘患者的嗜碱性粒细胞对 IgE 的反应在 24 小时内有明显的昼夜变化，其振幅、节律百分比和高峰相位与呼气峰流速或血清皮质醇相似，但对 fMLP 或 A23187 的反应则无明显变化。
使用综合统计方法，我们发现嗜碱性粒细胞反应具有明显的昼夜节律变化，并且可以根据所传递的信号、评估的激活参数和疾病状态识别不同的节律模式。
