Basophil degranulation in response to IgE ligation is controlled by a distinctive circadian clock in asthma

Background: 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. Methods: 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 Ca2+ 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. Results: 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. Conclusion: 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