Biological clocks: their relevance to immune-allergic diseases

Abstract

The 2017 Nobel Prize for Physiology or Medicine, awarded for the discoveries made in the past 15 years on the genetic and molecular mechanisms regulating many physiological functions, has renewed the attention to the importance of circadian rhythms. These originate from a central pacemaker in the suprachiasmatic nucleus in the brain, photoentrained via direct connection with melanopsin containing, intrinsically light-sensitive retinal ganglion cells, and it projects to periphery, thus creating an inner circadian rhythm. This regulates several activities, including sleep, feeding times, energy metabolism, endocrine and immune functions. Disturbances of these rhythms, mainly of wake/sleep, hormonal secretion and feeding, cause decrease in quality of life, as well as being involved in development of obesity, metabolic syndrome and neuropsychiatric disorders. Most immunological functions, from leukocyte numbers, activity and cytokine secretion undergo circadian variations, which might affect susceptibility to infections. The intensity of symptoms and disease severity show a 24 h pattern in many immunological and allergic diseases, including rheumatoid arthritis, bronchial asthma, atopic eczema and chronic urticaria. This is accompanied by altered sleep duration and quality, a major determinant of quality of life. Shift work and travel through time zones as well as artificial light pose new health threats by disrupting the circadian rhythms. Finally, the field of chronopharmacology uses these concepts for delivering drugs in synchrony with biological rhythms.

Keywords: Allergy; Biological clock; Chronopharmacology; Circadian rhythm; Immune system; Shift work.

Fig. 1

Schematic representation of the master clock regulation of the immune system. Entrainment of the suprachiasmatic nuclei (SCN) is mediated by the input from intrinsically photosensitive retinal ganglion cells activated by light (from the sun and artificial lights from screens and indoor illumination). SCN controls directly the hypothalamus and the hypothalamus–pituitary–adrenal gland (HPA) axis, the autonomous nervous system and the pineal gland. Hormones and neurotransmitters (in boxes) from these clock-regulated structures modulate the activation and functions of different cell types of both the innate and adaptive immune system. Cytokines and chemokines produced by immune cells feed back on the SCN (dotted line). Through transcriptional mechanisms the SCN indirectly regulates also the synchronization of secondary clocks in peripheral tissues and other circadian cycles (wake/sleep, fast/feeding, etc.). NE norepinephrine