The circadian clock (also called circadian rhythm) regulates many physiological activities including the sleep-wake cycle, metabolism, digestion and immune processes. It is essentially a system that tells cells in the body what to do based on a 24 hour cycle, which can be influenced by such things as light cues, sleep and medication. Many cell types in the body have been shown to maintain their own internal circadian clocks and to change their behavior based upon time. Mast cells and eosinophils have been shown to maintain their own internal clocks.
On a cellular level, the circadian clock is maintained by the expression of clock genes. Inside the cell, a protein called CLOCK attaches to another protein (BMAL1) and they initiate expression of several genes that regulate circadian rhythm in the cell. These genes are called Period 1, Period 2, Period 3, Cryptochrome 1 and Cryptochrome 2. The proteins made by those genes regulate the expression of other genes based upon time.
An interesting facet of allergic disease is the well established variation in symptom severity depending on the time of day. This is seen in a variety of allergic conditions, such as asthma and atopic dermatitis. Allergic symptoms, including those that affect pulmonary function, are worse between midnight and morning, with a ramping up of symptoms seen around 10pm. This worsening overnight often results in sleep disruptions and “morning attacks”, which affect rest and result in decreased quality of life for patients. This has been verified repeatedly both through mouse studies and in reports of human patients.
Circadian rhythm has been shown to affect mediator release in mast cells, and this has been shown to be regulated by the five genes listed above. If even one of those genes are mutated, the mediator release becomes uniform and does not shown the peaks and lows observed normally. Both tryptase and plasma histamine levels have been observed to have lower levels in the afternoon and to peak at night. A marker associated with degranulation (b-hexosaminidase) showed the same pattern.
There is currently no information available on how mast cells tell time in relation to the rest of the body, though it is thought that mast cells receive molecular signals that “start the clock”. Importantly, in mice that have had their adrenal glands removed, mast cells do not shown circadian rhythms in mediator release. This indicates that the signal that “starts the clock” comes to mast cells from the adrenal glands. Corticosterone is being investigated as the possible signal, as it has been shown to induce expression of at least two clock genes, Period 1 and Period 2.
References:
Silver, A.C., Arjona, A., Hughes, M.E., Nitabach, M.N., Fikrig, E., 2012. Circadian expres-sion of clock genes in mouse macrophages, dendritic cells, and B cells. BrainBehav. Immun. 3, 407–413.
Smolensky, M.H., Lemmer, B., Reinberg, A.E., 2007. Chronobiology and chronother-apy of allergic rhinitis and bronchial asthma. Adv. Drug Deliv. Rev. 9–10,852–882.
Baumann, A., Gonnenwein, S., Bischoff, S.C., Sherman, H., Chapnik, N., Froy, O.,Lorentz, A., 2013. The circadian clock is functional in eosinophils and mast cells. Immunology 4, 465–474.
Burioka, N., Fukuoka, Y., Koyanagi, S., Miyata, M., Takata, M., Chikumi, H., Takane, H.,Watanabe, M., Endo, M., Sako, T., Suyama, H., Ohdo, S., Shimizu, E., 2010. Asthma: chronopharmacotherapy and the molecular clock. Adv. Drug Deliv. Rev. 9–10,946–955.
Cermakian, N., Lange, T., Golombek, D., Sarkar, D., Nakao, A., Shibata, S., Mazzoccoli, G., 2013. Crosstalk between the circadian clock circuitry and the immune system.Chronobiol. Int. 7, 870–888.
IgE-dependent activation of human mast cells and fMLP-mediatedactivation of human eosinophils is controlled by the circadian clockAnja Baumanna, Katharina Feilhauerb, Stephan C. Bischoffa, Oren Froyc, Axel Lorentza. Molecular Immunology 64 (2015) 76–81.
Yuki Nakamura, et al. Circadian regulation of allergic reactions by the mast cell clock in mice. J Allergy Clin Immunol 133 (2014) 568-575.