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SP0040 The Immune/Inflammatory Response Follows Circadian Rhythms
  1. M. Cutolo
  2. on behalf of EULAR NEIRD Study Group
  1. Rheumatology Internal Medicine, University of Genova, Genova, Italy

Abstract

Alternating sunlight and darkness regulate the cyclical 24-hour period of human biological activity, generally reported as “circadian rhythms” or referred as “chronobiology”, and biological signaling occur in a complex network with cyclical interactions between the central and the autonomic nervous systems, the endocrine glands and the immune system.

The central nervous biological CLOCK system (highly conserved and sophisticated molecular 'clock'), under the influence of light/dark alternations, 'creates' the internal circadian rhythms and synchronise the physical and functional activities, mainly the immune functions. Moreover, different immune cell types, such as macrophages, natural killer cells, and lymphocytes, contain a circadian molecular clockwork. This tight crosstalk between the circadian and immune systems has wide-ranging implications for disease, as shown by the higher incidence of cancer (night growth factors) and the exacerbation of autoimmune symptoms upon circadian disruption.

Nocturnal hormones such as melatonin and prolactin that activate the night-time immune response, and the successive rise of cortisol that dowregulates the ongoing immune reactivity very early in the morning, are involved in the circadian neuroendocrine immune network. In addition, is recognized a relevant role for sleep and body energy daily distribution, since important factors for the homoeostatic regulation of circadian physiological/pathological processes of the immune netwok.

In chronic immune/inflammatory conditions such as rheumatoid arthritis (RA), stiffness and functional disability, are evident in the early morning hours since the night adrenal cortisol production, under the chronic stress of the disease, becomes insufficient to inhibit ongoing nocturnal immune/inflammatory reaction (melatonin sustained). In addition, it is now also clear that RA symptoms, which is T helper 1 (Th1) dependent, but also asthma, which is T helper 2 (Th2) dependent, are influenced by diurnal rhythms and natural regulatory T cells (nTreg). In particular, IL-2, IFN-γ and IL-10 secretion by naïve CD4(+) T cells follows a diurnal rhythm.

Therefore, understanding the daily rhythm of the immune system could have also implications for vaccinations and how we manage infectious and several inflammatory diseases. In inflammatory recurrent bowel diseases, including ulcerative colitis and Crohn's disease, it has been demonstrated that sleep disturbances are involved in the pathogenesis and melatonin (night hormone), plays an important role as regulators of inflammation as well as a player in proper immune system and antioxidant system in the intestinal disorders.

In particular, the onset of sleep corresponds with an increase in the serum levels of some cytokines, peaking at 2.5 h after sleep onset and their pro-inflammatory effects are suggested to be linked with nocturnal exacerbations of diseases like asthma and RA and polymyalgia rheumatica (but also chronic/acute gout!). Converserly, an activated immune system alters sleep and sleep abnormalities further affect immune function. Recently, high serum levels of TNF-α has been linked to sleepiness in patients with obstructive sleep apnea and RA.

Since circadian rhythmicity of neuroendocrine pathways are closely coupled to the immune/inflammatory reactions and related clinical symptoms, new approaches at least concerning inflammatory diseases management, have been recently suggested for the optimization of the timing for therapeutical intervention.

Reference

  1. Cutolo M. Chronobiology and the treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2012;24:312-8.

Disclosure of Interest None declared

DOI 10.1136/annrheumdis-2014-eular.6294

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