The salivary gland is rhythmically controlled by sympathetic nerve activation from the suprachiasmatic nucleus (SCN), which functions as the main oscillator of circadian rhythms. In humans, salivary IgA concentrations reflect circadian rhythmicity, which peak during sleep. However, the mechanisms controlling this rhythmicity are not well understood. Therefore, we examined whether the timing of parasympathetic (pilocarpine) or sympathetic (norepinephrine; NE) activation affects IgA secretion in the saliva. The concentrations of saliva IgA modulated by pilocarpine activation or by a combination of pilocarpine and NE activation were the highest in the middle of the light period, independent of saliva flow rate. The circadian rhythm of IgA secretion was weakened by an SCN lesion and Clock gene mutation, suggesting the importance of the SCN and Clock gene on this rhythm. Adrenoceptor antagonists blocked both NE-and pilocarpine-induced basal secretion of IgA. Dimeric IgA binds to the polymeric immunoglobulin receptor (pIgR) on the basolateral surface of epithelial cells and forms the IgA-pIgR complex. The circadian rhythm of Pigr abundance peaked during the light period, suggesting pIgR expression upon rhythmic secretion of IgA. We speculate that activation of sympathetic nerves during sleep may protect from bacterial access to the epithelial surface through enhanced secretion of IgA.Mammals possess circadian clock systems that control various physiological phenomena such as body temperature, sleep-wake cycles, and liver metabolism 1, 2 . Circadian clock systems are organized by a central clock called the suprachiasmatic nuclei (SCN) 3 , and by peripheral clocks located in many peripheral organs 4,5 . In addition to this system, biological functions of metabolism and the immune system are also known to affect circadian rhythms 6,7 .IgA is a type of antibody that works mainly in the mucosal immune system. It is abundant in the mucus of saliva and the small intestine 8 . Since plasma cells produce IgA in the salivary glands, there is a large amount of IgA in saliva. Therefore, IgA plays an important role as the first line of defense in oral immunity 9 . Monomers of IgA form dimeric IgA (dIgA) through the J chain. This dIgA binds the polymeric immunoglobulin receptor (pIgR) on the basolateral surface of epithelial cells and forms the IgA-pIgR complex. The IgA-pIgR complex is transported to the lumen from the basolateral surface. Proteolytic cleavage occurs at the apical surface, and a fragment of pIgR becomes a secretory component (SC) that binds dIgA. In this way, secretory IgA (sIgA) combines with other SCs, and free SCs are released. As a result, sIgA binds to luminal bacteria and prevents them from accessing the epithelial surface 9 . Therefore, a reduction in salivary IgA levels allows bacterial access to the epithelial surface and leads to various diseases such as upper respiratory tract infections (URTI) and periodontal disease 10 . A few studies demonstrated that salivary IgA concentrations display diurnal variat...

The mammalian circadian clock controls many physiological processes that include immune responses and allergic reactions. Several studies have investigated the circadian regulation of intestinal permeability and tight junctions known to be affected by cytokines. However, the contribution of circadian clock to food allergy symptoms remains unclear. Therefore, we investigated the role of the circadian clock in determining the severity of food allergies. We prepared an ovalbumin food allergy mouse model, and orally administered ovalbumin either late in the light or late in the dark period under light-dark cycle. The light period group showed higher allergic diarrhea and weight loss than the dark period group. The production of type 2 cytokines, IL-13 and IL-5, from the mesenteric lymph nodes and ovalbumin absorption was higher in the light period group than in the dark period group. Compared to the dark period group, the mRNA expression levels of the tight junction proteins were lower in the light period group. We have demonstrated that increased production of type 2 cytokines and intestinal permeability in the light period induced severe food allergy symptoms. Our results suggest that the time of food antigen intake might affect the determination of the severity of food allergy symptoms.