Kanami Orihara

Antigen exposure in the late light period induces severe symptoms of food allergy in an OVA-allergic mouse model.

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.

Controlling the peripheral clock might be a new treatment strategy in allergy and immunology

Virtually all organisms on Earth maintain an internal rhythm that oscillates approximately 24 hours per cycle. This is known as the endogenous circadian system. The master clock of the circadian rhythm is located in the suprachiasmatic nuclei in the anterior hypothalamus, and it is oriented to the external environment through the retinohypothalamic tract, receiving light information from the eye. Importantly, the circadian clock system influences most peripheral tissues, including immune and structural cells. For example, in human blood numbers of naive, central memory, and effector memory T cells increase at night. It is well known that allergic symptoms can worsen at nighttime, particularly in the still-dark hours of early morning, and mouse models have demonstrated circadian rhythm in allergic responses. Nocturnal peaks of signals, such as cortisol and histamine levels in blood, were implicated in those circadian variations of allergic responses; however, the precise mechanisms have remained unclear. The circadian clock is guided by an interaction of genes that results in a 24-hour autoregulatory feedback loop. There are 2 interlocking phases of this transcriptional-translational feedback loop, which containsBMAL1,CLOCK, E-box promoter elements, Period (PER1-3), cryptochrome (CRY1/2), NR1D1 (Rev-erba), and retinoic acid–related orphan receptor A (RORA). Gradually, PER and cryptochrome proteins start to degrade, after which suppression on BMAL1 and CLOCK is relieved. The timing regulation produced by the system synchronizes peripheral clocks, inducing rhythmic expression of approximately 10% of all genes in each peripheral cell. Murine bone marrow–derived mast cells (BMMCs) assessed after cell activation have shown circadian variations in the

Gene Expression Patterns in Distinct Endoscopic Findings for Eosinophilic Gastritis in Children

BACKGROUNDnEosinophilic gastritis (EG) is clinicopathologically characterized by both marked gastric eosinophilia and clinical symptoms. The endoscopic findings in EG vary among patients, leading to clinical confusion. However, little is known about the relationship between precise endoscopic findings and the pathophysiological process responsible for EG.nnnOBJECTIVEnWe aimed to elucidate whether the gross endoscopic findings of EG can be classified into distinct gene expression profiles.nnnMETHODSnWe enrolled pediatric patients who underwent gastrointestinal endoscopy for clinical symptoms suggestive of eosinophilic gastrointestinal disorder between 2011 and 2016. EG was diagnosed when gastric eosinophilia was greater than or equal to 30 eosinophils/hpf. The gene expression profiles of gastric biopsies were assessed using microarray technology.nnnRESULTSnPatients with EG and control subjects (nxa0= 8, each) were examined. On the microarray, 1,999 genes were differentially expressed between EG and the controls (≥2-fold difference, adjusted P value < .05), including significant upregulation of eotaxin-3 (C-C chemokine ligand 26). The endoscopic findings of patients with EG fell roughly into 2 types, namely, ulcerative and nodular lesions. Despite identifying distinct patterns of gene expression, most differentially regulated genes overlapped between the 2 endoscopic finding types. Several gene ontology terms were enriched in the substantially overlapped genes, but not in each of the distinct genes.nnnCONCLUSIONSnOur results strongly indicate that ulcerative and nodular lesions are a single disease, EG, or a variation thereof, in spite of morphological differences. Our findings may contribute to a better understanding of the pathogenesis of EG, as well as to more accurate diagnosis of this disease.

Circadian clock-dependent increase in salivary IgA secretion modulated by sympathetic receptor activation in mice

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.