Abstract

Discoveries from basic science research in the last decade have brought significant progress in knowledge of pathophysiologic processes of allergic diseases, with a compelling impact on understanding of the natural history, risk prediction, treatment selection or mechanism-specific prevention strategies. The view of the pathophysiology of allergic diseases developed from a mechanistic approach, with a focus on symptoms and organ function, to the recognition of a complex network of immunological pathways. Several subtypes of inflammation and complex immune-regulatory networks and the reasons for their failure are now described, that open the way for the development of new diagnostic tools and innovative targeted-treatments. An endotype is a subtype of a disease condition, which is defined by a distinct pathophysiological mechanism, whereas a disease phenotype defines any observable characteristic of a disease without any implication of a mechanism. Another key word linked to disease endotyping is biomarker that is measured and evaluated to examine any biological or pathogenic processes, including response to a therapeutic intervention. These three keywords will be discussed more and more in the future with the upcoming efforts to revolutionize patient care in the direction of precision medicine and precision health. The understanding of disease endotypes based on pathophysiological principles and their validation across clinically meaningful outcomes in asthma, allergic rhinitis, chronic rhinosinusitis, atopic dermatitis and food allergy will be crucial for the success of precision medicine as a new approach to patient management.

Abstract

The chemokine receptor, CC-chemokine receptor 3 (CCR3), and its major ligands, eotaxin, RANTES, and MCP-4, are involved in eosinophil chemotaxis. It is thought that CCR3 plays an important role in the recruitment and activation of eosinophils in nasal polyposis. We examined nasal polyp extract-induced eosinophil chemotaxis and the effect of a CCR3 antagonist using EZ-TAXIScan, a novel real-time chemotaxis assay device. Nasal polyps were obtained from chronic rhinosinusitis (CRS) patients during surgery. The polyps were homogenized and eotaxin levels in the extracts were measured. Eosinophils were purified from human peripheral blood by the CD16 negative selection method. Nasal polyp extract-induced eosinophil chemotaxis, with or without CCR3 antagonist, was assessed by EZ-TAXIScan. There was a significant positive correlation between the eosinophil counts in nasal polyp and eotaxin levels in the nasal polyp extracts. Using EZ-TAXIScan, eosinophil chemotactic responses were observed following stimulation with nasal polyp extracts. There was a significant positive correlation between the chemotactic index toward the nasal polyp extracts and their eotaxin levels. Nasal polyp extract-induced chemotaxis was completely inhibited by CCR3 antagonist but not by chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonist which inhibited PGD2-induced eosinophil chemotaxis. The CCR3 pathway may play an important role in the pathogenesis of eosinophil recruitment in nasal polyps through selective eosinophil chemotaxis.

Abstract

Inducible nitric oxide synthase (iNOS) induced by inflammatory cytokines and iNOS activity in bronchial epithelial cells is a major determinant of fractional exhaled nitric oxide (FeNO) levels. The aim of this study was to investigate the association of iNOS promoter gene polymorphisms and FeNO levels in Japanese asthmatics before the introduction of asthma treatment. Asthmatics were recruited from Fukushima Medical University Hospital. Genotyping of the pentanucleotide repeat (CCTTT)n and seven previously detected single nucleotide polymorphisms (SNPs) in the iNOS promoter lesion was performed. The relationships between the genotypes and FeNO levels before the introduction of asthma treatment were compared. In 91 asthmatics, the number of microsatellite repeats ranged from 9 to 20 and showed a bimodal distribution. According to this distribution, asthmatics were divided into two groups: genotypes with at least one long allele with more than 14 repeats (L/s or L/L) and genotypes with both short alleles with 14 or fewer repeats (s/s). No significant differences were observed in each parameter between the two groups. The mean FeNO level before treatment was significantly higher in the L/s or L/L subjects than in the s/s subjects. After treatment, the lowest FeNO level did not differ between the two groups. Three SNPs detected in the Japanese subjects were not associated with FeNO levels. The number of CCTTT repeats in the iNOS promoter region was associated with FeNO levels in asthmatics before treatment, suggesting the importance of iNOS genotype in the clinical application of FeNO for asthmatics.

Abstract

The prevalence of maternal oral contraceptive pills (OCP) use and that of childhood asthma are high in western countries. The aim of this study is to examine the association of OCP use with childhood wheeze and allergic diseases in Japan. Relevant data were extracted from a hospital based birth cohort study named as Tokyo-Childrens Health, Illness and Development Study (T-CHILD) of which questionnaire conducted during pregnancy included maternal history and duration of OCP use. To identify wheeze and allergic diseases in the children, the questionnaire of the International Study of Asthma and Allergies in Childhood (ISAAC) was used. Logistic regression models were applied to estimate those association and adjustments were made for maternal history of allergy, maternal education level, maternal age at pregnancy, maternal BMI, maternal smoking during pregnancy, mode of delivery, gestational age at delivery, daycare attendance, number of previous live births, and gender of child. OCP use was associated with ever wheeze (adjusted odds ratio [aOR], 1.62, 95% confidence interval [CI], 1.10–2.40), current wheeze (aOR, 1.59, 95% CI, 1.01–2.50), ever asthma (aOR, 1.65, 95% CI, 1.02–2.65), and ever rhinitis (aOR, 1.90, 95% CI, 1.30–2.80). Compared with no prior OCP use, using OCP for more than three months statistically increased the odds of ever wheeze (P = 0.012), current wheeze (P = 0.035), and ever rhinitis (P = 0.002). Our findings suggest that maternal OCP use has a role in the development of wheeze, asthma and rhinitis in children. Extended use of OCP is likely to increase the risk of wheeze and rhinitis.