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Summary Rhinitis and asthma are linked closely epidemiologically, as has been known for quite some time and emphasized in recent surveys (ISAAC study). Patients with seasonal allergic rhinitis without asthma symptoms can, as a group, be shown to have increased bronchial hyperresponsiveness. During the course of seasonal allergen exposure, patients with allergic rhinitis can be shown to have increased numbers of inflammatory cells (eosinophils and mast cells) in the lower airways, even without symptoms of lower airway disease. Long-standing observations from our laboratory have indicated fluctuations of eosinophil/basophil (Eo-B) progenitors in the peripheral blood in patients with seasonal allergic rhinitis, paralleling changes that are recognized in mature eosinophils and basophils in circulation. The finding of Eo-B progenitor decreases during the height of seasonal allergen exposure led us to hypothesize the concept of ‘in situ haemopoiesis’ to explain a process of systemic activation of haemopoietic mechanisms, in which communication among bone marrow peripheral blood and airway tissue compartments contributed to the allergic inflammatory process at a systemic level. Indeed, allergen challenge to the lower airways in atopic asthmatics elicits an immediate rise in Eo-B progenitors, especially in subjects with late phase responses. These original observations have been buttressed by a series of investigations demonstrating conclusively that exacerbations of asthma are attended by increases in peripheral blood Eo-B progenitors; that allergen challenge to dogs or mice with allergic airways inflammation elicits bone marrow progenitor responses, with trafficking of bone marrow cells to the airway either in pure upper or lower airway disease; and that allergen challenge to atopic asthmatics up-regulates the high affinity receptor for IL-5 on bone marrow progenitors (IL-5Rα), beginning a process of eosinophil differentiation that is probably driven by the release of a serum haemopoietic factor – as we have found in the canine model – which acts on the bone marrow and initiates a series of systemic events. [ABSTRACT FROM AUTHOR]

This article focuses on basophil mast cell and eosinophil growth and differentiation factors in human allergic disease. The synergistic action of cytokines and the involvement of tissue micro-environments, including factors from fibroblasts, endothelial cells and epithelial cells, appear to be important determinants of both the numbers of effector cells, as well as their phenotype and heterogeneity in various tissues such as the nasal mucosa, lung, gastrointestinal tract and skin. It is tempting to speculate that the genetic underpinnings of the allergic diathesis involve basic defects in epithelial, endothelial or other micro-environmental controls, for classical and lineage-specific haemopoietic, and/or pro-inflammatory cytokine production.

Haemopoietic myeloid progenitors contribute to the ongoing recruitment of pro-inflammatory cells, such as eosinophils and basophils (Eo/B), to target tissue sites in allergic diseases. It is apparent that the development of allergic inflammation is critically dependent on the ability of the bone marrow to support the proliferation, differentiation and mobilization of haemopoietic progenitors. The haemopoietic inductive microenvironment in the bone marrow is crucial for providing signals necessary for maintenance of progenitor populations at varying stages of lineage commitment and permitting these cells to circulate in the bloodstream. Progenitors demonstrate responsiveness to specific cytokines, which varies with stage of differentiation. Pro-inflammatory signals, Th2 cytokines in particular, generated following allergen challenge, can impact on haemopoietic progenitor differentiation and mobilization, leading to accelerated Eo/B production. Allergen inhalation by allergic asthmatics induces a time-dependent change in cytokine levels within the bone marrow compartment, influencing differentiation of Eo/B progenitors, as evidenced by the relationship between increased bone marrow IL-5 levels and Eo/B production. It is proposed that inhaled allergen induces trafficking of IL-5-producing T lymphocytes to the bone marrow, further promoting eosinophilopoiesis through IL-5R signalling. In this manner, Th2 lymphocyte trafficking from the airway may regulate events occurring in the bone marrow. Negative regulators of Eo/B differentiation, including Th1 cytokines, may prove to be important for restoring homeostasis. Eo/B progenitors are also altered in cord blood of infants at risk of atopy and asthma, offering a potential biomarker for, and raising the possibility that Eo/B progenitors are directly involved in the development of allergic disease. For example, changes in the expression of haemopoietic cytokine receptors on cord blood progenitor cells are associated with maternal allergic sensitization, atopic risk and its development, suggesting that haemopoietic processes underlying the allergic phenotype may begin to evolve in the perinatal period. [ABSTRACT FROM AUTHOR]

Recent candidate gene and genome-wide association studies have identified 'protective' associations between the single-nucleotide polymorphism (SNP) rs1837253 in the TSLP gene and risk for allergy, asthma, and airway hyperresponsiveness. The absence of linkage disequilibrium of rs1837253 with other SNPs in the region suggests it is likely a causal polymorphism for these associations, having functional consequences. We hypothesized that rs1837253 genotype would influence TSLP secretion from mucosal surfaces. We therefore evaluated the secretion of TSLP protein from primary nasal epithelial cells (NECs) of atopic and nonatopic individuals and its association with rs1837253 genotype. We found that although atopic sensitization does not affect the secretion of TSLP from NECs, there was decreased TSLP secretion in NECs obtained from heterozygous (CT; 1.8-fold) and homozygous minor allele (TT; 2.5-fold) individuals, as compared with NECs from homozygous major allele individuals (CC; P<0.05), after double-stranded RNA (dsRNA) stimulation (50 μg ml−1). Our novel results show that rs1837253 polymorphism may be directly involved in the regulation of TSLP secretion. This may help explain the protective association of this genetic variant with asthma and related traits. Identifying functional consequences of SNPs in genes with previously reported clinical associations is critical in understanding and targeting allergic inflammation. [ABSTRACT FROM AUTHOR]

Background Hematopoietic progenitor cells, especially those committed to the Eo/ B lineage, are known to contribute to allergic inflammation. Objective The aim of the present study was to investigate whether environmental factors are associated with changes in numbers of circulating Eo/ B progenitors at 1 year of age. Methods Peripheral blood from 60 1-year-old children enrolled in the LINA (Lifestyle and environmental factors and their Influence on Newborns Allergy risk) birth cohort was assessed for Eo/ B progenitor cells ( Eo/ B CFU) using standardized and validated methylcellulose assays. Frozen peripheral blood mononuclear cells ( PBMC) were cultured in the presence of IL-3, IL-5 or GM- CSF, and Eo/ B CFUs enumerated. Clinical outcomes and exposure to environmental tobacco smoke ( ETS) were documented by standardized questionnaires, and indoor volatile organic compound ( VOC) concentrations were assessed by passive sampling. Results Children with skin manifestations (atopic dermatitis or cradle cap) within the first year of life had higher numbers of circulating IL-3-, IL-5- or GM- CSF-stimulated Eo/ B CFUs ( P < 0.05) at 1 year. In children with cradle cap, a positive correlation was found between Eo/ B CFUs and exposure to ETS-related VOCs during pregnancy or at 1 year of age ( P < 0.05). Conclusions and Clinical Relevance This is the first demonstration that environmental exposures are positively associated with levels of circulating Eo/ B progenitors. The recruitment and differentiation of Eo/ B progenitors in response to environmental triggers may play a role in the development of skin manifestations during the first year of life. [ABSTRACT FROM AUTHOR]

Allergic rhinitis is a major chronic respiratory disease because of its prevalence, impacts on quality of life and work/school performance, economic burden, and links with asthma. Family doctors (also known as ‘primary care physicians’ or ‘general practitioners’) play a major role in the management of allergic rhinitis as they make the diagnosis, start the treatment, give the relevant information, and monitor most of the patients. Disease management that follows evidence-based practice guidelines yields better patient results, but such guidelines are often complicated and may recommend the use of resources not available in the family practice setting. A joint expert panel of the World Organization of Family Doctors (Wonca), the International Primary Care Airways Group (IPAG) and the International Primary Care Respiratory Group (IPCRG), offers support to family doctors worldwide by distilling the globally accepted, evidence-based recommendations from the Allergic Rhinitis and its Impact on Asthma (ARIA) initiative into this brief reference guide. This guide provides tools intended to supplement a thorough history taking and the clinician’s professional judgment in order to provide the best possible care for patients with allergic rhinitis. A diagnostic Questionnaire specifically focuses the physician’s attention on key symptoms and markers of the disease. When questionnaire responses suggest a diagnosis of allergic rhinitis, a Diagnosis Guide and a simple flowchart then lead the clinician through a series of investigations commonly available in primary care to support the diagnosis. In addition, key aspects of differential diagnosis are illuminated. According to ARIA, allergic rhinitis may be classified as Intermittent or Persistent, and as Mild or Moderate/Severe. The classification of rhinitis determines the treatment necessary, as set out in an ARIA flowchart included in this guide. The guide also includes information about the strength of evidence for efficacy of certain rhinitis treatments, a brief discussion of pediatric aspects, and a glossary of allergic rhinitis medications to assist the clinician in making medication choices for each individual patient. Finally, many patients with allergic rhinitis also have concomitant asthma, and this must be checked. The World Organization of Family Doctors has been delegated by WHO as the group that will be taking primary responsibility for education about chronic respiratory diseases among primary care physicians globally. This document will be a major resource in this educational program. [ABSTRACT FROM AUTHOR]