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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]

Focuses on the role of the bone marrow in providing an ongoing source of differentiating inflammatory cells to the upper and lower airways. Relationship between rhinitis and asthma; Sensitivity of a systemic hemopoietic process to inhaled corticosteroids; Production of growth factors.

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]

The development of FcR∊-bearing histamine-containing basophilic cells was studied in cultures of peripheral blood leucocytes and bone marrow leucocytes from normal individuals. The determination of basophilic cells was performed blindly. Before cultivation there were fairly similar numbers of basophilic cells in the samples from the three different sources (1.6 ± 1.6 n= 13; 1.4 ± 2.0 n=21; 4.3 ± 4.7 n =8, respectively). During cultivation, spontaneously appearing large blast-like basophilic cells were seen in good correspondence with a formation of histamine in the cultures (Spearman rank correlation coefficient = 0.9135, n = 13. P < 0.001). This was more accentuated with bone marrow cells than with peripheral blood and cord blood cells. Conditioned medium (CM) was prepared from cells isolated from various tissues and stimulated by different means, e.g. peripheral blood from atopic individuals stimulated with allergen and unstimulated tonsil cells. Addition of the CM resulted in increased development of histamine-containing basophilic cells. Optimum stimulation was achieved with 10% CM. The basophilic stimulation by CM, as assessed as indices vs. unstimulated cultures, was more accentuated in cultures of peripheral blood cells than of bone marrow and cord blood cells (2.8 ± 1.2; 1.8 ± 0.5; 2.0 ± 0.4, respectively). In contrast, the histamine formation was particularly evident in stimulated cultures of bone marrow cells, where more than four-fold increases of histamine were found. In bone marrow cells the histamine levels per basophilic cell also increased, whereas this was not the case in cord blood cells. A pronounced development of basophilic cells was achieved when using leukoagglutinin, provided the mitogen in the CM was eliminated. The formation of basophilic cells was prevented with mitomycin c and cycloheximide. in conclusion, the system described may provide important information on the development of histamine-containing basophilic cells at various maturation stages from different compartments, and mechanisms in a developing atopic disease. [ABSTRACT FROM AUTHOR]