Haemopoietic mechanisms in allergic rhinitis

In the adult, haemopoietic stem cell differentiation and maturation have traditionally been thought to be restricted to the bone marrow microenvironment. However, a novel view has emerged in recent years according to which at least some haemopoietic (and non-haemopoietic) stem cells present in adult tissue may be recruited from the bone marrow, through the peripheral circulation, into mucosal tissues, becoming part of a regenerative and/or inflammatory process at ‘distal’ tissue sites. This process has been referred to as the plasticity of stem cells [1]. More specifically, haemopoietic progenitor cells have the potential not only to give rise to mature cells within the bone marrow, which can then egress into the circulation, but may themselves also egress from the bone marrow, and home to various organs and tissues under the orchestrated control of specific chemokines and cytokines. Once within the tissue, the fate of these primitive haemopoietic progenitor cells is determined by locally elaborated growth factors that permit a process termed ‘in situ haemopoiesis’ [2–5]. We provide herein an overview of the role of systemic and in situ haemopoiesis, as components of the already complex scenario of allergic inflammation within the airways in allergic rhinitis (AR) and related disorders. A considerable body of evidence now exists showing that activation of selective haemopoietic processes is not only associated with the onset and maintenance of allergic inflammation in atopic adults but also with the development of allergic diathesis in infants. Using antibodies in a haemopoietic progenitor membrane protein marker, CD34, and in haemopoietic cytokine receptors, we have demonstrated alterations relevant to eosinophil/basophil lineage commitment of progenitors in neonates at risk for atopy [6, 7]. CD34 is a stage-specific antigen, which, used in combination with small-size and low-granularity determinants, can accurately enumerate progenitor cells in cord blood, peripheral blood, bone marrow and, more recently, lung tissue and sputum by flow cytometric methodologies [8–11]. The CD34 antigen is also expressed on tissue structural cells, including fibroblasts and vascular endothelial cells, and thus caution should be exercised when enumerating progenitor cells by single-stain immunocytochemistry [12, 13]. However, the use of double-staining techniques where CD34 cells are costained with CD133, expressed by primitive haemopoietic stem and progenitor cells and retinoblastoma [14], may provide more accurate estimates of progenitor cells within human tissue. The exact role of CD34 has not yet been elucidated, although it has been suggested that it maintains stem cells in the G0 phase [15]. Properties as an adhesion ligand for L-selectin are now known to be restricted to CD34 expressed on high-vein endothelial cells in lymph nodes only and not to haemopoietic CD34 [16]. Although the expression of CD34 has recently been described on immature but not mature eosinophils [17], its role in the maturation and migrational responses of these cells remains to be clarified. This is particularly important in light of studies with CD34 knockout mouse models, in which in only one of two reports was there a down-modulation of leucocyte trafficking [18] and a reduction of numbers of myeloid progenitor cells [19]. Studies in adult subjects have shown that circulating, common progenitors of eosinophils and basophils, measured as in vitro colony-forming units (Eo/B-CFU), are detected in greater numbers in the peripheral blood of asymptomatic atopics, compared with non-atopic controls; these Eo/B-CFU are responsive to activated T cell supernatants and, specifically, to IL-5 [8, 20]. Additional studies extended these findings by showing relevant fluctuations in blood and bone marrow Eo/B-CFU in response to allergen-induced allergic inflammatory responses [21–23]. Of note, the finding that following natural allergen exposure, the numbers of circulating Eo/B-CFU were greatly reduced in symptomatic AR at the peak of a pollen season was the first indication that, during the inflammatory process, progenitor cells may home to tissue site(s) of inflammation [24–27]. In addition, the detection of locally elaborated haemopoietic growth factors and Eo/B-CFU within nasal polyps further supported the concept of in situ haemopoiesis [5, 28]. This view was strengthened by findings that: (i) CD34-immunopositive/ IL5Ra mRNA cells were detected in lung biopsies from atopic asthmatics [29]; (ii) ex vivo allergen challenge of nasal explant tissue from AR demonstrated IL-5-driven eosinophil differentiation [30]; and (iii) in mouse models of allergeninduced airway eosinophilia, increased numbers of IL-5responsive Eo/B-CFU could be grown from lung-extracted progenitors following allergen, compared with saline challenge [11]. Mouse models of AR have highlighted the multifactorial nature of this inflammatory disease, and directly implicate the role of haemopoietic processes in allergic airways disease, specifically in AR. The up-regulation of myeloid progenitors in the bone marrow after airway allergen inhalation [31, 32], and their trafficking to the airways from the marrow in several animal models of either upper or lower airways inflammation have been demonstrated [33–35]. The resultant blood, nasal and/or pulmonary eosinophilia in these models can be blocked by antibodies to IL-5 [36], or by deletion of the gene encoding IL-5 [37, 38]; eotaxin is also critical in this process [9, 39]. Rather than demonstrating a complete ablation of the allergic inflammatory response in the nose, IL-5-deficient mice develop delayed nasal symptoms and basophilic, rather than eosinophilic, inflammation within the nasal mucosa [32, 33]. Haemopoietic cytokine redundancy among IL-3, IL-5 and granulocyte macrophage-colony stimulating factor is thought to ensure adequate production Clin Exp Allergy 2005; 35:1–3 doi:10.1111/j.1365-2222.2005.02140.x