title: Allergen-induced fluctuation in CC chemokine receptor 3 expression on bone marrow CD34+ cells from asthmatic subjects: significance for mobilization of haemopoietic progenitor cells in allergic inflammation.
abstract: There is increasing evidence that primitive progenitors migrate from the bone marrow (BM) via the peripheral circulation to tissue sites where they undergo in situ differentiation to provide a continued source of effector cells, such as eosinophils, during an allergic inflammatory response. To study mechanisms of progenitor cell mobilization in allergic reactions, we investigated fluctuations in the expression of the eotaxin receptor, CC chemokine receptor 3 (CCR3), on CD34+ cells from stable asthmatics following allergen (i.e. antigen) challenge. BM aspirates were taken from seven early responder (ER) and 10 dual responder (DR) asthmatics who, following antigen challenge developed only an early bronchoconstrictor response and an early and late- bronchoconstrictor response, respectively. Expression of CCR3 was detected on primitive (CD34+ cells) and eosinophil-lineage committed progenitors (CD34+ interleukin-5 receptor alpha-subunit+ cells) by flow cytometry and confirmed by co-localization of CCR3 messenger RNA to CD34 immunopositive cells using in situ hybridization. When preantigen levels were compared to 24-hr postantigen levels, significant increases in BM CD34+ CCR3+ cells were detected in DR, who also developed a significant sputum and blood eosinophilia and increased methacholine airway responsiveness. In contrast, a significant attenuation of BM CD34+ CCR3+ cells was observed in ER. In a dose-dependent manner eotaxin, but not interleukin (IL)-5, stimulated CD34+ progenitor cell migration in vitro. This migrational response to eotaxin was abrogated by anti-CCR3 monoclonal antibody and primed by preincubation with IL-5. We propose that fluctuations in CCR3 expression on human BM CD34+ cells may facilitate chemokine-mediated progenitor cell mobilization to the peripheral circulation and the resultant development of pulmonary eosinophilia, a cardinal feature of asthma.
authors.affiliation: Firestone Institute of Respiratory Health, Asthma Research Group, St. Joseph's Healthcare, Divisions of Clinical Immunology, McMaster University, Hamilton, Ontario, Canada. sehmir@mcmaster.ca
authors.forename: Roma
authors.initials: R
authors.lastname: Sehmi
authors.forename: Sandra
authors.initials: S
authors.lastname: Dorman
authors.forename: Adrian
authors.initials: A
authors.lastname: Baatjes
authors.forename: Rick
authors.initials: R
authors.lastname: Watson
authors.forename: Ronan
authors.initials: R
authors.lastname: Foley
authors.forename: Sun
authors.initials: S
authors.lastname: Ying
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Robinson
authors.forename: A Barry
authors.initials: AB
authors.lastname: Kay
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Byrne
authors.forename: Judah A
authors.initials: JA
authors.lastname: Denburg
mesh_terms: D000328:Adult; D000485:Allergens / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D018952:Antigens, CD34 / Q000276:immunology*; D001249:Asthma / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000276:immunology; D003114:Colony-Forming Units Assay / Q000379:methods; D004804:Eosinophils / Q000276:immunology; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods; D015848:Interleukin-5 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000276:immunology*
chemical_list: D000485:Allergens; D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D015848:Interleukin-5; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019707:Receptors, Chemokine