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The immunopathology of extrinsic (atopic) and intrinsic (non-atopic) asthma: more similarities than differences

Abstract Intrinsic asthma shows no clinical or serological evidence of IgE-mediated allergy to common environmental agents. Similar to extrinsic asthma, bronchial biopsies from such patients show enhanced expression of Th2-type cytokines, CC chemokines and Iϵ/Cϵ compared with controls. These findings suggest there might be local IgE production directed against unknown antigens, possibly of viral origin or even autoantigens, in this important clinically distinct variant of the disease.

Fel d 1-derived T cell peptide therapy induces recruitment of CD4+CD25+; CD4+ interferon-γ+ T helper type 1 cells to sites of allergen-induced late-phase skin reactions in cat-allergic subjects

Background Specific immunotherapy with whole allergen extracts is associated with local accumulation of IFN‐γ+ and CD25+ cells indicating recruitment of activated T‐helper type 1 (Th1) and/or T regulatory cells. We have studied allergen‐induced, late‐phase skin biopsies before and after T cell peptide therapy for evidence of alterations in the pattern of local recruitment of Th1, T‐helper type 2 (Th2) and T regulatory cells.

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

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+u2003CCR3+ 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+u2003CCR3+ 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.

Molecular concepts of IgE-initiated inflammation in atopic and nonatopic asthma

Atopic and nonatopic (intrinsic) asthmatics were characterized by a broadly conserved bronchial mucosal proeosinophilic cytokine network in which IL-5 appears to play a key role. Inappropriate IgE-mediated mechanisms may occur in asthma, irrespective of its atopic status, as suggested by elevated serum IgE concentrations and bronchial mucosal expression of FcepsilonRI, IL-4, IL-13, Iepsilon, and Cepsilon. In general, these observations support the concept that these subtypes of asthma, despite showing distinct clinical and biologic features, share many common immunopathologic mechanisms. The most promising future directions of research regarding intrinsic asthma concern the possible identification of novel allergens or antigens, the detailed description of local bronchial mucosal IgE production, and the understanding of a possible macrophage dysfunction. Furthermore, a role for infectious (viral?) or autoimmune processes has yet to be firmly identified in intrinsic asthma. Animal models may also help us to understand the role of IgE and atopy in asthma. Although these are largely IgE-mediated mechanisms, allergen-induced bronchial hyperresponsiveness and eosinophilic inflammation can also occur in the absence of IgE (null mutation of the Cepsilon locus), as shown in a mouse model of hypersensitivity to Aspergillus fumigatus (57). Thus, despite the absence of atopy, IgE-mediated mechanisms may operate in intrinsic asthma (Fig. 1).

Increases in eotaxin-positive cells in induced sputum from atopic asthmatic subjects after inhalational allergen challenge

Background: Eosinophils are believed to be critical proinflammatory cells in airway mucosal damage in asthma. Eotaxin is a C‐C chemokine with selective activity for eosinophils and basophils. Previous studies have shown increased expression of eotaxin in the airways of asthmatics at baseline. We aimed to investigate eotaxin expression during the late‐phase reaction to allergen inhalation in atopic asthmatics.

Effects of rapamycin, cyclosporin A, and dexamethasone on interleukin 5-induced eosinophil degranulation and prolonged survival

Interleukin‐5 (IL‐5) enhances eosinophil degranulation and prolongs eosinophil survival. Rapamycin, cyclosporin A, and dexamethasone have been shown to influence either cytokine transcription, cytokine‐mediated signalling, or degranulation by granulocytes. The study aimed to determine whether these agents inhibited IL‐5‐enhanced eosinophil survival or degranulation. Peripheral blood eosinophils were isolated from atopic subjects. The effects of serial dilutions (10−6‐10−9 M) of these drugs or vehicle control on 1) the viability of eosinophils cultured (1–5 days) in the presence and absence of recombinant human IL‐5, as measured by propidium iodide staining and flow cytometry, and 2) degranulation of eosinophils preincubated (45 min) with rhIL‐5 or medium control, as measured by eosinophil cationic protein (ECP) release after stimulation with serum‐coated Sephadex beads, were assessed. Dexamethasone and rapamycin produced significant, concentration‐dependent inhibition of IL‐5‐enhanced eosinophil survival at pharmacologic concentrations, whereas cyclosporin A did not. Prior incubation of eosinophils with IL‐5, as compared with medium control, significantly enhanced ECP release by eosinophils on subsequent exposure to serum‐coated Sephadex beads. Cyclosporin A and rapamycin significantly inhibited IL‐5‐enhanced ECP release in a concentration‐dependent fashion, whereas dexamethasone did not. All three drugs had no significant effect on eosinophil survival and degranulation in the absence of IL‐5. Our results suggest that immunosuppressive drugs may inhibit IL‐5‐mediated mechanisms in eosinophils which result in enhanced survival and release of granule contents. These findings may be relevant to the further development of therapeutic strategies in allergic diseases.

Expression of eotaxin in induced sputum of atopic and nonatopic asthmatics

Background:u2002The chemokine eotaxin has been implicated in airway eosinophilia in atopic asthma. We have compared airway eosinophils and eotaxin expression in induced sputum from well‐matched atopic and nonatopic asthmatics.

Mechanisms of T Cell Peptide Epitope-Dependent Late Asthmatic Reactions

Short peptide sequences corresponding to T cell epitopes have been identified in the major cat allergen Fel d 1. In order to directly activate allergen-specific T cells in cat-allergic asthmatic individuals, peptides were administered by intradermal injection. Subsequently, a proportion of subjects experienced a delayed reduction of airway calibre manifested as a decrease in FEV1. Changes in lung function occurred approximately 3 h after peptide injection, peaked at 6 h and resembled an isolated late asthmatic reaction (LAR). Using molecular tissue typing techniques, it was determined that many of the individuals experiencing isolated LAR expressed particular HLA-DR molecules. These molecules were shown in subsequent experiments to bind individual peptides within the preparation and thus to activate T cells in a major histocompatibility complex (MHC)-restricted fashion. The precise mechanisms whereby MHC-restricted activation of allergen-specific T cells gives rise to bronchoconstriction are currently under investigation.