Delayed eosinophil programmed cell death in vitro: A common feature of inhalant allergy and extrinsic and intrinsic atopic dermatitis,☆☆,,★★

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Abstract

The present studies were undertaken to characterize the potential role of eosinophil programmed cell death (PCD) in atopic diseases. Peripheral blood eosinophil PCD was found to be delayed in inhalant allergy (p < 0.05) and delayed to an even greater extent in atopic dermatitis (AD) (p < 0.0001) when compared to nonatopic subjects. There was no difference in the occurrence of PCD between the extrinsic and the intrinsic type of AD, pointing to a secondary role of specific sensitization. Blockade of eosinophil PCD was not responsible for peripheral blood eosinophilia, because we found no obvious relationship of eosinophil survival to blood eosinophil count. Eosinophil supernatants of more patients with AD than of patients with inhalant allergy dose-dependently inhibited PCD in nonatopic eosinophils, and it was shown that this effect was possibly due to autocrine production of granulocyte-macrophage–colony stimulating factor, probably IL-5. Eosinophil expression of CD95 (Fas antigen) did not change over time in culture and was not modulated by cytokines prolonging eosinophil survival. In contrast, IL-3, IL-5, and granulocyte-macrophage–colony stimulating factor caused an upregulated expression of CD69. However, in AD, CD69 on eosinophils was upregulated without the need of exogenous growth factor or factors over time in culture, thus confirming an autocrine production of proeosinophilic cytokines. In conclusion, our data clearly indicate that eosinophil PCD is markedly delayed in the so-called atopic diseases irrespective of allergen sensitization and suggest that this effect is mediated by the autocrine production of growth factors by eosinophils. (J Allergy Clin Immunol 1997;100:536-43.)

Section snippets

Reagents

Human recombinant GM-CSF (6.85 × 108 U/mg), IL-3 (6.9 × 107 U/mg), and IL-5 (4 × 107 U/mg) were obtained from Genzyme (Cambridge, Mass.). Before testing, all stimulating reagents were diluted in control medium (Hanks balanced salt solution [HBSS] containing 1 mg/ml bovine serum albumin). Dynabeads M-450 sheep anti-mouse IgG were purchased from Dynal A.S. (Oslo, Norway). All monoclonal antibodies were purchased from Immunotech (Marseille, France) except for CD69, which was from Becton Dickinson

Eosinophil count and total IgE level

Patients with AD (mean eosinophil count ± SEM was 16.7 ± 1.7% in ADe type and 10.4 ± 2.5% in ADi) and IA (eosinophil count, 17.6 ± 2.7%) did not show increased absolute eosinophil numbers when compared to NA volunteers (eosinophil count, 14.2 ± 1.6%).

In contrast, total IgE levels were significantly higher in patients with ADe (geometric mean, 2989.5 kU/L) as compared to NA subjects (15.5 kU/L) (p < 0.0001), patients with IA (286.6 kU/L) (p < 0.05), and patients with ADi (22.2 kU/L) (p < 0.005).

Effect of culture on eosinophil viability

Discussion

The data presented clearly demonstrate by qualitative and quantitative assays that PCD is significantly delayed in eosinophils of subjects with IA and particularly in those with AD, as compared to NA controls. Furthermore, the results suggest that delayed PCD may be mediated at least in part by an autocrine production of GM-CSF and probably of IL-5.

The demonstrated survival rates of eosinophils from NA subjects in culture are consistent with published work showing low viability in healthy

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      In vitro and in vivo eosinophil apoptosis is delayed by cytokines such as interleukin-5 and granulocyte-macrophage colony-stimulating factor and enhanced by glucocorticoids and death receptors i.e. Fas [2–4]. We, and others, have previously shown that eosinophil apoptosis is delayed in patients with asthma or inhalant allergy [7–9]. Bronchoconstriction in asthma or COPD is commonly relieved with β2-agonists.

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    From the Department of Dermatology, Hannover Medical School, Hannover.

    ☆☆

    Supported by research grant We-1912/1-1 and Ka-578/7-1 from the Deutsche Forschungsgemeinschaft.

    Reprint requests: Bettina Wedi, MD, Department of Dermatology, Hannover Medical School, Ricklinger Str. 5, D-30449 Hannover, Germany.

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