T-cell activation during exacerbations: a longitudinal study in refractory asthma (original) (raw)

Abstract

Exacerbations induce the main costs of asthma, consisting of hospital admissions and loss of working days. They alter quality of life in at risk patients, these subjects being mainly severe asthmatics. Treatment of exacerbations is based on systemic corticosteroids, inducing various adverse effects. A major challenge in severe asthma management is therefore to prevent exacerbations. However, whereas inflammation in controlled asthmatics has been widely investigated, pathophysiology of exacerbations is still largely unknown (1). Activated T helper 2 (Th2) cells are responsible for the bronchial infiltration by eosinophils, a signature of the asthmatic inflammation (2). However, bronchial hyperresponsiveness to methacholine or allergens, another hallmark of asthma, can be dissociated from the airway eosinophilia, showing that Th2 activation is not sufficient to explain the whole pathophysiology of asthma (3, 4). This could be because of non-Th2 activation present in asthmatics, and indeed several groups have reported interferon (IFN)-c-producing cells in asthmatics, both in blood and in situ (5). The importance of a T-regulatory cell (Treg) deficiency in atopic diseases has been suggested (6-8). T-regulatory cells represent small T-cell populations producing anti-inflammatory cytokines. Natural Treg cells are characterized by a high expression of the interleukin (IL)-2 receptor alpha chain CD25, among the CD4+ T-cell population. These CD4+CD25+ high cells are deficient in atopics compared to controls, particularly when they are symptomatic (7). However, data are published neither in severe asthma, nor in exacerbations so far. Whereas extensive knowledge of T-cell phenotype and activation is provided in asthmatics compared to controls, longitudinal data are missing in exacerbating patients (9). We undertook a follow-up of T-cell phenotype and activation in severe refractory asthmatics Background: Asthma exacerbations represent the main source of costs and morbidity in asthma care, and drugs specifically designed to prevent exacerbations are needed. A prerequisite is to dispose of a precise knowledge of inflammatory events leading to exacerbations. Objective: To study T-cell activation during exacerbations from severe refractory asthmatics. Methods: Proportions of blood T-cell interleukin (IL)-13, interferon-c, IL-4, IL-5, IL-10 production and of CD4+CD25+ high CD62L+CD45RO+ [T regulatory (Treg)] cells were determined by flow cytometry. Blood cytokine mRNA was studied by reverse transcription-polymerase chain reaction and the respective protein levels were determined by cytokine beads array. Depletion of Treg cells was performed to study their activation. T-cell cytokines were detected in parallel in induced sputum. Results: At baseline, T helper 2 (Th2) cells were increased in asthmatics, whereas T helper 1 (Th1) and Treg T cells were decreased. T helper 2 cells increased before exacerbations, followed by Th1 cells, in blood and induced sputum, albeit Treg cells decreased in parallel with IL-10-producing T cells. Concordant results were found at the mRNA level. The suppressive activity of Treg cells was impaired during exacerbations compared to baseline. Conclusions: New insights are given into pathophysiology of asthma exacerbations: Although at baseline T-cell activation is Th2-biased, a mixed Th1/Th2 activation occurs during exacerbations. The Treg cell deficiency found at baseline in SRA increases during exacerbations.

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References (29)

  1. * Results are expressed as the percentage of cytokine-expressing T cells upon stimulation divided by the same percentage without stimulation (mean € standard error). Comparisons between controls and B (unpaired t-test), and between E and B, BE, or AE (paired t-test).
  2. B, baseline; BE, before exacerbation; E, exacerbation; AE, after exacerbation.
  3. *P < 0.05
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