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Evaluating impact in pulmonary rehabilitation
S114 Adaptive and Innate-Like T Cell Phenotypes in Asthma in Relationship to Compartment and Severity
  1. TSC Hinks1,
  2. KJ Staples1,
  3. C Smith1,
  4. J Ward1,
  5. S Mansour1,
  6. P Monk2,
  7. PH Howarth1,
  8. HW Virgin3,
  9. S Gadola1,
  10. R Djukanovic1
  1. 1Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton School of Medicine, Southampton, UK
  2. 2Synairgen Research Ltd, Mail Point 810, Southampton General Hospital, Southampton, UK
  3. 3Department of Pathology and Immunology, Washington University School of Medicine, St Louis, USA

Abstract

Introduction and Objectives Asthma is a heterogeneous disease affecting 150–300 million people. Underlying mechanisms remain unclear. TH17 cells expressing interleukin-17 are widely hypothesised to play a role, particularly in severe neutrophilic asthma. Mucosal associated invariant T (MAIT) cells are novel innate-like T-cells of unknown function which express CD161 and an invariant TCRα chain (Vα7.2-Jα33) and recognise the highly conserved restriction molecule MR1.

We undertook to analyse IL-17 and key T-cell subsets, namely TH17, TH1, TH2, TREG, and MAIT cells in relation to asthma severity and virus-induced exacerbations.

Methods Cross sectional study: 76 subjects underwent detailed phenotyping, sputum induction, phlebotomy, and bronchoscopy. Samples were analysed by 9-colour flow-cytometry, RT-PCR, multiplex ELISA, microarray, and deep sequencing of the airway microbiome. Longitudinal study: 35 frequently exacerbating asthmatics: followed at 7 time-points during a naturally occurring cold.

Results Contrary to initial hypotheses TH17 cell frequencies did not differ between health and any asthmatic phenotype, in any tissue compartment. TH2 cell frequencies were elevated in asthma in bronchoalveolar-lavage (BAL) (ANOVA p=0.041) and markedly in bronchial biopsies (p=0.048), as expected[1]. BAL TH1 cell frequencies were also increased in asthma (p=0.01) as described[2], whilst TREG frequencies were lower in severe asthma (p=0.019).

TH2 cytokines were increased in asthma in sputum (IL-5 p=0.005) and BAL (IL-5 p<0.0001, IL-13 p=0.017), but IL-17 was elevated only in BAL in steroid-naive, mild asthmatics (ANOVA p=0.04) who were older (p=0.039).

Longitudinal follow-up revealed no significant differences in T-cell frequencies during exacerbations, though sputum TH17 cells tended to increase (NS).

We observed that frequencies of Vα7.2+CD161+ (MAIT) cells in blood are lower in asthma than in health (p=0.013), and correlated with severity in blood (p for linear trend <0.0001), and sputum (p=0.018, Figure 1). This deficiency is specific to MAIT cells, and is not related to age or inhaled steroid therapy.

Conclusions A role for TH17 cells in asthma, particularly severe neutrophilic disease has been widely hypothesised, but is not supported by these data. High BAL IL-17 levels in older, steroid-naive, mild asthmatics may have a different cellular source. We describe a novel finding of deficient Vα7.2+CD161+ (MAIT) cells in severe asthma.

References

  1. Robinson, DS, et al., Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med, 1992. 326(5): p. 298–304.

  2. Krug, N, et al., T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma. Am J Respir Cell Mol Biol, 1996. 14(4): p. 319–26.

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