Innate and adaptive T cells in asthmatic patients: Relationship to severity and disease mechanisms

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:136

Article

Hinks, Timothy S. C.^1,2  Zhou, Xiaoying¹  Staples, Karl J.¹  Dimitrov, Borislav D.^2,3  Manta, Alexander⁴  Petrossian, Tanya⁵  Lum, Pek Y.⁵  Smith, Caroline G.³  Ward, Jon A.^1,2  Howarth, Peter H.^1,2  Walls, Andrew F.¹  Gadola, Stephan D.^1,6  Djukanovic, Ratko^1,2 

[1] Univ Southampton, Fac Med, Sir Henry Wellcome Labs, Clin & Expt Sci, Southampton SO16 6YD, Hants, England

[2] Univ Southampton, Fac Med, Southampton Univ Hosp, NIHR Southampton Resp Biomed Res Unit, Southampton SO16 6YD, Hants, England

[3] Univ Southampton, Fac Med, Southampton Univ Hosp, Primary Care & Populat Sci, Southampton SO16 6YD, Hants, England

[4] MantaMat UG, Geretsried, England

[5] Ayasdi, Palo Alto, CA USA

[6] Novartis, Novartis Inst Biomed Res, Basel, Switzerland

关键词: Asthma;    T lymphocytes;    cytokines;    mast cells;    phenotype;    endotype;    regulatory T;    T(H)17;    T(H)2;    mucosal-associated invariant T-cell;   

DOI  :  10.1016/j.jaci.2015.01.014

来源: Elsevier

【 摘 要 】

Background: Asthma is a chronic inflammatory disease involving diverse cells and mediators whose interconnectivity and relationships to asthma severity are unclear. Objective: We performed a comprehensive assessment of T(H)17 cells, regulatory T cells, mucosal-associated invariant T (MAIT) cells, other T-cell subsets, and granulocyte mediators in asthmatic patients. Methods: Sixty patients with mild-to-severe asthma and 24 control subjects underwent detailed clinical assessment and provided induced sputum, endobronchial biopsy, bronchoalveolar lavage, and blood samples. Adaptive and invariant T-cell subsets, cytokines, mast cells, and basophil mediators were analyzed. Results: Significant heterogeneity of T-cell phenotypes was observed, with levels of IL-13-secreting T cells and type 2 cytokines increased at some, but not all, asthma severities. T(H)17 cells and gamma d-17 cells, proposed drivers of neutrophilic inflammation, were not strongly associated with asthma, even in severe neutrophilic forms. MAIT cell frequencies were strikingly reduced in both blood and lung tissue in relation to corticosteroid therapy and vitamin D levels, especially in patients with severe asthma in whom bronchoalveolar lavage regulatory T-cell numbers were also reduced. Bayesian network analysis identified complex relationships between pathobiologic and clinical parameters. Topological data analysis identified 6 novel clusters that are associated with diverse underlying disease mechanisms, with increased mast cell mediator levels in patients with severe asthma both in its atopic (type 2 cytokine-high) and nonatopic forms. Conclusion: The evidence for a role for T(H)17 cells in patients with severe asthma is limited. Severe asthma is associated with a striking deficiency of MAIT cells and high mast cell mediator levels. This study provides proof of concept for disease mechanistic networks in asthmatic patients with clusters that could inform the development of new therapies.

【 授权许可】

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