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Multidimensional endotypes of asthma: topological data analysis of cross-sectional clinical, pathological, and immunological data

Multidimensional endotypes of asthma: topological data analysis of cross-sectional clinical, pathological, and immunological data
Multidimensional endotypes of asthma: topological data analysis of cross-sectional clinical, pathological, and immunological data
Background: Incomplete understanding of mechanisms and clinicopathobiological heterogeneity in asthma hinders research progress. Pathogenic roles for T-helper-type 17 (Th17) cells and invariant T cells implied by murine data have yet to be assessed in man. We aimed to investigate the role of Th17 and mucosal associated invariant T (MAIT) cells in airway inflammation; to characterise associations between diverse clinical and immunological features of asthma; and to identify novel multidimensional asthma endotypes.

Methods: In this single-centre, cross-sectional observational study in the UK, we assessed volunteers with mild-to-severe asthma and healthy non-atopic controls using clinical and physiological assessment and immunological sampling of blood, induced sputum, endobronchial biopsy, and bronchoalveolar lavage for flow cytometry and multiplex-electrochemiluminescence assays. Primary outcomes were changes in frequencies of Th17 and MAIT cells between health and asthma using Mann-Whitney U tests and the Jonckheere-Terpstra test (linear trend across ranked groups). The study had 80% power to detect 60% differences in T-cell frequencies at p<0·05. Bayesian Network Analysis (BNA) was used to explore associations between parameters. Topological Data Analysis (TDA) was used to identify multidimensional endotypes. The study had local research ethics approval. All participants provided informed consent.

Findings: Participants were 84 male and female volunteers (60 with mild-to-severe asthma and 24 healthy, non-atopic controls) aged 18–70 years recruited from clinics and research cohorts. Th17 cells and ??17 cells were not associated with asthma, even in severe neutrophilic forms. MAIT-cell frequencies were strikingly reduced in asthma compared with health (median frequency in blood 0·9% of CD3+ cells [IQR 0·3–1·8] in asthma vs 1·6 [1·2–2·6] in health, p=0·005; in sputum 1·1 [0·7–2·0] vs 1·8 [1·6–2·3], p=0·002; and in biopsy samples 1·3 [0·7–2·3] vs 3·9% [1·3–5·3%], p=0·02), especially in severe asthma where BAL regulatory T cells were also reduced compared with those in health (4·4, 3·1–6·1, vs 8·1, 5·6–10; p=0·02). BNA and TDA identified six novel clinicopathobiological clusters of underlying disease mechanisms, with elevated mast cell mediators tryptase (p<0·0001), chymase (p=0·02), and carboxypeptidase A3 (p=0·02) in severe asthma.

Interpretation: This study suggests that Th17 cells do not have a major pathogenic role in human asthma. We describe a novel deficiency of MAIT cells in severe asthma. We also provide proof of concept for application of TDA to identification of multidimensional clinicopathobiological endotypes. Endotypes will require validation in further cohorts.
0140-6736
S42
Hinks, Timothy
97bf168b-fd21-4e42-a4cf-34f85abe9e74
Zhou, Xiaoying
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Staples, Karl
e0e9d80f-0aed-435f-bd75-0c8818491fee
Dimitrov, Borislav
366d715f-ffd9-45a1-8415-65de5488472f
Manta, Alexander
2e91eac1-1d67-44ab-b3c1-0b47fa95bf93
Petrossian, Tanya
b52cc87c-f889-4c8b-8d71-7947e58158e9
Lum, Pek
eb5ce5d1-2523-48cf-a219-a76954db6946
Smith, Caroline
c53cf3b5-c529-48a9-aa7a-f983b28c8ce8
Ward, Jon
a8107b98-069d-4263-bd70-d29d79f07edc
Howarth, Peter
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Walls, Andrew
aaa7e455-0562-4b4c-94f5-ec29c74b1bfe
Gadola, Stephan D.
4564bcf6-21ab-45e4-9c29-c6fd81b146b0
Djukanović, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Hinks, Timothy
97bf168b-fd21-4e42-a4cf-34f85abe9e74
Zhou, Xiaoying
84558a96-3129-44de-b295-869d9ee4d19f
Staples, Karl
e0e9d80f-0aed-435f-bd75-0c8818491fee
Dimitrov, Borislav
366d715f-ffd9-45a1-8415-65de5488472f
Manta, Alexander
2e91eac1-1d67-44ab-b3c1-0b47fa95bf93
Petrossian, Tanya
b52cc87c-f889-4c8b-8d71-7947e58158e9
Lum, Pek
eb5ce5d1-2523-48cf-a219-a76954db6946
Smith, Caroline
c53cf3b5-c529-48a9-aa7a-f983b28c8ce8
Ward, Jon
a8107b98-069d-4263-bd70-d29d79f07edc
Howarth, Peter
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Walls, Andrew
aaa7e455-0562-4b4c-94f5-ec29c74b1bfe
Gadola, Stephan D.
4564bcf6-21ab-45e4-9c29-c6fd81b146b0
Djukanović, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d

Hinks, Timothy, Zhou, Xiaoying, Staples, Karl, Dimitrov, Borislav, Manta, Alexander, Petrossian, Tanya, Lum, Pek, Smith, Caroline, Ward, Jon, Howarth, Peter, Walls, Andrew, Gadola, Stephan D. and Djukanović, Ratko (2015) Multidimensional endotypes of asthma: topological data analysis of cross-sectional clinical, pathological, and immunological data. [in special issue: Spring Meeting for Clinician Scientists in Training 2015] The Lancet, 385 (Supplement 1), supplement 1, S42. (doi:10.1016/S0140-6736(15)60357-9). (PMID:26312864)

Record type: Article

Abstract

Background: Incomplete understanding of mechanisms and clinicopathobiological heterogeneity in asthma hinders research progress. Pathogenic roles for T-helper-type 17 (Th17) cells and invariant T cells implied by murine data have yet to be assessed in man. We aimed to investigate the role of Th17 and mucosal associated invariant T (MAIT) cells in airway inflammation; to characterise associations between diverse clinical and immunological features of asthma; and to identify novel multidimensional asthma endotypes.

Methods: In this single-centre, cross-sectional observational study in the UK, we assessed volunteers with mild-to-severe asthma and healthy non-atopic controls using clinical and physiological assessment and immunological sampling of blood, induced sputum, endobronchial biopsy, and bronchoalveolar lavage for flow cytometry and multiplex-electrochemiluminescence assays. Primary outcomes were changes in frequencies of Th17 and MAIT cells between health and asthma using Mann-Whitney U tests and the Jonckheere-Terpstra test (linear trend across ranked groups). The study had 80% power to detect 60% differences in T-cell frequencies at p<0·05. Bayesian Network Analysis (BNA) was used to explore associations between parameters. Topological Data Analysis (TDA) was used to identify multidimensional endotypes. The study had local research ethics approval. All participants provided informed consent.

Findings: Participants were 84 male and female volunteers (60 with mild-to-severe asthma and 24 healthy, non-atopic controls) aged 18–70 years recruited from clinics and research cohorts. Th17 cells and ??17 cells were not associated with asthma, even in severe neutrophilic forms. MAIT-cell frequencies were strikingly reduced in asthma compared with health (median frequency in blood 0·9% of CD3+ cells [IQR 0·3–1·8] in asthma vs 1·6 [1·2–2·6] in health, p=0·005; in sputum 1·1 [0·7–2·0] vs 1·8 [1·6–2·3], p=0·002; and in biopsy samples 1·3 [0·7–2·3] vs 3·9% [1·3–5·3%], p=0·02), especially in severe asthma where BAL regulatory T cells were also reduced compared with those in health (4·4, 3·1–6·1, vs 8·1, 5·6–10; p=0·02). BNA and TDA identified six novel clinicopathobiological clusters of underlying disease mechanisms, with elevated mast cell mediators tryptase (p<0·0001), chymase (p=0·02), and carboxypeptidase A3 (p=0·02) in severe asthma.

Interpretation: This study suggests that Th17 cells do not have a major pathogenic role in human asthma. We describe a novel deficiency of MAIT cells in severe asthma. We also provide proof of concept for application of TDA to identification of multidimensional clinicopathobiological endotypes. Endotypes will require validation in further cohorts.

Full text not available from this repository.

More information

Published date: 26 February 2015
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 386242
URI: https://eprints.soton.ac.uk/id/eprint/386242
ISSN: 0140-6736
PURE UUID: 9e6955f5-b42f-4908-94db-0ac47860a543
ORCID for Karl Staples: ORCID iD orcid.org/0000-0003-3844-6457
ORCID for Ratko Djukanović: ORCID iD orcid.org/0000-0001-6039-5612

Catalogue record

Date deposited: 29 Jan 2016 10:34
Last modified: 06 Oct 2018 00:40

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