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Article ; Online: Pulmonary immune profiling reveals common inflammatory endotypes of childhood wheeze and suppurative lung disease.

Neeland, Melanie R / Gubbels, Liam / Wong, Anson Tsz Chun / Walker, Hannah / Ranganathan, Sarath C / Shanthikumar, Shivanthan

Mucosal immunology

2024

Abstract: Suppurative lung disease and wheezing are common respiratory diseases of childhood, however, due to poor understanding of underlying pathobiology, there are limited treatment options and disease recurrence is common. We aimed to profile the pulmonary and ...

Abstract	Suppurative lung disease and wheezing are common respiratory diseases of childhood, however, due to poor understanding of underlying pathobiology, there are limited treatment options and disease recurrence is common. We aimed to profile the pulmonary and systemic immune response in children with wheeze and chronic suppurative lung disease for identification of endotypes that can inform improved clinical management. We used clinical microbiology data, highly multiplexed flow cytometry and immunoassays to compare pulmonary [bronchoalveolar lavage (BAL)] and systemic immunity in children with lung disease and controls. Unsupervised analytical approaches were applied to BAL immune data to explore biological endotypes. We identified two endotypes that were analogous in both frequency and immune signature across both respiratory diseases. The hyper-inflammatory endotype had a 12-fold increase in neutrophil infiltration and upregulation of 14 soluble signatures associated with type 2 inflammation and cell recruitment to tissue. The non-inflammatory endotype was not significantly different from controls. We showed these endotypes are measurable in a clinical setting and can be defined by measuring only three immune factors in BAL. We identified hyper-inflammatory and non-inflammatory endotypes common across pediatric wheeze and chronic suppurative lung disease that, if validated in future studies, have the potential to inform clinical management.
Language	English
Publishing date	2024-03-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2411370-0
ISSN	1935-3456 ; 1933-0219
ISSN (online)	1935-3456
ISSN	1933-0219
DOI	10.1016/j.mucimm.2024.03.001
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Zs.A 6796: Show issues

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Article ; Online: Ivacaftor, not ivacaftor/lumacaftor, associated with lower pulmonary inflammation in preschool cystic fibrosis.

Shanthikumar, Shivanthan / Ranganathan, Sarath / Neeland, Melanie R

Pediatric pulmonology

2022 Volume 57, Issue 10, Page(s) 2549–2552

MeSH term(s)	Aminophenols/therapeutic use ; Aminopyridines/therapeutic use ; Benzodioxoles/therapeutic use ; Child, Preschool ; Cystic Fibrosis/complications ; Cystic Fibrosis/drug therapy ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Drug Combinations ; Humans ; Mutation ; Pneumonia ; Quinolones
Chemical Substances	Aminophenols ; Aminopyridines ; Benzodioxoles ; Drug Combinations ; Quinolones ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; ivacaftor (1Y740ILL1Z) ; lumacaftor (EGP8L81APK)
Language	English
Publishing date	2022-07-12
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	632784-9
ISSN	1099-0496 ; 8755-6863
ISSN (online)	1099-0496
ISSN	8755-6863
DOI	10.1002/ppul.26063
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Zs.A 2143: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
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Article: Eosinophilia and wheeze: thinking beyond asthma.

Kuek, Stephanie L / Pettman, Colin / Neeland, Melanie R / Harrison, Joanne / Mehr, Sam / Shanthikumar, Shivanthan / Beggs, Sean

Breathe (Sheffield, England)

2024 Volume 20, Issue 1, Page(s) 230126

Abstract: Primary idiopathic hypereosinophilic syndrome is a rare condition that can cause end-organ damage in multiple systems. The advent of targeted monoclonal antibodies, such as mepolizumab, provides a safe and effective steroid-sparing treatment. ...

Abstract	Primary idiopathic hypereosinophilic syndrome is a rare condition that can cause end-organ damage in multiple systems. The advent of targeted monoclonal antibodies, such as mepolizumab, provides a safe and effective steroid-sparing treatment.
Language	English
Publishing date	2024-03-12
Publishing country	England
Document type	Case Reports
ZDB-ID	2562899-9
ISSN	2073-4735 ; 1810-6838
ISSN (online)	2073-4735
ISSN	1810-6838
DOI	10.1183/20734735.0126-2023
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Article ; Online: Mapping Pulmonary and Systemic Inflammation in Preschool Aged Children With Cystic Fibrosis.

Shanthikumar, Shivanthan / Ranganathan, Sarath C / Saffery, Richard / Neeland, Melanie R

Frontiers in immunology

2021 Volume 12, Page(s) 733217

Abstract: The immune landscape of the paediatric respiratory system remains largely uncharacterised and as a result, the mechanisms of globally important childhood respiratory diseases remain poorly understood. In this work, we used high parameter flow cytometry ... ...

Abstract	The immune landscape of the paediatric respiratory system remains largely uncharacterised and as a result, the mechanisms of globally important childhood respiratory diseases remain poorly understood. In this work, we used high parameter flow cytometry and inflammatory cytokine profiling to map the local [bronchoalveolar lavage (BAL)] and systemic (whole blood) immune response in preschool aged children with cystic fibrosis (CF) and aged-matched healthy controls. We demonstrate that children with CF show pulmonary infiltration of CD66b
MeSH term(s)	Biomarkers/blood ; Bronchoalveolar Lavage Fluid/immunology ; Case-Control Studies ; Cystic Fibrosis/diagnosis ; Cystic Fibrosis/immunology ; Cystic Fibrosis/metabolism ; Cytokines/blood ; Flow Cytometry ; Humans ; Immunophenotyping ; Inflammation/diagnosis ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation Mediators/blood ; Leukocytes/immunology ; Leukocytes/metabolism ; Phenotype ; Pneumonia/diagnosis ; Pneumonia/immunology ; Pneumonia/metabolism
Chemical Substances	Biomarkers ; Cytokines ; Inflammation Mediators
Language	English
Publishing date	2021-10-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.733217
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Article ; Online: DNA Methylation Profiles of Purified Cell Types in Bronchoalveolar Lavage: Applications for Mixed Cell Paediatric Pulmonary Studies.

Shanthikumar, Shivanthan / Neeland, Melanie R / Saffery, Richard / Ranganathan, Sarath C / Oshlack, Alicia / Maksimovic, Jovana

Frontiers in immunology

2021 Volume 12, Page(s) 788705

Abstract: In epigenome-wide association studies analysing DNA methylation from samples containing multiple cell types, it is essential to adjust the analysis for cell type composition. One well established strategy for achieving this is reference-based cell type ... ...

Abstract	In epigenome-wide association studies analysing DNA methylation from samples containing multiple cell types, it is essential to adjust the analysis for cell type composition. One well established strategy for achieving this is reference-based cell type deconvolution, which relies on knowledge of the DNA methylation profiles of purified constituent cell types. These are then used to estimate the cell type proportions of each sample, which can then be incorporated to adjust the association analysis. Bronchoalveolar lavage is commonly used to sample the lung in clinical practice and contains a mixture of different cell types that can vary in proportion across samples, affecting the overall methylation profile. A current barrier to the use of bronchoalveolar lavage in DNA methylation-based research is the lack of reference DNA methylation profiles for each of the constituent cell types, thus making reference-based cell composition estimation difficult. Herein, we use bronchoalveolar lavage samples collected from children with cystic fibrosis to define DNA methylation profiles for the four most common and clinically relevant cell types: alveolar macrophages, granulocytes, lymphocytes and alveolar epithelial cells. We then demonstrate the use of these methylation profiles in conjunction with an established reference-based methylation deconvolution method to estimate the cell type composition of two different tissue types; a publicly available dataset derived from artificial blood-based cell mixtures and further bronchoalveolar lavage samples. The reference DNA methylation profiles developed in this work can be used for future reference-based cell type composition estimation of bronchoalveolar lavage. This will facilitate the use of this tissue in studies examining the role of DNA methylation in lung health and disease.
MeSH term(s)	Alveolar Epithelial Cells/immunology ; Bronchoalveolar Lavage Fluid/cytology ; Bronchoscopy ; Cell Count ; Child, Preschool ; CpG Islands/genetics ; Cystic Fibrosis/diagnosis ; Cystic Fibrosis/genetics ; Cystic Fibrosis/immunology ; DNA Methylation/immunology ; Epigenomics/methods ; Female ; Flow Cytometry ; Granulocytes/immunology ; Humans ; Infant ; Lymphocytes/immunology ; Macrophages, Alveolar/immunology ; Male ; Reference Values
Language	English
Publishing date	2021-12-22
Publishing country	Switzerland
Document type	Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.788705
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Article ; Online: Single-Cell Flow Cytometry Profiling of BAL in Children.

Shanthikumar, Shivanthan / Burton, Matthew / Saffery, Richard / Ranganathan, Sarath C / Neeland, Melanie R

American journal of respiratory cell and molecular biology

2020 Volume 63, Issue 2, Page(s) 152–159

Abstract: Childhood pulmonary diseases not only cause childhood morbidity and mortality but also can cause long-term pulmonary impairment. The clinical management of many childhood pulmonary diseases is hampered by a limited understanding of the underlying ... ...

Abstract	Childhood pulmonary diseases not only cause childhood morbidity and mortality but also can cause long-term pulmonary impairment. The clinical management of many childhood pulmonary diseases is hampered by a limited understanding of the underlying pathophysiological mechanisms. Flow cytometry, which can be used to phenotype individual cell populations or isolate cells for downstream analysis, represents a crucial technology that can help to elucidate the pathophysiology of these conditions. Here, we describe a flow cytometry-based method for purification and characterization of cell populations in BAL from children. This includes assessment of the effect of cryopreservation on cell phenotype and frequency, a knowledge gap recently identified by an American Thoracic Society report on flow cytometry in lung samples. To our knowledge, this is the first study to simultaneously quantify alveolar macrophages, T cells (CD4 and CD8), B cells, natural killer cells, dendritic cells, granulocytes, and monocytes (CD16
MeSH term(s)	Bronchoalveolar Lavage/methods ; Bronchoalveolar Lavage Fluid/immunology ; Child, Preschool ; Female ; Flow Cytometry/methods ; Granulocytes/immunology ; Humans ; Infant ; Leukocyte Count/methods ; Lung/immunology ; Lung Diseases/immunology ; Macrophages, Alveolar/immunology ; Male ; Monocytes/immunology ; Single-Cell Analysis/methods ; T-Lymphocytes/immunology
Language	English
Publishing date	2020-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2019-0453MA
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Zs.A 2851: Show issues

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Article ; Online: Hyper-Inflammatory Monocyte Activation Following Endotoxin Exposure in Food Allergic Infants.

Neeland, Melanie R / Novakovic, Boris / Dang, Thanh D / Perrett, Kirsten P / Koplin, Jennifer J / Saffery, Richard

Frontiers in immunology

2020 Volume 11, Page(s) 567981

Abstract: Several recent studies have reported a key role for innate cell hyper-responsiveness in food allergy. This has predominantly been observed in early life, with evidence that innate immune function may return to baseline if food allergy resolves in later ... ...

Abstract	Several recent studies have reported a key role for innate cell hyper-responsiveness in food allergy. This has predominantly been observed in early life, with evidence that innate immune function may return to baseline if food allergy resolves in later childhood. Hallmarks of hyper-responsiveness include increased circulating frequency of monocytes and altered innate cell cytokine responses to
MeSH term(s)	Age Factors ; Allergens/immunology ; Biomarkers ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Cells, Cultured ; Cytokines/biosynthesis ; Disease Susceptibility ; Egg Hypersensitivity/diagnosis ; Egg Hypersensitivity/etiology ; Egg Hypersensitivity/metabolism ; Endotoxins/adverse effects ; Female ; Food Hypersensitivity/diagnosis ; Food Hypersensitivity/etiology ; Food Hypersensitivity/metabolism ; Humans ; Immunization ; Immunoglobulin E/immunology ; Immunophenotyping ; Infant ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism ; Male ; Monocytes/immunology ; Monocytes/metabolism
Chemical Substances	Allergens ; Biomarkers ; Cytokines ; Endotoxins ; Immunoglobulin E (37341-29-0)
Language	English
Publishing date	2020-09-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.567981
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Article: DNA methylation biomarkers of future health outcomes in children.

Shanthikumar, Shivanthan / Neeland, Melanie R / Maksimovic, Jovana / Ranganathan, Sarath C / Saffery, Richard

Molecular and cellular pediatrics

2020 Volume 7, Issue 1, Page(s) 7

Abstract: Biomarkers which predict future health outcomes are key to the goals of precision health. Such biomarkers do not have to be involved in the causal pathway of a disease, and their performance is best assessed using statistical tests of clinical ... ...

Abstract	Biomarkers which predict future health outcomes are key to the goals of precision health. Such biomarkers do not have to be involved in the causal pathway of a disease, and their performance is best assessed using statistical tests of clinical performance and evaluation of net health impact. DNA methylation is the most commonly studied epigenetic process and represents a potential biomarker of future health outcomes. We review 25 studies in non-oncological paediatric conditions where DNA methylation biomarkers of future health outcomes are assessed. Whilst a number of positive findings have been described, the body of evidence is severely limited by issues with outcome measures, tissue-specific samples, accounting for sample cell type heterogeneity, lack of appropriate statistical testing, small effect sizes, limited validation, and no assessment of net health impact. Future studies should concentrate on careful study design to overcome these issues, and integration of DNA methylation data with other 'omic', clinical, and environmental data to generate the most clinically useful biomarkers of paediatric disease.
Language	English
Publishing date	2020-07-09
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2785551-X
ISSN	2194-7791
ISSN	2194-7791
DOI	10.1186/s40348-020-00099-0
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Article ; Online: Primary Prevention of Food Allergy.

Peters, Rachel L / Neeland, Melanie R / Allen, Katrina J

Current allergy and asthma reports

2017 Volume 17, Issue 8, Page(s) 52

Abstract: Purpose of review: This article summarises recent developments on the prevention of food allergy in terms of the 5 D's of the development of food allergy: dry skin, diet, dogs, dribble, and vitamin D.: Recent findings: While several advances have ... ...

Abstract	Purpose of review: This article summarises recent developments on the prevention of food allergy in terms of the 5 D's of the development of food allergy: dry skin, diet, dogs, dribble, and vitamin D. Recent findings: While several advances have improved our understanding of the development of food allergy, few preventive strategies have been implemented beyond changes in infant feeding guidelines. These now state that the introduction of allergenic solids such as peanuts should occur in the first year of life. Results from randomised controlled trials on other allergenic solids, vitamin D supplementation, BCG immunisation at birth and eczema prevention are eagerly anticipated in order to inform further preventative strategies.
Language	English
Publishing date	2017-08
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2057370-4
ISSN	1534-6315 ; 1529-7322
ISSN (online)	1534-6315
ISSN	1529-7322
DOI	10.1007/s11882-017-0718-x
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Zs.A 5548: Show issues

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Article ; Online: Altered immune cell profiles and impaired CD4 T-cell activation in single and multi-food allergic adolescents.

Neeland, Melanie R / Andorf, Sandra / Dang, Thanh D / McWilliam, Vicki L / Perrett, Kirsten P / Koplin, Jennifer J / Saffery, Richard

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

2021 Volume 51, Issue 5, Page(s) 674–684

Abstract: Background: Approximately 5% of adolescents have a food allergy, with peanut and tree nut allergies the most common. Having two or more food allergies in adolescence also doubles the risk of any adverse food reaction, and is associated with increased ... ...

Abstract	Background: Approximately 5% of adolescents have a food allergy, with peanut and tree nut allergies the most common. Having two or more food allergies in adolescence also doubles the risk of any adverse food reaction, and is associated with increased dietary and social burden. Investigations of immune function in persistently food allergic children are rare. Objective: In the present study, we aimed to investigate the immune mechanisms that underlie food allergy in adolescence. Methods: We used high-dimensional flow cytometry, unsupervised computational analysis and functional studies to comprehensively phenotype a range of non-antigen-specific immune parameters in a group of well-characterized adolescents with clinically defined single peanut allergy, multi-food allergy and aged-matched non-food allergic controls. Results: We show that food allergic adolescents have higher circulating proportions of dendritic cells (p = .0084, FDR-adjusted p = .087, median in no FA: 0.63% live cells, in FA: 0.93%), and higher frequency of activated, memory-like Tregs relative to non-food allergic adolescents (p = .011, FDR-adjusted p = .087, median in no FA: 0.49% live cells, in FA: 0.65%). Cytokine profiling revealed that CD3/CD28 stimulated naïve CD4 T cells from food allergic adolescents produced less IL-6 (p = .0020, FDR-adjusted p = .018, median log2 fold change [stimulated/unstimulated] in no FA: 3.03, in FA: 1.92) and TNFα (p = .0044, FDR-adjusted p = .020, median in no FA: 9.16, in FA: 8.64) and may secrete less IFNγ (p = .035, FDR-adjusted p = .11, median in no FA: 6.29, in FA: 5.67) than naïve CD4 T cells from non-food allergic controls. No differences between clinical groups were observed for LPS-stimulated monocyte secretion of cytokines. Conclusions: These results have important implications for understanding the evolution of the immune response in food allergy throughout childhood, revealing that dendritic cell and T-cell signatures previously identified in early life may persist through to adolescence.
MeSH term(s)	Adolescent ; CD4-Positive T-Lymphocytes/immunology ; Case-Control Studies ; Child ; Cluster Analysis ; Cytokines/immunology ; Egg Hypersensitivity/complications ; Egg Hypersensitivity/immunology ; Female ; Food Hypersensitivity/classification ; Food Hypersensitivity/immunology ; Humans ; Immunophenotyping ; Interferon-gamma/immunology ; Interleukin-6/immunology ; Leukocytes, Mononuclear/immunology ; Male ; Nut Hypersensitivity/complications ; Nut Hypersensitivity/immunology ; Peanut Hypersensitivity/complications ; Peanut Hypersensitivity/immunology ; Tumor Necrosis Factor-alpha/immunology
Chemical Substances	Cytokines ; IFNG protein, human ; IL6 protein, human ; Interleukin-6 ; TNF protein, human ; Tumor Necrosis Factor-alpha ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2021-03-08
Publishing country	England
Document type	Journal Article
ZDB-ID	645204-8
ISSN	1365-2222 ; 0954-7894 ; 0960-2178
ISSN (online)	1365-2222
ISSN	0954-7894 ; 0960-2178
DOI	10.1111/cea.13857
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