Airway inflammation and dysbiosis in antibody deficiency despite the presence of IgG - 21/01/22

Doi : 10.1016/j.jaci.2021.12.778

Anna Schnell, PhD ^a,^b, Mehmet Davrandi, PhD ^c,^d, Moritz Saxenhofer, PhD ^a,^b, Clara Leboreiro, BSc ^c,^d, Stefanie Graeter, PhD ^a,^b, Fernando Moreira, BSc ^e, Maria Hauswald, PhD ^a,^b, Carolin Witte, PhD ^a,^b, Irina Irincheeva, PhD ^a,^b, Annette Feussner, PhD ^a,^b, Cedric Vonarburg, PhD ^a,^b, Ilka Schulze, MD, PhD ^a,^b, Alexander Schaub, PhD ^a,^b, Siobhan O. Burns, PhD ^c,^e, David M. Lowe, FRCP, PhD ^c,^e,^⁎
^a CSL Behring, Research Europe, Bern, Switzerland
^b CSL Behring, Research Europe, Marburg, Germany
^c Institute of Immunity and Transplantation, University College London, London, United Kingdom
^d Centre for Clinical Microbiology, University College London, London, United Kingdom
^e Department of Clinical Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom

^∗Corresponding author: David M. Lowe, FRCP, PhD, Institute of Immunity and Transplantation, University College London, Royal Free Campus, Pond St, London NW3 2QG, UK.Institute of Immunity and TransplantationUniversity College LondonRoyal Free CampusPond StLondonNW3 2QGUK

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Abstract

Background

Patients with antibody deficiency suffer chronic respiratory symptoms, recurrent exacerbations, and progressive airways disease despite systemic replacement of IgG. Little is known about the respiratory tract biology of these patients.

Objective

We sought to measure immunoglobulin levels, inflammatory cytokines, and mediators of tissue damage in serum and sputum from patients with antibody deficiency and healthy controls; to analyze the respiratory microbiome in the same cohorts.

Methods

We obtained paired sputum and serum samples from 31 immunocompetent subjects and 67 antibody-deficient patients, the latter divided on computed tomography scan appearance into “abnormal airways” (bronchiectasis or airway thickening) or “normal airways.” We measured inflammatory cytokines, immunoglobulin levels, neutrophil elastase, matrix-metalloproteinase-9, urea, albumin, and total protein levels using standard assays. We used V3-V4 region 16S sequencing for microbiome analysis.

Results

Immunodeficient patients had markedly reduced IgA in sputum but higher concentrations of IgG compared with healthy controls. Inflammatory cytokines and tissue damage markers were higher in immunodeficient patients, who also exhibited dysbiosis with overrepresentation of pathogenic taxa and significantly reduced alpha diversity compared with immunocompetent individuals. These differences were seen regardless of airway morphology. Sputum matrix-metalloproteinase-9 and elastase correlated inversely with alpha diversity in the antibody-deficient group, as did sputum IgG, which correlated positively with several inflammatory markers, even after correction for albumin levels.

Conclusions

Patients with antibody deficiency, even with normal lung imaging, exhibit inflammation and dysbiosis in their airways despite higher levels of IgG compared with healthy controls.

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Key words : Immunodeficiency, immunoglobulin, sputum, respiratory tract, microbiome, inflammation

Abbreviations used : HiB, IC, ID, MMP, PCP, RT

Plan

Methods

Patients and clinical data

Sputum collection and processing

Serum collection

Immuno-based assays

Nephelometry

Colorimetric quantification of total protein and urea

Neutrophil elastase

DNA isolation

Microbiome sequencing

Patients with antibody deficiency have reduced airway IgA but increased airway IgG concentrations compared with healthy controls

The sputum of patients with antibody deficiency demonstrates marked increases in markers of inflammation and airway damage compared with healthy controls

Sputum IgG concentration correlates with markers of inflammation and tissue damage

Concentrations of specific antibodies against respiratory pathogens correlate with the total IgG in the ID sputum

ID patients demonstrate greater prevalence of pathogenic bacterial species and have reduced microbial alpha diversity, which correlates negatively with markers of tissue destruction and sputum IgG concentration

Immunoglobulins, elastase, albumin, and MMP-9 may be suitable markers for prediction of abnormal airways status in ID subjects

Discussion

This study was funded in part by CSL Behring AG.

Disclosure of potential conflict of interest: The following contributors are employees of CSL Behring AG Bern, Switzerland—A. Schnell, M. Saxenhofer, S. Graeter, I. Irincheeva, C. Vonarburg, I. Schulze, and A. Schaub—or CSL Behring GmbH Marburg, Germany: M. Hauswald, C. Witte, and A. Feussner. S. O. Burns and D. M. Lowe have received travel and accommodation costs from CSL Behring. S. O. Burns has also received grant support from the European Union, the National Institute of Health Research, University College London Hospitals (UCLH), and Great Ormond Street Hospital (GOSH)/Institute of Child Health (ICH) Biomedical Research Centers and personal fees or travel expenses from Immunodeficiency Canada/IAACI, Baxalta US, Inc, and Biotest. D. M. Lowe has also received grant support from LifeArc, Bristol-Myers-Squibb, Blood Cancer UK, the Medical Research Council, and the British Society for Antimicrobial Chemotherapy and personal fees from Merck. The rest of the authors declare that they have no relevant conflicts of interest.