Regulatory B cells control airway hyperreactivity and lung remodeling in a murine asthma model - 03/06/21

Doi : 10.1016/j.jaci.2020.09.041

Anika Habener, Dipl-Biol ^a,^b, Christine Happle, MD, PhD ^a,^b, Ruth Grychtol, MD ^a,^b, Jelena Skuljec, PhD ^a,^c, Mandy Busse, PhD ^a,^d, Kathleen Dalüge, PhD ^a, Helena Obernolte, MSc ^b,^e, Katherina Sewald, PhD ^b,^e, Armin Braun, PhD ^b,^e, Almut Meyer-Bahlburg, MD ^a,^b,^f,^{∗
These authors contributed equally to this work.}, Gesine Hansen, MD ^a,^b,^g,^⁎^{∗
These authors contributed equally to this work.}
^a Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
^b Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover, Germany
^c Department of Neurology, University Medicine Essen, Essen, Germany
^d Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
^e Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
^f Department of Pediatrics, University Medicine Greifswald, Greifswald, Germany
^g Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany

^∗Corresponding author: Gesine Hansen, MD, Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.Department of Pediatric PneumologyAllergology and NeonatologyHannover Medical SchoolCarl-Neuberg-Str. 1Hannover30625Germany

Abstract

Background

Asthma is a widespread, multifactorial chronic airway disease. The influence of regulatory B cells on airway hyperreactivity (AHR) and remodeling in asthma is poorly understood.

Objective

Our aim was to analyze the role of B cells in a house dust mite (HDM)-based murine asthma model.

Methods

The influence of B cells on lung function, tissue remodeling, and the immune response were analyzed by using wild-type and B-cell–deficient (μMT) mice and transfer of IL-10–proficient and IL-10–deficient B cells to μMT mice.

Results

After HDM-sensitization, both wild-type and μMT mice developed AHR, but the AHR was significantly stronger in μMT mice, as confirmed by 2 independent techniques: invasive lung function measurement in vivo and examination of precision-cut lung slices ex vivo. Moreover, airway remodeling was significantly increased in allergic μMT mice, as shown by enhanced collagen deposition in the airways, whereas the numbers of FoxP3⁺ and FoxP3^– IL-10–secreting regulatory T cells were reduced. Adoptive transfer of IL-10–proficient but not IL-10–deficient B cells into μMT mice before HDM-sensitization attenuated AHR and lung remodeling. In contrast, FoxP3⁺ regulatory T cells were equally upregulated by transfer of IL-10–proficient and IL-10–deficient B cells.

Conclusion

Our data in a murine asthma model illustrate a central role of regulatory B cells in the control of lung function and airway remodeling and may support future concepts for B-cell–targeted prevention and treatment strategies for allergic asthma.

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Key words : Experimental asthma, allergy, house dust mite, airway hyperreactivity, lung remodeling, regulatory B cells, IL-10, B-cell transfer, precision-cut lung slices

Abbreviations used : AHR, BALF, Breg, DC, FM, GC, HDM, IT, LN, μMT, PB, PC, PCLS, Tr1, Treg, WT

Plan

Methods

Animals

Experimental model of HDM-induced asthma

B-cell isolation and adoptive transfer

Lung function

Bronchoconstriction and cytokine production of PCLS

Analysis of BALF

Lung histology

Sircol soluble collagen assay

Preparation of serum and lung supernatant

Cell isolation

Gene expression

In vitro cytokine production

Flow cytometry and antibodies

Immunoglobulin measurements

Statistical analysis

Results

HDM-sensitized μMT mice develop significantly increased AHR but display diminished airway inflammation compared with WT mice

Pulmonary collagen deposition is augmented in sensitized μMT mice compared with in WT mice

Treg cell and IL-10 levels are reduced in sensitized μMT mice compared with in WT mice

HDM immunization induces a strong B-cell response in the lung

IL-10–secreting B-cell subsets are increased in lungs of allergic WT mice

Transfer of WT but not IL-10^–/– B cells significantly reduces AHR in allergic μMT mice

Both WT and IL-10^–/– B-cell transfer affect antigen-specific cytokine production, FoxP3⁺ Treg expansion, and IgE secretion

Discussion

	Supported by the German Center for Lung Research (DZL/BREATH, BMBF, Federal Ministry of Education and Research), Cluster of Excellence RESIST (EXC 2155, DFG, German Research Foundation) at Hannover Medical School, Hannover, Germany and by the Dörenkamp Foundation.
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 147 - N° 6

P. 2281 - juin 2021 Retour au numéro

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Regulatory B cells control airway hyperreactivity and lung remodeling in a murine asthma model - 03/06/21

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