IgA+ memory B-cells are significantly increased in patients with asthma and small airway dysfunction

Abstract

Background: Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma.

Methods: In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models.

Results: Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgA⁺ memory B-cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA⁺ memory B-cells, particularly in patients with mild-moderate asthma. Additionally, IgA⁺ memory B-cells significantly correlated with clinical features of SAD such as exacerbations.

Conclusions: With this study we demonstrate for the first time a significant association of increased IgA⁺ memory B-cells with asthma and SAD, pointing towards future options for B-cell-directed strategies in preventing and treating asthma.

Trial registration: ClinicalTrials.gov NCT02419274.

FIGURE 1

Pairwise a) comparisons and b) correlations between B-cell populations and clinical parameters of asthma patients and healthy controls. Colour code shows a) significant p-values and b) estimate for significant correlations analysed by Kruskal–Wallis or Spearman's correlation, respectively, with adjustment for multiple testing (p_adjusted). B-cell subsets are presented as percentage of total CD19⁺ B-cells. BMI: body mass index; GINA: Global Initiative for Asthma; BDR: bronchodilator response; FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; FEF_25–75%: forced expiratory flow at 25–75% of FVC; AX: reactance area; R5–R20: resistance at 5 Hz−resistance at 20 Hz; OCS: oral corticosteroids; T1: transitional 1; T2: transitional 2. ns: nonsignificant.

FIGURE 2

Associations between B-cell subsets and clinical parameters of asthma patients and healthy controls. Associations with a) asthma severity, b) oral corticosteroid (OCS) intake, c) asthma control and sputum inflammation, and d) forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC), forced expiratory flow at 25–75% of FVC (FEF_25–75%), reactance area (AX) and resistance at 5 Hz−resistance at 20 Hz (R5−R20) are shown for asthma patients and healthy controls. Overall adjusted p-values after multiple test corrections and p-values from categorical group comparisons are shown as well as R and adjusted p-values from Spearman correlations. Further significant associations are shown in supplementary figure S2. T1: transitional 1; mod: moderate; T2: transitional 2; OCS: oral corticosteroids; C: controlled; PC: partly controlled; UC: uncontrolled; P: paucigranulocytic; E: eosinophilic; N: neutrophilic; M: mixed granulocytic. ns: nonsignificant; *: p<0.05; **: p<0.01; ***: p<0.001; ****: p<0.0001.

FIGURE 3

IgA⁺ memory B-cells and small airway dysfunction (SAD). a) CD27⁺IgA⁺ memory B-cells in patients with or without SAD. b) CD27⁺IgA⁺ B-cells in patients with or without SAD in mild–moderate (mild-mod) asthma and severe asthma. c) CD27⁺IgA⁺ B-cells in patients with or without central airway obstruction (forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC)<lower limit of normal (LLN; z-score −1.64)) and with or without SAD. **: p<0.01; ***: p<0.001.

FIGURE 4

Correlations of number of exacerbations with clinical and B-cell parameters. Dark red defines the highest positive correlation between the parameters and dark blue shows the lowest negative correlation between the variables. Adjusted p-values after multiple test corrections are shown next to the bars. AX: reactance area; ICS: inhaled corticosteroids; R5–R20: resistance at 5 Hz−resistance at 20 Hz; BMI: body mass index; F_ENO: exhaled nitric oxide fraction; OCS: oral corticosteroids; FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; FEF_25–75%: forced expiratory flow at 25–75% of FVC. ns: nonsignificant; *: p<0.05; **: p<0.01; ***: p<0.001.