Circulating mast cell progenitors correlate with reduced lung function in allergic asthma

Abstract

Background: Studies using mouse models have revealed that mast cell progenitors are recruited from the blood circulation to the lung during acute allergic airway inflammation. The discovery of a corresponding human mast cell progenitor population in the blood has enabled to study the relation of circulating mast cell progenitors in clinical settings.

Objectives: To explore the possible association between the frequency of mast cell progenitors in the blood circulation and allergic asthma, we assessed the relation of this recently identified cell population with asthma outcomes and inflammatory mediators in allergic asthmatic patients and controls.

Methods: Blood samples were obtained, and spirometry was performed on 38 well-controlled allergic asthmatic patients and 29 controls. The frequency of blood mast cell progenitors, total serum IgE and 180 inflammation- and immune-related plasma proteins were quantified.

Results: Allergic asthmatic patients and controls had a similar mean frequency of blood mast cell progenitors, but the frequency was higher in allergic asthmatic patients with reduced FEV₁ and PEF (% of predicted) as well as in women. The level of fibroblast growth factor 21 (FGF-21) correlated positively with the frequency of mast cell progenitors, independent of age and gender, and negatively with lung function. The expression of FcεRI on mast cell progenitors was higher in allergic asthmatic patients and correlated positively with the level of total IgE in the controls but not in the asthmatic patients.

Conclusion: Elevated levels of circulating mast cell progenitors are related to reduced lung function, female gender and high levels of FGF-21 in young adults with allergic asthma.

Keywords: allergic asthma; asthma; lung function; mast cell progenitors; mast cells.

Figure 1

Allergic asthmatic patients and controls have a similar frequency of circulating MCp. A, The flow cytometry gating strategy for quantifying blood MCp. MCp were identified as CD4⁻ CD8⁻ CD19⁻ CD14⁻ CD34^hi CD117⁺ FcεRI ⁺ cells. B, The frequency of MCp/L blood correlates to the frequency of MCp/10⁶ PBMC in all subjects. Pearson's correlation was used to determine linear regression. C, The study subjects were grouped as allergic asthmatic patients (AA) and controls (C). The overall mean±SD frequency of MCp/L blood in C and AA are shown. The difference between two groups was tested with Student's t test

Figure 2

Individuals with a reduced lung function have an increased frequency of circulating MCp. (A, B) Correlation analysis of MCp/L blood with FEV ₁% of predicted (A) and PEF % of predicted (B), among all subjects, allergic asthmatic patients (AA) and controls (C). A possible correlation between the MCp frequency and the different lung function parameters was tested using Spearman's correlation analysis. (C, D) The allergic asthmatic patients (C) and controls (D) were divided according to gender and the frequency of MCp compared between the groups. Means ±SD; *P ≤ 0.05; **P < 0.01

Figure 3

The expression of FcεRI on MCp is higher in allergic asthmatic patients and correlates with the level of total IgE in the controls. A, The geometric mean fluorescence intensity (gMFI) for the surface expression of FcεRI on the MCp was compared between allergic asthmatic patients and controls. The mean±SD is shown; *P ≤ 0.05. B, Spearman's correlation analysis of the surface expression of FcεRI on the MCp with the level of total IgE. In two analyses (2/67), a different fluorophore was used to determine the expression FcεRI; thus, these analyses were excluded for the calculation of gMFI. C, Correlation analysis of the frequency of MCp with the level of total IgE using Spearman's analysis

Figure 4

High plasma concentration of FGF‐21 and DCBLD2 correlates with high frequency of MCp among allergic asthmatic patients and FEV ₁ of predicted among all subjects. (A‐D) The level of plasma proteins was quantified using the Inflammation and Immune response panels from Olink Proteomics. The proteins levels (normalized protein expression on a log₂ scale; NPX) and the MCp frequency (expressed as log₁₀) among allergic asthmatic patients and controls were plotted against each other. (E, F) The protein levels (normalized protein expression on a log₂ scale; NPX) of FGF‐21 (E), or DCBLD2 (F), and the FEV ₁ of predicted were plotted against each other. Linear regression analysis was determined with Pearson's correlation. P ≤ 0.05 was considered significant