Tissue levels of Alternaria allergen Alt a 1 reflect recurrence
of refractory airway diseases.
To the Editors,
The quantification of Alternaria allergen in the local airway tissues is
quite unknown, while Alternaria alternata is a widespread fungal
species in the airway discharge and known to be one source of
aeroallergens which contribute to development of asthma (1,2) and
chronic rhinosinusitis (CRS) (3,4). We have recently been established
the method for quantifying allergen in the local airway tissues (5).
Since Alt a 1 is the main sensitizing allergen component and it is
useful in diagnosis and immunotherapy (6), we have measured the levels
of Alt a 1 in the local airway tissues and examined whether the
quantification of Alt a 1 could reflect the allergic airway inflammation
and recurrence of refractory allergic respiratory diseases.
We obtained nasal polyp tissues from 64 patients with refractory CRS
with nasal polyp (CRSwNP) and homogenized them. The tissue levels of Alt
a 1, Alternaria specific IgE, IL-4, IL-5, IL-13, IL-33, galectin-10 in
nasal polyp supernatant were measured. The tissue eosinophil numbers
were also counted. We searched for the existence of postoperative nasal
polyp for in the medical records in order to examine the usefulness of
Alt a 1 as a predictor of nasal polyp recurrence after surgery.
First, we measured the levels of Alt a 1 in airway tissues and ROC curve
based on nasal polyp recurrence data was developed, with a cut-off value
of 1.84 ng/g of local Alt a 1 (AUC = 0.75, Figure 1A). According to the
presence or absence of nasal polyp recurrence, patients were divided
into two groups and the levels of Alt a 1 were compared. The tissue
levels of Alt a 1 were significantly higher in recurrence group.
(p < 0.01, Figure 1B). Kaplan–Meier curves at the
cut-off point of the local tissue Alt a 1 levels shows that of the
recurrence-free rate in the low- Alt a 1 group is lower rate than that
in the high- Alt a 1 group (p < 0.05, log-rank
test, Figure 1C).
We further measured Alternaria specific IgE level in the airway tissues
in order to determine the sensitization to Alt a 1. The levels of Alt a
1 in nasal polyps had a significant positive correlation with the levels
of Alternaria specific IgE (rs=0.56, p<0.0001, Figure 2A). We
divided patients into two groups according to the local tissue levels of
local Alt a 1, and compared the levels of Alternaria-specific IgE
antibody between two groups. As result, the levels of
Alternaria-specific IgE antibody were significantly higher in high- Alt
a 1 group than those in low- Alt a 1 group. (p<0.0001, Figure
2B)
Fungi induce alarmins which promote the development of type 2 response
via increase in the number of eosinophils, accompanied by an increase in
innate lymphoid cells (ILCs) and effector cells such as mast cells
(7,8). We measured the level of type2 cytokines (IL-4, IL-5, IL-13) in
the airway tissues and analyzed between high- and low- Alt a 1group
respectively in order to assess the contribution of type2 inflammation
to local allergic reaction to Alternaria alterna . Patients were
divided into two groups according to the tissue levels of Alt a 1. The
levels of IL-4 were significantly higher in high- Alt a 1 group than
those in low- group. IL-4 plays an essential role in IgE class switching
and production. The levels of IL-5 and IL-13 didn’t show significant
difference but tended to be higher in the high- Alt a 1 group. (Figure
2C)
Epithelial cells which activated by antigens induce proinflammatory
responses due to the production of alarmins. Alternaria alternataexposure evokes IL-33 secretion and extracellular DNA from the airway
epithelium, which functions as an alarmin to stimulate type 2 immunity
in airway diseases (9). The levels of IL-33 in NPs were significantly
higher in high- Alt a 1 group than those in the low- group (Figure 2C).
Galectin-10 is relatively eosinophil specific protein which released
from cytolytic cells is expected to be a biomarker for activated
eosinophils in eosinophilic inflammatory diseases (10). The levels of
galectin-10 in the airway tissues were significantly higher in high Alt
a 1 group than low group. (Figure 2C)
This is the first report to have quantified the levels of Alt a 1 in
airway tissues and investigated the association to the type2 molecules
of allergic reaction. Alternaria alterna is common fungi as an
environmental antigen and the increase in the local tissue levels of Alt
a 1 were associated with the recurrence of refractory CRSwNP. These
results might explain the tissue levels of Alt a 1 can be a predictor of
recurrence for refractory respiratory airway disease.