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Seung-Hyun Kim1, 2, Eun-Mi Yang2, Hye-Min Jung2, Duy Le Pham1, Hyun-Na Choi2, Ga-Young Ban1, Hae-Sim Park1, 2
Abstract
Purpose
Toll-like receptor 3 (TLR3) recognizes to viral double-stranded RNA and is involved in antiviral defenses. A probable role of TLR3 gene variants in the pathogenesis of aspirin-intolerant asthma (AIA) has been suggested. AIA patients present more frequent asthma exacerbations in which respiratory viral infections could be an exacerbating factor. IgG subclass deficiency was commonly present with bronchial asthma. Based on previous findings, we investigated whether TLR3 variants could affect IgG3 subclass deficiency in AIA.
Methods
We enrolled 279 AIA patients, 403 aspirin-tolerant asthma (ATA) patients, and 315 normal healthy controls (NC) in this study. TLR3 polymorphism at the promoter region -299698G>T was genotyped. The serum levels of IgG subclasses were determined by the single radial immunodiffusion method. Expressions of IgG3 and TLR3 on Epstein-Barr virus transformed-B cells isolated from asthmatic patients were evaluated by flow cytometry to investigate B-cell functions.
Results
The TLR3 -299698 T allele was significantly associated with severity and IgG3 deficiency in the AIA group (P=0.044 and P=0.010, respectively), but not in the ATA group. IgG3 expression on B cells from asthmatics with IgG3 deficiency was significantly lower compared to those without (P=0.025). There was a positive correlation between IgG3 expression levels on B cells and serum IgG3 levels (r2=0.434, P=0.002).
Figures and Tables
Fig. 1
IgG3 expression in the Epstein-Barr virus-transformed B-cell lines isolated from asthmatic patients. (A) IgG3 surface expression on B cells. (B) Correlation between IgG3 expression levels on B cells and IgG3 serum levels. P-values were determined using the independent t-test and Pearson correlation coefficient. The deficiency group included asthmatic patients who had at least one IgG subclass deficiencies; the normal control group included asthmatic patients who did not have any IgG subclass deficiency.
Table 1
Clinical characteristics of the study subjects
NAValues are presented as mean±standard deviation or number (%).
AIA, aspirin-intolerant asthma; ATA, aspirin-tolerant asthma; NC, normal control; ECP, eosinophil cationic protein; PC20, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second; FEV1, forced expiratory volume in 1 second; LM score, Lund-Mackay computed tomography score; IgG subclass deficiency, asthmatic patients who had at least one of IgG subclass deficiencies; NA, not applicable.
P-values were determined using Pearson chi-square test for categorical variables and the independent t-test for continuous variables.
Table 2
Distribution of immunoglobulin G subclass deficiency
| IgG subclass deficiency | AIA (n = 279) | ATA (n = 403) |
|---|---|---|
| IgG1 | 2 (0.71) | 2 (0.50) |
| IgG2 | 3 (1.08) | 1 (0.25) |
| IgG3 | 14 (5.02) | 20 (4.96) |
| IgG4 | 0 (0) | 1 (0.25) |
Table 3
Clinical characteristics of asthma patients with IgG subclass deficiency
Values are presented as mean±standard deviation or number (%).
AIA, aspirin-intolerant asthma; ATA, aspirin-tolerant asthma; ECP, eosinophil cationic protein; LM score, Lund-Mackay computed tomography score.
Deficiency group included the asthma patients who had at least one IgG subclass deficiency. Normal group included the asthma patients who did not have any IgG subclass deficiency.
P-values were determined using Pearson chi-square test for categorical variables and the independent t-test for continuous variables.
Table 4
Genotype frequency of TLR3 -299698G>T
Values are presented as number (%).
AIA, aspirin-intolerant asthma; ATA, aspirin-tolerant asthma; NC, normal control; q, minor allele frequency.
Each P-value was calculated with codominant, dominant, and recessive models. Logistic regression analysis was applied to control for age and genders as covariables.
Table 5
Association of immunoglobulin G3 deficiency as well as severe asthma according to the genotype of TLR3 -299698 G>T in AIA group
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