The HLA DRB1*1501-DQB1*0602-DPB1*0501 Haplotype Is a Risk Factor for Toluene Diisocyanate-Induced Occupational Asthma

Abstract

Background: Although the pathogenesis of toluene diisocyanate (TDI)-induced occupational asthma (TDI-OA) is incompletely understood, several studies have suggested immunologic mechanisms, including specific IgE responses. A few studies have suggested human leukocyte antigen (HLA) associations with TDI-induced asthma in Western countries, but this is the first investigation of associations between HLA class I and II alleles and TDI-induced asthma patients in Asia, using high-resolution analysis. Methods: Patients with TDI-OA (n = 84), asymptomatic exposed controls (AECs, n = 47) and unexposed normal controls (NCs, n = 127) were enrolled. HLA class I and II genotyping was performed by the direct DNA sequencing analysis. Specific serum IgE antibodies to the vapor type TDI-albumin conjugate were measured by ELISA. Results: There was no significant association between the allele frequencies and the phenotype of TDI-OA. However, the frequency of the HLA DRB1*1501-DQB1*0602-DPB1*0501 haplotype was significantly higher in TDI-OA patients (19%) than in AEC (2.1%, p = 0.007, OR 4.429, CI 1.497–13.103) or NC (3.1%, p < 0.001, OR 7.235, CI 2.236–22.510) subjects, with statistical significance persisting after correction for multiple comparisons. DQB1*0402 was significantly associated with the presence of specific IgE to TDI-albumin conjugates in serum (p = 0.006, OR 4.552, CI 1.540–13.449). This p value remained significant after correction for multiple comparison. Conclusion: The HLA DRB1*1501-DQB1*0602-DPB1*0501 haplotype may be a genetic marker for the development of TDI-induced asthma in Koreans. Several HLA alleles that enhance specific IgE sensitization in exposed subjects are indicated.

Cells and mediators in diisocyanate-induced occupational asthma

“…TDI exposure was shown to induce permeability of AECs partly through the vascular endothelial growth factor (VEGF) pathway, which plays a crucial role in airway obstruction and hyperresponsiveness in TDI-induced asthma [11,12,13 && ]. In addition, diisocyanates induce oxidative stress by inducing reactive oxygen species (ROS) generation [14,15], which can induce epithelial cell inflammation by directly causing tissue injury [16] and altering various antioxidant systems, such as thioredoxin, glutathione, ferritin, and heme oxygenase-1 [17][18][19][20][21]. The imbalance between oxidant and antioxidant systems leads to the activation of the transcription factors activator protein-1 and NF-kB, which in turn mediate the production of proinflammatory mediators, such as TNF-a, interleukin (IL)-1, IL-8, and IL-6, from AECs [22].…”

“…Recent studies [32,33] have identified the presence of autoantibodies to CK18 and CK19 in TDI-induced asthma patients. TDI exposure could activate tissue transglutaminase (tTG) present in AECs and induce the production of IgG against tTG [14]. Moreover, patients with high levels of tTG-specific IgG showed more severe airway hyperresponsiveness.…”

“…An inability to efficiently manage ROS would result in development of inflammatory processes and cause asthmatic symptoms. Glutathione-dependent enzymes, such as Glutathione S-transferase P1 and Glutathione S-transferase Mu 1, have known polymorphisms associated with diisocyanate-induced occupational asthma [82,83], and some HLA alleles, such as DQA1Ã0104, DQB1Ã0503, DRB1Ã1501, DQB1Ã0602, and DPB1Ã0501, were significantly increased in diisocyanate-induced occupational asthma in different populations [14,84]. Because prolonged exposure to diisocyanates leads to permanent respiratory impairment, an early genetic diagnosis may be the key to a favorable outcome in these high-risk patients.…”

Environmental Isocyanate-Induced Asthma: Morphologic and Pathogenetic Aspects of an Increasing Occupational Disease

“…In a recently published investigation Choi et al aimed to clarify the influence of HLA I and HLA II gene polymorphisms on the risk to develop diisocyanate-induced occupational asthma [69]. Two hundred and fifty eight (258) people were enrolled in this study, 84 patients showed a diisocyanate induced asthma, 47 were exposed controls and 127 people served as non exposed controls.…”

Beneficial role of vitamin D3 in the prevention of certain respiratory diseases

“…The HLA DRB1*130101-DQB1*060101 haplotype is associated with acute chest syndrome in sickle cell anemia patients [Mahdi et al 2009]. The HLA DRB1*1501-DQB1*0602-DPB1*0501 haplotype was found to be a genetic marker for the development of toluene diisocyanate-induced occupational asthma in Koreans [Choi et al 2009]. Flow cytometric analysis revealed that a major portion of CD14 + macrophages in COPD have lower forward scatter, i.e.…”