Elsevier

Immunobiology

Volume 217, Issue 1, January 2012, Pages 8-12
Immunobiology

Association of HLA class II alleles with sensitization to cow dander Bos d 2, an important occupational allergen

https://doi.org/10.1016/j.imbio.2011.08.012Get rights and content

Abstract

Allergic sensitization results from a complex interaction between genetic and environmental factors. Earlier studies have shown that highly polymorphic HLA genes are associated with a variety of allergies. Several important respiratory allergens belong to the family of lipocalin proteins. These include occupational sensitizers, such as cow Bos d 2 or rat Rat n 1, and prevalent indoor sensitizers, such as dog Can f 1 or cockroach Bla g 4. HLA associations with sensitization to lipocalin allergens are incompletely known. In the present study we have investigated an association between HLA alleles and sensitization to the major cow allergen Bos d 2. The HLA-DR/DQ genotypes of 40 Bos d 2-sensitized subjects having occupational asthma were determined by polymerase chain reaction (PCR) and the results were compared with the genotypes of 151 unrelated Finnish subjects. The frequencies of HLA class II alleles DRB1*0101, DRB1*0404, DQB1*0302, and DQB1*0501 were significantly higher among Bos d 2-sensitized than among control subjects. In addition, the allergic subjects expressed significantly lower frequencies of HLA-DRB1*0301 and DQB1*0201 alleles than did the control subjects. These data suggest that the HLA class II alleles DRB1*0101, DRB1*0404, DQB1*0302, and DQB1*0501, and the haplotypes that include them, are associated with sensitization to the major cow allergen Bos d 2, whereas HLA-DRB1*0301 and DQB1*0201 are dissociated with it. Amino acid analysis provides a biologically plausible explanation for the HLA associations.

Introduction

Asthma is the most common occupational respiratory disorder in developed countries (Kogevinas et al. 1999). In a study including 12 industrialized countries, farmers were found to be among the occupations with the highest risk of asthma (Kogevinas et al. 1999). In Finland, cow dander is an important work-related sensitizer and responsible for the most cases of occupational asthma among farmers (Koskela et al., 2003, Virtanen et al., 1996).

The major allergen found in bovine dander is the lipocalin protein Bos d 2 (Rautiainen et al. 1997). In addition to Bos d 2, the majority of important mammalian respiratory allergens are lipocalins (Virtanen and Kinnunen 2008). These include, for example, major allergens of dog, cat, horse, rabbit, mouse, rat, and guinea-pig (Virtanen and Kinnunen 2008). Lipocalin proteins share a similar three-dimensional structure although their sequential identity at the amino acid level is often relatively low, between 20 and 30% (Akerstrom et al., 2000, Flower et al., 2000). One of their functions in the body is to carry hydrophobic ligands, such as pheromones and vitamins (Akerstrom et al. 2000).

Allergic sensitization results from a complex interaction between genetic and environmental factors. It has become obvious that there is no single susceptibility gene that increases the risk for allergies. Among the most investigated genes are those of human leucocyte antigens (HLA) which are the most polymorphic genes in the human genome (The MHC sequencing consortium 1999). The function of HLA class II molecules is to present peptides derived from exogenous proteins on the surface of antigen-presenting cells (APCs) to specific CD4+ T lymphocytes.

Sensitization, for example, to Art v 1 of mugwort (Jahn-Schmid et al., 2002, Torio et al., 2003) or phospholipase A2 (PLA2) of bee venom (Sanchez-Velasco et al. 2005) have been associated with HLA-DRB1*01 and HLA-DRB1*16, or with DRB1*0101, DRB1*0103 and DQB1*0501, respectively. Associations with HLA class II alleles have also been shown with allergies to cockroach (Donfack et al., 2000, Kalpaklioglu and Turan, 2002) and rat (Jeal et al. 2003). Both of these allergen sources contain important lipocalin allergens. Therefore, it is possible that HLA associations are also found with sensitization to additional lipocalin allergens. In this study, associations between HLA genotypes and sensitization to the major cow allergen Bos d 2 were investigated.

Section snippets

Subjects

The study included 40 asthmatic farmers whose allergy to cow dander had been confirmed at the Pulmonary Clinic of Kuopio University Hospital. The gender distribution was near to equal (21 female and 19 male). The average age of the subjects was 46.75 ± 1.44 years (mean ± SEM). All subjects showed a positive response (a decrease in the forced expiratory volume in one second (FEV1) of >15%) in the specific inhalation challenge with bovine dander allergens (Soluprick SQ, ALK Abelló, Hørsholm, Denmark),

Results

According to the skin prick tests, all 40 cow-asthmatic subjects were sensitized to cow and its major allergen Bos d 2. The average wheal diameters (±standard errors of the mean) to cow dander and to Bos d 2 were 5.83 ± 0.43 mm and 5.00 ± 0.25 mm, respectively.

Discussion

In the present study, we have shown that the frequencies of HLA class II alleles DRB1*0101, DRB1*0404, DQB1*0302, and DQB1*0501 were significantly higher among Bos d 2-sensitized than the control subjects. Due to linkage disequilibrium, DRB1*0101 is known to be inherited with DQB1*0501 and DRB1*0404 with DQB1*0302 (Klitz et al. 2003). As indicated in Table 1, our results suggest that these alleles are significant in increasing the risk for cow allergy and occupational asthma in farmers (see

Acknowledgements

The skilful technical assistance of Virpi Fisk, Pirjo Vänttinen and Raija Tukiainen is gratefully acknowledged. This work was financially supported by the Academy of Finland (contract #115160), Kuopio University Hospital (project #5021605) and the foundation of Väinö and Laina Kivi.

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