HLA-DRB1 alleles control allergic bronchopulmonary aspergillosis-like pulmonary responses in humanized transgenic mice.

BACKGROUND

Allergic bronchopulmonary aspergillosis (ABPA) is a lung hypersensitivity disease mediated in part by CD4(+) T(H)2 cells. There is a significant association between ABPA and the HLA-DR2 genotypes DRB1()1501 and DRB1()1503, whereas resistance might be associated with HLA-DRB1(*)1502.

OBJECTIVE

We sought to elucidate the role of HLA-DR alleles in allergic inflammation in lungs.

METHODS

HLA-DR humanized transgenic mice expressing either the susceptible or resistant alleles were analyzed for the nature and extent of pulmonary inflammation after exposure to Aspergillus species antigens.

RESULTS

Exposed DRB1()1501 and DRB1()1503 transgenic mice displayed infiltrates made up prominently of eosinophils, which is consistent with the inflammation found in ABPA. The resistant DRB1()1502 mice, on the other hand, displayed minimal to moderate inflammation, consisting mainly of T-cell infiltrates. Significantly more mucin was produced in the DRB1()1503 and DRB1()1501 mice, and their ability to limit the number of Aspergillus species conidia within the lung parenchyma was impaired. Despite their differences, both the DRB1()1503 and DRB1(*)1502 strains mounted comparable T cell-proliferative responses to Aspergillus species antigens.

CONCLUSION

The HLA-DR2 alleles DRB1()1501 and DRB1()1503 play a major role in the development of allergic pulmonary inflammation. In contrast, the HLA-DR2 allele DRB1(*)1502 mediates a nonallergic T(H)1-like response to the organism, possibly explaining an ABPA resistance factor. These results are in support of our published human studies in patients with cystic fibrosis and asthma.

CLINICAL IMPLICATIONS

HLA-DR typing in patients with cystic fibrosis and asthma will aid in the identification of individuals at risk for ABPA.