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_H2 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_H1-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.