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

2007; Elsevier BV; Volume: 120; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2007.04.037

1097-6825

Sherri Koehm, Raymond G. Slavin, Patricia S. Hutcheson, Theodore Trejo, Chella S. David, Clifford J. Bellone,

Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

BackgroundAllergic bronchopulmonary aspergillosis (ABPA) is a lung hypersensitivity disease mediated in part by CD4+ TH2 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.ObjectiveWe sought to elucidate the role of HLA-DR alleles in allergic inflammation in lungs.MethodsHLA-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.ResultsExposed 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.ConclusionThe 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 TH1-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 implicationsHLA-DR typing in patients with cystic fibrosis and asthma will aid in the identification of individuals at risk for ABPA. Allergic bronchopulmonary aspergillosis (ABPA) is a lung hypersensitivity disease mediated in part by CD4+ TH2 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. We sought to elucidate the role of HLA-DR alleles in allergic inflammation in lungs. 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. 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. 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 TH1-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.