Evidence for the involvement of two different MHC class II regions in susceptibility or protection in allergic bronchopulmonary aspergillosis

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a disease wit h uncertain pathology. Studies have suggested a pathogenic role for T(H)2 c ells. Previously, we demonstrated, in a small group of patients, that T(H)2 reactivity to a major Aspergillus fumigatus antigen was restricted by HLA- DR2 or HLA-DR5 alleles. Objectives: We sought to confirm whether susceptibility to ABPA is exclusiv ely associated with HLA-DR locus and to investigate the involvement of HLA- DQ genes in the development of ABPA. Methods: Genomic DNA was extracted from patients with ABPA, patients withou t ABPA but with positive A fumigatus skin test responses and asthma or cyst ic fibrosis, and healthy control subjects. HLA-DR and HLA-DQ genes were det ected by using low-resolution typing; high-resolution typing was done only on HLA-DR2- and HLA-DR5-positive individuals by using sequence-specific pri mers (PCR-SSP). Results: A significantly higher frequency of HLA-DR2 was observed in patien ts with ABPA versus those without ABPA (corrected P < .01) or healthy contr ol subjects (corrected P < .01). Genotype analysis revealed that susceptibi lity to ABPA is associated with HLA-DR2 alleles DRB1*1503 and DRB1*1501 and , to a lesser extent, with the HLA-DR5 allele DRB1*1104. The presence of DR 4 or DR7 alleles in non-DR2/5 patients with ABPA suggests that these allele s may also be contributing factors in this disease. Another striking observ ation was the significantly high frequency of HLA-DQ2 in patients without A BPA (67.4%) compared with patients with ABPA (20.5%) and normal control sub jects (37.7%), suggesting that these alleles may confer protection in the p opulation without ABPA. Conclusion: These genetic studies suggest that HLA-DR molecules DR2, DR5, a nd possibly DR4 or DR7 contribute to susceptibility while HLA-DQ2 contribut es to resistance and that a combination of these genetic elements determine s the outcome of ABPA in patients with cystic fibrosis and asthma.