Genetic and respiratory tract risk factors for aspergillosis: ABPA and asthma with fungal sensitization.

Abstract

Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 allergic hypersensitivity lung disease due to bronchial colonization of Aspergillus fumigatus that affects 1-2% of asthmatic and 7-9% of cystic fibrosis (CF) patients. We hypothesize that genetic risk factors predispose these patients to develop ABPA. We previously reported HLA-DR2 and DR5 restriction as a risk factor for the development of ABPA. We further propose that HLA-DR restriction is necessary but not sufficient for the development of ABPA. Recently, we reported that IL-4Rα single nucleotide polymorphisms (SNP) and in particular the ile75val SNP in the IL-4 binding region is another risk factor and is associated with increased sensitivity to IL-4 stimulation. It has been reported that the combination of IL-4Rα and IL-13 SNP, ile75val/arg110gln, is associated with more severe asthma. In preliminary studies, we have observed increased frequency of this combination in ABPA asthmatic and CF patients. Another genetic risk factor reported by Brouard et al. is the -1082 GG genotype in the IL-10 promoter in CF patients for the colonization of A. fumigatus and development of ABPA. This genotype was associated with increased plasma IL-10 levels, and perhaps may be associated with increased skewing of Th2 Aspergillus responses rather than down-regulation of inflammatory responses. We hypothesize that increased sensitivity of IL-4 mediated activities secondary to polymorphisms IL-4R in conjunction of other polymorphisms such as IL-13 and IL-10 in conjunction with HLA-DR2/DR5 restriction to Aspergillus antigens in ABPA patients result in increased B-cell activity, monocyte/dendritic cell phenotype that skews Th2 responses, and skewing of Aspergillus-specific Th2 cells. This model system may be applicable to other fungi such as Alternaria and Cladosporium which is associated with increased asthma severity.