MHC restriction in allergic bronchopulmonary aspergillosis

Abstract

Allergic bronchopulmonary aspergillosis (ABPA) is a rare complication in patients with asthma but more common in patients with cystic fibrosis. In the presence of the fungus Aspergillus fumigatus (Af) in the lower respiratory tract, patients mount a heightened IgG and IgE humoral response specific for Af antigens. Studies on ABPA have suggested a pathogenic role for antigen specific CD4+ Th2 like T lymphocytes producing increased levels of IL-4 and IL-5. MHC class II genes coding for highly polymorphic HLA molecules have been shown to be the likely candidates for controlling immune responses to common allergens. However there has been a lack of information on the pathophysiological role of HLA genes in the development of ABPA. This review describes an association between HLA- class II alleles and the specific responses to Af antigen (Asp f 1) in ABPA. These studies focused on MHC restriction and distribution of HLA- class II alleles in two groups of unrelated North American Caucasian patients with cystic fibrosis and/or asthma. One group consisted of patients with a confirmed diagnosis of ABPA and a second group of patients with Af sensitivity but no ABPA. HLA association studies revealed that the predisposition to develop ABPA is associated with HLA-DR2 and DR5, and possibly DR4 or DR7. A strong association of HLA-DR antigens with ABPA reflects that HLA-DR molecules may present disease-causing peptides. On the other hand a significant association of HLA-DQ2 with Af sensitive nonABPA indicates the involvement of HLA-DQ molecules in protection. A combination of these genetic factors determines the outcome of ABPA in patients with cystic fibrosis and asthma.

Cystic Fibrosis Lung Immunity: The Role of the Macrophage

“…Communication between antigen presenting cells, or phagocytes such as MΦs, their environment and downstream adaptive immunity is essential for an effective immune response. Studies from the CF GWAS project have shown that there is a significant correlation between MHC class II polymorphisms in the HLA-DR and HLA-DQ regions and overall disease severity 89,92 , implicating differences in the capacity to communicate to T-cells and other adaptive immune cells. This is not unique to CF since there have been several instances of the association between specific MHC class II alleles and increased susceptibility or severity of inflammatory diseases, including allergic broncho-pulmonary aspergillosis, multiple sclerosis, rheumatoid arthritis, sarcoidosis, asthma and diabetes 93,94 .…”

Genetic susceptibility to allergic bronchopulmonary aspergillosis in asthma: a genetic association study

“…In one case series from India, 5 % of cases were found to be familial in nature [ 10 ]. The structural gene CFTR has been previously associated with ABPA [ 11 ], and small genetic association studies (involving ≤38 patients) have identified associations between ABPA and SNPs in the immune genes IL4R, IL10, TLR9, SFTPA2 and HLA (HLA-DR) [ 12 – 16 ], however, these results do not explain all cases of ABPA, and the immune mechanisms that underlie ABPA remain unclear.…”

Immunoglobulin allotypes and IgG subclass antibody response to Aspergillus fumigatus in cystic fibrosis patients

“…IL-4 is a critical mediator of B-cell switching to IgE as well as IgG4 synthesis. Markers around the IL-4 locus on chromosome 5q31.1 linked to a gene controlling IgE levels, GM allotypes on chromosome 14q32 and six HLA-DR2/5 subtypes on chromosome 6 reported to be of pathophysiological importance to ABPA [38] indicate a polygenic inheritance of the immune response.…”