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(H)2 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.


CONCLUSIONS
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(H)1-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.


CONCLUSIONS
HLA-DR typing in patients with cystic fibrosis and asthma will aid in the identification of individuals at risk for ABPA.
Koehm
Sherri
S
Department of Molecular Microbiology and Immunology, Saint Louis University, St Louis, MO, USA.
Slavin
Raymond G
RG
Hutcheson
Patricia S
PS
Trejo
Theodore
T
David
Chella S
CS
Bellone
Clifford J
CJ
D000483:Alleles; D000818:Animals; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007073:Immunoglobulin E