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 with uncertain pathology. Studies have suggested a pathogenic role for T(H)2 cells. 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.


OBJECTIVE
We sought to confirm whether susceptibility to ABPA is exclusively 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 without ABPA but with positive A fumigatus skin test responses and asthma or cystic fibrosis, and healthy control subjects. HLA-DR and HLA-DQ genes were detected by using low-resolution typing; high-resolution typing was done only on HLA-DR2- and HLA-DR5-positive individuals by using sequence-specific primers (PCR-SSP).


RESULTS
A significantly higher frequency of HLA-DR2 was observed in patients with ABPA versus those without ABPA (corrected P <.01) or healthy control subjects (corrected P <.01). Genotype analysis revealed that susceptibility 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 DR4 or DR7 alleles in non-DR2/5 patients with ABPA suggests that these alleles may also be contributing factors in this disease. Another striking observation was the significantly high frequency of HLA-DQ2 in patients without ABPA (67. 4%) compared with patients with ABPA (20.5%) and normal control subjects (37.7%), suggesting that these alleles may confer protection in the population without ABPA.


CONCLUSIONS
These genetic studies suggest that HLA-DR molecules DR2, DR5, and possibly DR4 or DR7 contribute to susceptibility while HLA-DQ2 contributes to resistance and that a combination of these genetic elements determines the outcome of ABPA in patients with cystic fibrosis and asthma.
Chauhan
B
B
Department of Internal Medicine, St Louis University School of Medicine, St Louis, MO 63104, USA.
Santiago
L
L
Hutcheson
P S
PS
Schwartz
H J
HJ
Spitznagel
E
E
Castro
M
M
Slavin
R G
RG
Bellone
C J
CJ
D000483:Alleles; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000276:immunology / Q000517:prevention & control*; D004198:Disease Susceptibility / Q000276:immunology; D006683:HLA-DQ Antigens / Q000097:blood / Q000235:genetics; D006684:HLA-DR Antigens / Q000097:blood / Q000235:genetics; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000737:chemistry*; D006801:Humans; D012016:Reference Values
D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II