Beryllium presentation to CD4+ T cells is dependent on a single amino acid residue of the MHC class II beta-chain.
Chronic beryllium disease (CBD) is characterized by a CD4+ T cell alveolitis and granulomatous inflammation in the lung. Genetic susceptibility to this disease has been linked with HLA-DP alleles, particularly those possessing a glutamic acid at position 69 (Glu69) of the beta-chain. However, 15% of CBD patients do not possess a Glu69-containing HLA-DP allele, suggesting that other MHC class II alleles may be involved in disease susceptibility. In CBD patients without a Glu69-containing HLA-DP allele, an increased frequency of HLA-DR13 alleles has been described, and these alleles possess a glutamic acid at position 71 of the beta-chain (which corresponds to position 69 of HLA-DP). Thus, we hypothesized that beryllium presentation to CD4+ T cells was dependent on a glutamic acid residue at the identical position of both HLA-DP and -DR. The results show that HLA-DP Glu69- and HLA-DR Glu71-expressing molecules are capable of inducing beryllium-specific proliferation and IFN-gamma expression by lung CD4+ T cells. Using fibroblasts expressing mutated HLA-DP2 and -DR13 molecules, beryllium recognition was dependent on the glutamic acid at position 69 of HLA-DP and 71 of HLA-DR, suggesting a critical role for this amino acid in beryllium presentation to Ag-specific CD4+ T cells. Thus, these results demonstrate that a single amino acid residue of the MHC class II beta-chain dictates beryllium presentation and potentially, disease susceptibility.
Bill
Jerome R
JR
Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80206, USA.
Mack
Douglas G
DG
Falta
Michael T
MT
Maier
Lisa A
LA
Sullivan
Andrew K
AK
Joslin
Fenneke G
FG
Martin
Allison K
AK
Freed
Brian M
BM
Kotzin
Brian L
BL
Fontenot
Andrew P
AP
D000483:Alleles; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001483:Base Sequence; D001607:Berylliosis / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D001608:Beryllium / Q000276:immunology* / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018076:DNA, Complementary / Q000235:genetics; D006682:HLA-DP Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D016297:Mutagenesis, Site-Directed
D018076:DNA, Complementary; D006682:HLA-DP Antigens; D006684:HLA-DR Antigens; D007371:Interferon-gamma; D001608:Beryllium