title: Beryllium presentation to CD4+ T cells is dependent on a single amino acid residue of the MHC class II beta-chain.
abstract: 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.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80206, USA.
authors.forename: Jerome R
authors.initials: JR
authors.lastname: Bill
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Mack
authors.forename: Michael T
authors.initials: MT
authors.lastname: Falta
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Maier
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sullivan
authors.forename: Fenneke G
authors.initials: FG
authors.lastname: Joslin
authors.forename: Allison K
authors.initials: AK
authors.lastname: Martin
authors.forename: Brian M
authors.initials: BM
authors.lastname: Freed
authors.forename: Brian L
authors.initials: BL
authors.lastname: Kotzin
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
mesh_terms: 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
chemical_list: D018076:DNA, Complementary; D006682:HLA-DP Antigens; D006684:HLA-DR Antigens; D007371:Interferon-gamma; D001608:Beryllium