Beryllium Presentation to CD4 super(+) T Cells Is Dependent on a Single Amino Acid Residue of the MHC Class II beta -Chain

• Published in: Journal of Immunology 2005-11, Vol.175 (10), p.7029-7037
• Main Authors: Bill, Jerome R, Mack, Douglas G, Falta, Michael T, Maier, Lisa A, Sullivan, Andrew K, Joslin, Fenneke G, Martin, Allison K, Freed, Brian M, Kotzin, Brian L, Fontenot, Andrew P
• Format: Article
• Language: English
• ISSN: 0022-1767; 1365-2567

Chronic beryllium disease (CBD) is characterized by a CD4 super(+) 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 (Glu super(69)) of the beta -chain. However, 15% of CBD patients do not possess a Glu super(69)-containing HLA-DP allele, suggesting that other MHC class II alleles may be involved in disease susceptibility. In CBD patients without a Glu super(69)-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 super(+) 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 Glu super(69)- and HLA-DR Glu super(71)-expressing molecules are capable of inducing beryllium-specific proliferation and IFN- gamma expression by lung CD4 super(+) 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 super(+) 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.