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Beryllium Presentation to CD4⁺ T Cells Is Dependent on a Single Amino Acid Residue of the MHC Class II -Chain¹

Jerome R. Bill^*,, Douglas G. Mack^*, Michael T. Falta^*,, Lisa A. Maier^*,,, Andrew K. Sullivan^*, Fenneke G. Joslin^*, Allison K. Martin^*, Brian M. Freed^*,, Brian L. Kotzin^*, and Andrew P. Fontenot^2,*,

^* Department of Medicine, Department of Immunology, and Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO 80262; and Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206

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 -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 -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- 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 -chain dictates beryllium presentation and potentially, disease susceptibility.

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