Impact of negatively charged patches on the surface of MHC class II antigen-presenting proteins on risk of chronic beryllium disease.
Snyder JA; Demchuk E; McCanlies EC; Schuler CR; Kreiss K; Andrew ME; Frye BL; Ensey JS; Stanton ML; Weston A
J R Soc Interface 2008 Jul; 5(24):749-758
Chronic beryllium disease (CBD) is a granulomatous lung disease that occurs primarily in workers who are exposed to beryllium dust or fumes. Although exposure to beryllium is a necessary factor in the pathobiology of CBD, alleles that code for a glutamic acid residue at the 69th position of the HLA-DPß1 gene have previously been found to be associated with CBD. To date, 43 HLA-DPß1 alleles that code for glutamic acid 69 (E69) have been described. Whether all of these E69 coding alleles convey equal risk of CBD is unknown. The present study demonstrates that, on the one hand, E69 alleloforms of major histocompatibility complex class II antigen-presenting proteins with the greatest negative surface charge convey the highest risk of CBD, and on the other hand, irrespective of allele, they convey equal risk of beryllium sensitization (BeS). In addition, the data suggest that the same alleles that cause the greatest risk of CBD are also important for the progression from BeS to CBD. Alleles convey the highest risk code for E26 in a constant region and for E69, aspartic acid 55 (D55), E56, D84 and E85 in hypervariable regions of the HLA-DPß1 chain. Together with the calculated high binding affinities for beryllium, these results suggest that an adverse immune response, leading to CBD, is triggered by chemically specific metal-protein interactions.
Beryllium-disease; Dust-exposure; Dust-inhalation; Dust-particles; Fumes; Biological-effects; Genes; Genetic-factors; Immunologic-disorders; Chemical-composition; Chemical-properties; Chemoreceptors; Chemical-synthesis;
Author Keywords: HLA-DP; genetic epidemiology; beryllium sensitization; granulomas; free energy perturbation; molecular dynamics
Eugene Demchuk, Division of Toxicology and Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road, Atlanta, GA 30333
Journal of the Royal Society. Interface