Molecular basis of genetic risk assessment in chronic beryllium disease.
Snyder-J; Weston-A; Demchuk-E
American Industrial Hygiene Conference and Exposition, May 8-13, 2004, Atlanta, Georgia. Fairfax, VA: American Industrial Hygiene Association, 2004 May; :79
Chronic beryllium disease (CBD) represents a possible threat to approximately 800,000 workers and other individuals potentially exposed to beryllium. The pathobiology of chronic beryllium disease involves the major histocompatibility complex class II human leukocyte antigen (HLA). Molecular epidemiological studies suggest that inheritance of specific HLA-DPB1 alleles may be a factor contributing to disease susceptibility. We have studied three-dimensional structural models of HLA-DP proteins encoded by these genes. The extracellular domains of proteins encoded by HLA-DPA1*01031/B1*1701, *1901, *02012, and *0401, and HLA-DPA1*02011/B1*1701, *1901, *02012, *0401 were modeled from the X-ray coordinates of an HLA-DR template. Using these models the electrostatic potentials at the molecular surface of HLA-DP were calculated and compared. These comparisons show specific characteristics in the vicinity of the antigen-binding pocket that distinguish the different HLA-DP allotypes. The differences in electrostatics originate from the shape, specific disposition, and variation in the negatively charged groups around the pocket. The more negative the pocket potential, the greater the odds of CBD estimated from reported molecular epidemiologic studies. The impact is caused by substitutions in the beta-chain at positions B55, B56, B69, B84, and B85. Interestingly, these are the same loci that have been identified as genetic markers conferring susceptibility to CBD and other hard metal lung disease through epidemiological studies. These findings suggest that these substitutions may eventually promote an involuntary cation-binding site within the otherwise metal-free peptide-binding pocket, consequently demoting the innate function of HLA by changing the specificity of antigen recognition. Occupational risk assessment pertaining to beryllium exposures may benefit from consideration of the electrostatic characteristics of HLA-DP isotypes.
Risk-analysis; Beryllium-disease; Beryllium-compounds; Occupational-exposure; Epidemiology; X-ray-analysis; Models; Genes; Lung-disease; Pulmonary-system-disorders; Respiratory-system-disorders
American Industrial Hygiene Conference and Exposition, May 8-13, 2004, Atlanta, Georgia