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Electrostatic potential on human leukocyte antigen: implications for putative mechanism of chronic beryllium disease.

Authors
Snyder-JA; Weston-A; Tinkle-SS; Demchuk-E
Source
Environ Health Perspect 2003 Nov; 111(15):1827-1834
NIOSHTIC No.
20023883
Abstract
The pathobiology of chronic beryllium disease (CBD) involves the major histocompatibility complex class II human leukocyte antigen (HLA). Although occupational exposure to beryllium is the cause of CBD, molecular epidemiologic studies suggest that specific (Italic)HLA-DPB1(/Italic) alleles may be genetic susceptibility factors. We have studied three-dimensional structural models of HLA-DP proteins encoded by these genes. The extracellular domains of HLA-DPA1*0103/B1*1701, *1901, *0201, and *0401, and HLA-DPA1*0201/B1*1701, *1901, *0201, and *0401 were modeled from the X-ray coordinates of an HLA-DR template. Using these models, the electrostatic potential at the molecular surface of each HLA-DP was calculated and compared. These comparisons identify specific characteristics in the vicinity of the antigen-binding pocket that distinguish the different HLA-DP allotypes. 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 developing CBD estimated from reported epidemiologic studies. Adverse impact is caused by charged substitutions in positions 55, 56, 69, 84, and 85, namely, the exact same loci identified as genetic markers of CBD susceptibility as well as cobalt-lung hard metal disease. These findings suggest that certain substitutions may promote an involuntary cation-binding site within a putatively metal-free peptide-binding pocket and therefore change the innate specificity of antigen recognition.
Keywords
Leukocytes; Antigens; Beryllium-compounds; Beryllium-disease; Occupational-exposure; Epidemiology; Genes; Models; Genetic-factors; Heavy-metals
Contact
E. Demchuck, NIOSH, MS-3030, 1095 Willowdale Road, Morgantown, WV 26505, USA
CODEN
EVHPAZ
CAS No.
7440-41-7
Publication Date
20031101
Document Type
Journal Article
Email Address
edemchuck@cdc.gov
Fiscal Year
2004
NTIS Accession No.
NTIS Price
Issue of Publication
15
ISSN
0091-6765
NIOSH Division
HELD
Priority Area
Research Tools and Approaches: Risk Assessment Methods
Source Name
Environmental Health Perspectives
State
WV
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