Electrostatic Potential on Human Leukocyte Antigen: Implications for Putative Mechanism of Chronic Beryllium Disease

Details

• Journal Article:
  Environmental Health Perspectives
• Personal Author:
  Snyder, James A. ; Weston, Ainsley ; Tinkle, Sally S. ; Demchuk, Eugene
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Amino Acid Sequence Antigens Berylliosis Beryllium Cations Chronic Disease Epidemiology Genetic Predisposition To Disease Genetics Haplotypes HLA-DP Antigens Immunization Metals, Heavy Models, Molecular Molecular Sequence Data Occupational Exposure Occupational Health Risk Factors Safety Static Electricity

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• Keywords:
  Leukocytes; Antigens; Beryllium-compounds; Beryllium-disease; Occupational-exposure; Epidemiology; Genes; Models; Genetic-factors; Heavy-metals
• Source:
  Environ Health Perspect 2003 Nov; 111(15):1827-1834
• ISSN:
  0091-6765
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  8 pdf pages
• Volume:
  111
• Issue:
  15
• NIOSHTIC Number:
  nn:20023883
• Contact Point Address:
  E. Demchuck, NIOSH, MS-3030, 1095 Willowdale Road, Morgantown, WV 26505, USA
• Email:
  edemchuck@cdc.gov
• CAS Registry Number:
  Beryllium (CAS RN 7440-41-7)
• Federal Fiscal Year:
  2004
• NORA Priority Area:
  Research Tools and Approaches: Risk Assessment Methods
• Peer Reviewed:
  True
• Collection(s):
  National Institute for Occupational Safety and Health CDC Public Access
• Main Document Checksum:
  urn:sha-512:94273aa0486c722428c45accbd0f6bfe8aa483e5a51724bfb7ad7f873421e6d81062abd082cbab2637d75eeab0f95cebd96ac02f7d4f2324daac0c0add6d2443
• Download URL:
  https://stacks.cdc.gov/view/cdc/3844/cdc_3844_DS1.pdf
• File Type:
  [PDF - 1.55 MB ]