Electrostatic potential on human leukocyte antigen: implications for putative mechanism of chronic beryllium disease.
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.
Snyder
James A
JA
Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Road, Morgantown, WV 26505, USA.
Weston
Ainsley
A
Tinkle
Sally S
SS
Demchuk
Eugene
E
D000595:Amino Acid Sequence; D001607:Berylliosis / Q000276:immunology / Q000503:physiopathology*; D002412:Cations; D002908:Chronic Disease; D020022:Genetic Predisposition to Disease; D006682:HLA-DP Antigens / Q000737:chemistry* / Q000276:immunology*; D006239:Haplotypes; D006801:Humans; D007114:Immunization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016273:Occupational Exposure; D012307:Risk Factors; D055672:Static Electricity
D002412:Cations; D006682:HLA-DP Antigens