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.