Chronic
beryllium disease (CBD) is a fibrotic lung disorder caused by
beryllium (Be) exposure and is characterized by granulomatous
inflammation and the accumulation of Be-responsive CD4(+) T cells in the lung.
Genetic susceptibility to CBD has been associated with certain alleles of the MHCII molecule
HLA-DP, especially
HLA-DPB1*0201 and other alleles that contain a
glutamic acid residue at position 69 of the beta-chain (betaGlu69). The
HLA-DP alleles that can present Be to T cells match those implicated in the
genetic susceptibility, suggesting that the HLA contribution to disease is based on the ability of those molecules to bind and present Be to T cells. The structure of
HLA-DP2 and its interaction with Be are unknown. Here, we present the
HLA-DP2 structure with its
antigen-binding groove occupied by a self-
peptide derived from the
HLA-DR alpha-chain. The most striking feature of the structure is an unusual
solvent exposed acidic pocket formed between the
peptide backbone and the
HLA-DP2 beta-chain alpha-helix and containing three
glutamic acids from the beta-chain, including betaGlu69. In the crystal packing, this pocket has been filled with the
guanidinium group of an
arginine from a neighboring molecule. This positively charged moiety forms an extensive H-bond/
salt bridge network with the three
glutamic acids, offering a plausible model for how Be-containing complexes might occupy this site. This idea is strengthened by the demonstration that mutation of any of the three
glutamic acids in this pocket results in loss of the ability of DP2 to present Be to T cells.