Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity

Cell. 2014 Jul 3;158(1):132-42. doi: 10.1016/j.cell.2014.04.048.


T-cell-mediated hypersensitivity to metal cations is common in humans. How the T cell antigen receptor (TCR) recognizes these cations bound to a major histocompatibility complex (MHC) protein and self-peptide is unknown. Individuals carrying the MHCII allele, HLA-DP2, are at risk for chronic beryllium disease (CBD), a debilitating inflammatory lung condition caused by the reaction of CD4 T cells to inhaled beryllium. Here, we show that the T cell ligand is created when a Be(2+) cation becomes buried in an HLA-DP2/peptide complex, where it is coordinated by both MHC and peptide acidic amino acids. Surprisingly, the TCR does not interact with the Be(2+) itself, but rather with surface changes induced by the firmly bound Be(2+) and an accompanying Na(+) cation. Thus, CBD, by creating a new antigen by indirectly modifying the structure of preexisting self MHC-peptide complex, lies on the border between allergic hypersensitivity and autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmunity*
  • Berylliosis / immunology*
  • Beryllium / metabolism*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Crystallography, X-Ray
  • HLA-DP beta-Chains / chemistry
  • HLA-DP beta-Chains / metabolism*
  • Humans
  • Hypersensitivity / immunology*
  • Lung / pathology
  • Models, Molecular
  • Receptors, Antigen, T-Cell / metabolism*
  • Sodium / chemistry
  • Sodium / metabolism


  • HLA-DP beta-Chains
  • HLA-DPw2 antigen
  • Receptors, Antigen, T-Cell
  • Sodium
  • Beryllium

Associated data

  • PDB/4P4K
  • PDB/4P4R
  • PDB/4P57
  • PDB/4P5K
  • PDB/4P5M