Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity.
Publication Type:Journal Article
Source:Cell, Volume 158, Issue 1, p.132-42 (2014)
Keywords:Autoimmunity, Berylliosis, Beryllium, CD4-Positive T-Lymphocytes, Crystallography, X-Ray, HLA-DP beta-Chains, Humans, Hypersensitivity, Lung, Models, Molecular, Receptors, Antigen, T-Cell, Sodium
<p>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.</p>