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

Abstract

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.

• Authors: Gina M Clayton, Yang Wang, Frances Crawford, Andrey Novikov, Brian T Wimberly, Jeffrey S Kieft, Michael T Falta, Natalie A Bowerman, Philippa Marrack, Andrew P Fontenot, Shaodong Dai, John W Kappler
• Journal: Cell (Cell) Vol. 158 Issue 1 Pg. 132-42 (Jul 03 2014) ISSN: 1097-4172 [Electronic] United States
• PMID: 24995984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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