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

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

Author information

1
Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206, USA; Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
2
Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
3
Department of Biochemistry and Molecular Genetics, Howard Hughes Medical Institute, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Program in Structural Biology and Biochemistry, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
4
Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
5
Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206, USA; Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
6
Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
7
Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA. Electronic address: dais@njhealth.org.
8
Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206, USA; Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Program in Structural Biology and Biochemistry, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA. Electronic address: kapplerj@njhealth.org.

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.

Comment in

PMID:
24995984
PMCID:
PMC4269484
DOI:
10.1016/j.cell.2014.04.048
[Indexed for MEDLINE]
Free PMC Article

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