Misfolding of HLA-B27 as a Result of Its B Pocket Suggests a Novel Mechanism for Its Role in Susceptibility to Spondyloarthropathies

The MHC class I protein HLA-B27 is strongly associated with susceptibility to spondyloarthropathies and can cause arthritis when expressed in rats and mice, implying a direct role in disease pathogenesis. A prominent hypothesis to explain this role suggests that the unique peptide binding specificit...

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Bibliographic Details
Published in:The Journal of immunology (1950) 1999-12, Vol.163 (12), p.6665-6670
Main Authors: Mear, John P, Schreiber, Kathy L, Munz, Christian, Zhu, Xiaoming, Stevanovic, Stefan, Rammensee, Hans-Georg, Rowland-Jones, Sarah L, Colbert, Robert A
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Antigen Presentation
Arthritis - etiology
Arthritis - immunology
Arthritis - metabolism
Cytosol - immunology
Cytosol - metabolism
Disease Susceptibility
histocompatibility antigen HLA
HLA-B27 Antigen - chemistry
HLA-B27 Antigen - metabolism
HLA-B27 Antigen - physiology
Humans
Peptide Fragments - chemistry
Peptide Fragments - immunology
Peptide Fragments - metabolism
Peptide Fragments - physiology
Protein Binding - immunology
Protein Folding
Spondylitis - etiology
Spondylitis - immunology
Spondylitis - metabolism
spondyloarthropathy
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Summary:The MHC class I protein HLA-B27 is strongly associated with susceptibility to spondyloarthropathies and can cause arthritis when expressed in rats and mice, implying a direct role in disease pathogenesis. A prominent hypothesis to explain this role suggests that the unique peptide binding specificity of HLA-B27 confers an ability to present arthritogenic peptides. The B pocket, a region of the peptide binding groove that is an important determinant of allele-specific peptide binding, is thought to be critical for arthritogenicity. However, this hypothesis remains unproven. We show that in addition to its role in peptide selection, the B pocket causes a portion of the pool of assembling HLA-B27 heavy chains in the endoplasmic reticulum to misfold, resulting in their degradation in the cytosol. The misfolding phenotype is corrected by replacing the HLA-B27 B pocket with one from HLA-A2. Our results suggest an alternative to the arthritogenic peptide hypothesis. Misfolding and its consequences, rather than allele-specific peptide presentation, may underlie the strong link between the HLA-B27 B pocket and susceptibility to spondyloarthropathies.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.163.12.6665