title: Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies.
abstract: 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.
authors.affiliation: William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Mear
authors.forename: K L
authors.initials: KL
authors.lastname: Schreiber
authors.forename: C
authors.initials: C
authors.lastname: Münz
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.forename: S
authors.initials: S
authors.lastname: Stevanović
authors.forename: H G
authors.initials: HG
authors.lastname: Rammensee
authors.forename: S L
authors.initials: SL
authors.lastname: Rowland-Jones
authors.forename: R A
authors.initials: RA
authors.lastname: Colbert
mesh_terms: D019943:Amino Acid Substitution; D017951:Antigen Presentation; D001168:Arthritis / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004198:Disease Susceptibility; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000276:immunology; D017510:Protein Folding; D013166:Spondylitis / Q000209:etiology / Q000276:immunology* / Q000378:metabolism
chemical_list: D015796:HLA-B27 Antigen; D010446:Peptide Fragments