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 hypothes is to explain this role suggests that the unique peptide binding specificit y of HLA-B27 confers an ability to present arthritogenic peptides, The B po cket, a region of the peptide binding groove that is an important determina nt of allele-specific peptide binding, is thought to be critical for arthri togenicity, However, this hypothesis remains unproven. We show that in addi tion 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 mi sfold, resulting in their degradation in the cytosol. The misfolding phenot ype is corrected by replacing the HLA-B27 B pocket with one from HLA-A2, Ou r results suggest an alternative to the arthritogenic peptide hypothesis, M isfolding and its consequences, rather than allele-specific peptide present ation, may underlie the strong link between the HLA-B27 B pocket and suscep tibility to spondyloarthropathies.