Degradation of misfolded HLA B*2704 (associated with disease) involves UPR, autophagy and aggresomes whereas degradation of HLA B*2709 (non-associated with disease) involves the endosomal-lysosomal pathway

Ankylosing spondylitis (AS) belongs to a group of diseases, called spondyloarthropathies (SpA), which are strongly associated with the genetic marker, HLA-B27. AS is characterized by inflammation of joints, and primarily affects the spine. Over 200 subtypes of HLA B27 are known, owing to high polymorphism. Some are strongly associated with disease (e.g., B*2704) whereas others are rarely associated (e.g., B*2709). Misfolding of HLA-B27 molecules [as dimers, or as high molecular weight (HMW) oligomers] is one of several hypotheses proposed. Our group has previously established the existence of HMW species of HLA-B27 in AS patients. Still, very little is known about the mechanisms underlying differences in pathogenic outcomes of different HLA-B27 subtypes. We conducted a proteomics-based evaluation of the differential disease association of HLA B*2704 and B*2709, using stable transfectants of genes encoding the two proteins.