Targeting HLA-B27 Misfolding as a Potential Therapeutic Treatment of Ankylosying Spondylitis-Juniper Publishers

HLA-B27 is a Major Histocompatibility Complex (MHC) class I molecule whose predominant function is the presentation of short 8-10 amino acid long peptides to cytotoxic CD8+T cells. HLA-B27 exhibits a strong association with a group of inflammatory arthritic diseases referred to as the spondyloarthropathies (SpAs). The SpAs are characterized by inflammation at the entheses, followed by skeletal fusion, which predominantly occurs at the sacroiliac joint and along the vertebral column. In addition, the SpAs are characterized by inflammation of other organ systems such as the gastrointestinal tract, which is perhaps the next most common inflammatory lesion, manifesting as either a ‘Crohns’ or ‘colitis’ like disease. It remains unknown why these specific sites are targets for disease development but it has been proposed that exposure to mechanical stress could be a contributory factor. MHC class I heavy chains (PCs) assemble within the endoplasmic reticulum (ER) via transient associations with ER resident chaperones. MHC class I HCs form non-covalent interactions with the light chain beta-2 microglobulin (b2m) and associate with peptides of 8-10 amino acids long, before transiting through the secretory pathway to the plasma membrane. MHC class I molecules, which can misfold at any point along the assembly process, are expelled from the ER and targeted for degradation by the ubiquitin-proteasome pathway. The pathway for degrading ER associated proteins is known as ER associated degradation (ERAD). However, different proteins may employ different components of the ERAD pathway.

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