HLA-B27 is a Major Histocompatibility Complex (MHC) class I molecule which exhibits a strong association with the inflammatory arthritic disorder Ankylosing Spondylitis (AS). It has been postulated that the tendency for HLAB27 to misfold and form disulphide linked heavy chain homodimers may contribute to AS pathogenesis. However, it remains elusive how these aberrant forms occur and to which extent they participate in AS development. I have analysed the contribution of conserved cysteine residues at positions (p) 101, 164, 203 and 259 and unpaired cysteines at p67, 308 and 325, in the formation of ER resident heavy chain homodimers. I demonstrated that HLA-B27 dimerisation involves a hierarchy of disulphide bonding. Moreover, my study indicates that heavy chain-dimers are composed of multiple species, with each possibly exhibiting varying degrees of folding/unfolding. I found that HLA-B*27:05 adopts novel in vivo conformations within the ER lumen, which have yet be to identified for other HLA alleles. Detection of these conformations depends on cysteine residue exposure to the ER environment what can explain the propensity for heavy chains to misfold. Finally, I investigated the role of the MHC class I antigen presentation pathway in HLA-B27 dimerisation. I found that HLA-B27 retains its tendency to dimerise despite the presence of β2m and high affinity peptide and both β2m-free (unfolded) and β2m+peptide-associated (folded) homodimers can associate with the Peptide Loading Complex. Moreover, the tendency for HLA-B27 to dimerise is influenced by p116 within the peptide binding groove, which is a natural polymorphism within AS-associated and non-AS–associated HLA–B27 subtypes. These studies may have implications for inflammatory disease since they begin to provide a biochemical understanding for the ability of HLA-B27 to misfold.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626474 |
| Date | January 2013 |
| Creators | Lenart, I. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1416286/ |
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