HLA-B27

Due to its strong association with spondyloarthropathies, HLA-B27 is the most studied HLA-B allele. It is not entirely clear how HLA-B27 influences disease, however there are some prevailing theories as to the mechanism. The theories can be divided between antigen-dependent and antigen-independent categories.[5]

Antigen-dependent theories

These theories consider a specific combination of antigen peptide sequence and the binding groove (B pocket) of HLA-B27 (which will have different properties from the other HLA-B alleles). The arthritogenic peptide hypothesis suggests that HLA-B27 has a unique ability to bind antigens from a microorganism that trigger a CD8 T-cell response that then cross-reacts with a HLA-B27/self-peptide pair. Furthermore, it has been shown that HLA-B27 can bind peptides at the cell surface.[6] The molecular mimicry hypothesis is similar, however it suggests that cross reactivity between some bacterial antigens and self peptide can break tolerance and lead to autoimmunity.[5]

Antigen-independent theories

These theories refer to the unusual biochemical properties that HLA-B27 has. The misfolding hypothesis suggests that slow folding during HLA-B27's tertiary structure folding and association with β2 microglobulin causes the protein to be misfolded, therefore initiating the unfolded protein response (UPR) - a pro-inflammatory endoplasmic reticulum (ER) stress response. However, although this mechanism has been demonstrated both in vitro and in animals, there is little evidence of its occurrence in human spondyloarthritis.[6] Also, the HLA-B27 heavy chain homodimer formation hypothesis suggests that B27 heavy chains tend to dimerise and accumulate in the ER, once again, initiating the UPR.[5] Alternatively, cell surface B27 heavy chains and dimers can bind to regulatory immune receptors such as members of the killer cell immunoglobulin-like receptor family, promoting the survival and differentiation of pro-inflammatory leukocytes in disease.

One more misfolding theory, published in 2004,[7] proposes that β2 microglobulin-free heavy chains of HLA-B27 undergo a facile conformational change in which the C-terminal end of domain 2 (consisting of a long helix) becomes subject to a helix-coil transition involving residues 169-181 of the heavy chain, owing to the conformational freedom newly experienced by domain 3 of the heavy chain when there is no longer any bound light chain (i.e., β2 microglobulin) and owing to the consequent rotation around the backbone dihedral angles of residues 167/168. The proposed conformational transition is thought to allow the newly-generated coiled region (incorporating residues 'RRYLENGKETLQR' which have also been found to be naturally bound to HLA-B27 as a 9-mer peptide) to bind to either the peptide-binding cleft of the same polypeptide chain (in an act of self-display) or to the cleft of another polypeptide chain (in an act of cross-display). Cross-display is proposed to lead to the formation of large, soluble, high molecular weight (HMW), degradation-resistant, long-surviving aggregates of the HLA-B27 heavy chain. Together with any homodimers formed either by cross-display or by a disulfide-linked homodimerization mechanism, it is proposed that such HMW aggregates survive on the cell surface without undergoing rapid degradation, and stimulate an immune response. Three previously noted features of HLA-B27, which distinguish it from other heavy chains, underlie the hypothesis : (1) HLA-B27 has been found to be bound to peptides longer than 9-mers, suggesting that the cleft can accommodate a longer polypeptide chain; (2) HLA-B27 has been found to itself contain a sequence that has also been actually discovered to be bound to HLA-B27, as an independent peptide; and (3) HLA-B27 heavy chains lacking β2 microglobulin have been seen on cell surfaces.