Implications of structural and thermodynamic studies of HLA-B27 subtypes exhibiting differential association with...

Structural and thermodynamic properties of HLA-B27 molecules provide the basis for their function within the immune system and are probably also central for the understanding of the pathology of HLA-B27-associated diseases such as ankolysing spondylitis (AS). Several HLA-B27 alleles are AS-associated, whereas some are not, although the protein encoded by the former may differ in only a single amino acid exchange from those specified by the latter. This indicates that subtype-specific polymorphic residues play a key role in determining whether an HLA-B27 subtype is AS-associated or not and open the possibility to correlate structural, thermodynamic and functional characteristics ofa given subtype with the disease association. Our studies involved X-ray crystallography and various other biophysical techniques to examine how several different peptides are accommodated within the binding groove of the molecules. The HLA-B*2705 and HLA-B*2709 subtypes, whose products differ in only a single amino acid residue of their heavy chains from each other, were primarily chosen for these analyses, but our studies have recently also been extended to the closely related subtypes HLA-B*2703, HLA-B*2704 and HLA-B*2706. The analyses reveal that structural and thermodynamic differences between HLA-B27 complexes may exist, depending on the peptide that is displayed. Furthermore, aviralpeptide and two self-peptides were found that exhibit HLA-B27 subtype-dependent molecular mimicry, thereby providing a molecular basis to account for the subtype-dependent presence of autoreactive T-cells. Although these results do not exclude other theories for the pathogenesis of AS, they support the arthritogenic peptide hypothesis which envisages molecular mimicry between HLA-B27-presented foreign and self-peptides to explain the cross-reactivity of autoreactive T-cells that are found in HLA-B*2705-positive individuals, in particular when they suffer from AS.