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.