T-cell responses against viral and self-epitopes and HLA-B27 subtypes differentially associated with ankylosing spondylitis

HLA-B27 family comprehends some alleles strongly associated with Ankylosing Spondylitis (AS) and some others that are not. A comparative analysis at genetic and functional level is likely to give a clue to the understanding of disease pathogenesis. Here, we summarize our recent studies on the functional differences between B *270S, the most frequent and worldwide AS-associated allele and B *2709, an allele found in Sardinia where it accounts for 20% ofall B27 alleles and where it is not associated with AS. The two B27 alleles are distinguished by a single amino acid change, located in the peptide binding groove, that correlates with relevant structural and functional differences in presenting viral and self peptides to T-cells. In particular, B *2709 individuals lack in their T-cell repertoire of CD8+ T-cells specific for a self-epitope (pVIPR) derived from the vasoactive intestinal peptide Type 1 receptor (VPAC1). This peptide shares extensive homology with a viral epirope, pLMP2, derived from EBV,toward which, both B *270S and B *2709 individuals mount a vigorous CTL response. A likely explanation to this finding, also supported by crystallographic data, is that the auto reactivity present in the disease-prone B *Z70S individuals can be unleashed by a molecular mimicry mechanism which does not occur in the B *2709 individuals. The possible implications ofthe T-cell cross-reactivity between pLMP2, pVIPR and other related peptides in AS pathogenesis are discussed. © 2009 Landes Bioscience and Springer Science+Business Media