Abstract
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*2705, the most frequent and worldwide AS-associated allele and B*2709, an allele found in Sardinia where it accounts for 20% of all 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 epitope, pLMP2, derived from EBV, toward which, both B*2705 and B*2709 individuals mount a vigorous CTL response. A likely explanation to this finding, also supported by crystallographic data, is that the autoreactivity present in the disease-prone B*2705 individuals can be unleashed by a molecular mimicry mechanism which does not occur in the B*2709 individuals. The possible implications of the T-cell cross-reactivity between pLMP2, pVIPR and other related peptides in AS pathogenesis are discussed.
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Fiorillo, M.T., Sorrentino, R. (2009). T-Cell Responses Against Viral and Self-Epitopes and HLA-B27 Subtypes Differentially Associated with Ankylosing Spondylitis. In: López-Larrea, C., Díaz-Peña, R. (eds) Molecular Mechanisms of Spondyloarthropathies. Advances in Experimental Medicine and Biology, vol 649. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0298-6_19
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DOI: https://doi.org/10.1007/978-1-4419-0298-6_19
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