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*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.
Fiorillo
María T
MT
Department of Cell Biology and Development, Sapienza, Università di Roma, Roma, Italy.
Sorrentino
Rosa
R
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000956:Antigens, Viral; D000939:Epitopes; D015796:HLA-B27 Antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell