Large sharing of T-cell epitopes and natural ligands between HLA-B27 subtypes (B*2702 and B*2705) associated with spondyloarthritis.
HLA-B*2702 is an ankylosing spondylitis-associated allotype that differs from the more common B*2705 at residues 77, 80, and 81, in the peptide-binding site. The diversity and fine specificity of alloreactive cytolytic T-lymphocyte (CTL) raised against B*2702 were analyzed at the clonal level. Significant crossreaction with B*2705 and B*2709 indicated that the three subtypes share numerous T-cell epitopes. However, some epitopes shared by B*2702 and B*2705 were lost in B*2709, which correlates with weaker association of this subtype to disease. Clonal specificities were donor-dependent, indicating that allo-immunogenicity is variable among individuals. Anti-B*2702 CTL were little affected by single mutations mimicking B*2702/B*2705 polymorphism, but the double mutant at positions 77 and 81 was recognized worse than B*2705, suggesting a compensatory effect of residue 80. Thus, HLA-B27 polymorphism modulated alloreactivity through cooperative and compensatory effects on T-cell epitope structure. Comparison of B*2705- and B*2702-bound peptide repertoires revealed that they overlapped by 73% and 81%, respectively. This was larger than B*2702/B*2705 cross-reaction, indicating that HLA-B27 allospecificity is only partially determined by the nature of peptide repertoires. The large sharing of natural ligands and T-cell epitopes is consistent with a pathogenetic role of B*2702 and B*2705 in spondyloarthritis based on antigen presentation.
Martí
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Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Facultad de Ciencias, Cantoblanco, 28049 Madrid, Spain.
Alvarez
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Montserrat
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López de Castro
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JA
D017951:Antigen Presentation / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D015796:HLA-B27 Antigen / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D025241:Spondylarthritis / Q000235:genetics / Q000276:immunology*; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000276:immunology*
D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen