Two HLA-B14 subtypes (B*1402 and B*1403) differentially associated with ankylosing spondylitis differ substantially in peptide specificity but have limited peptide and T-cell epitope sharing with HLA-B27.
The peptide specificity of HLA-B*1403, an allotype associated with ankylosing spondylitis (Lopez-Larrea, C., Mijiyawa, M., Gonzalez, S., Fernandez-Morera, J. L., Blanco-Gelaz, M. A., Martinez-Borra, J., and Lopez-Vazquez, A. (2002) Arthritis Rheum. 46, 2968-2971) was compared with those of the non-associated B*1402 and the prototypic disease-associated B*2705 allotypes. Although differing by a single residue (L156R), B*1402 and B*1403 shared only 32-35% of their peptide repertoires. Subtype-related differences observed in multiple peptide positions, including P3 and P7, were largely explained by a direct effect of the L156R change on peptide specificity. The HLA-B14 subtypes shared only approximately 3% of their peptide repertoires with B*2705. This was due to distinct residue usage at most positions, as revealed by statistical comparison of B*1402, B*1403, and B*2705-bound nonamers. Nevertheless, shared ligands between B*2705 and B*1403 were formally identified, although ligands common to B*2705 and B*1403, but absent from B*1402, were not found. Alloreactive T-cells were used as a tool to analyze epitope sharing among B*1402, B*1403, and B*2705. The percentage of cross-reactive T-cell clones closely paralleled peptide overlap, suggesting that shared ligands tend to maintain their antigenic features when bound to the different allotypes. Our results indicate that B*1403 and B*2705 can present common peptides. However, both the disparity of their peptide repertoires and the lack of binding features shared by these two allotypes, but not B*1402, argue against, although do not exclude, a mechanism of spondyloarthritis mediated by specific ligands of B*2705 and B*1403.
Merino
Elena
E
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Facultad de Ciencias, Universidad Autónoma, 28049 Madrid, Spain.
Montserrat
Verónica
V
Paradela
Alberto
A
López de Castro
José A
JA
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry; D017951:Antigen Presentation; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry*; D005434:Flow Cytometry; D015235:HLA-B Antigens / Q000737:chemistry / Q000502:physiology*; D059909:HLA-B14 Antigen; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014162:Transfection
D000911:Antibodies, Monoclonal; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D059909:HLA-B14 Antigen; D015796:HLA-B27 Antigen; D008024:Ligands; D010455:Peptides; D004247:DNA