Influencia del polimorfismo molecular y del procesamiento antigénico en la selección del repertorio peptídico de HLA-B27 implicaciones para la patogenia de las espondiloartropatías

Resumen

HLA-B27 is strongly associated with a group of rheumatic diseases collectively designed as spondyloarthropathies, that include ankylosing spondilitis (AS) and reactive arthritis. An issue of the highest interest is the differential association of HLA-B27 subtypes to AS. The structural polymorphism influences the peptide binding specificity and other biochemical and functional features of HLA-B27 determining differential association with AS. HLA-B27 binds peptides with R at position 2. HLA-B27 subtypes differ among each other in their peptide specificity by differential modulation of residue preferences at the C-terminal position and at multiple secondary anchor positions. A substantial fraction of the HLA-B27-bound peptide repertoire has basic residues at position 1. It is unclear whether this is determined by structural complementarity with the A pocket of the peptidebinding site, by the increased availability of peptides with dibasic N-terminal sequences resulting from their cytosolic stability, or both. HLA-B*2707 is associated with AS in most populations. Like the non-associated allotypes B*2706 and B*2709, it lacks D116 and shows preference for peptides with nonpolar C-terminal residues. The relationship between the peptide specificity of B*2707 and those of the diseaseassociated B*2705 and the non-associated subtypes was analysed. The B*2707-bound repertoire was as different from that of B*2705, as from those of B*2706, B*2709, or the two latter subtypes with each other. Differences between B*2707 and B*2705 were based on their C-terminal residue specificity and a subtle modulation at other positions. Differential usage of secondary anchor residues explained the disparity between the B*2707, B*2706 and B*2709-bound repertoires. T-cell crossreaction paralleled peptide sharing, suggesting that many shared ligands conserve their alloantigenic features on distinct subtypes. Our results indicate that association of HLA-B27 subtypes with AS does not correlate with higher peptide sharing among disease-associated subtypes or with obvious peptide motifs. To asses the role of the A pocket in the preference of HLA-B27 for peptides with dibasic Nterminal sequences, two B*2705 mutants were generated in which one or two A pocket surface residues stabilizing the R1 side chain were changed: E163T and E163T-W167S. The E163T mutation alone had a limited effect on binding of peptides with R1 or K1 and on the relative frequencies of Nterminal residues. However, it decreased the overall stability of the molecule. The E163T-W167S mutant also bound many of the B*2705 ligands with N-terminal basic residues, but its preference for G1 was significantly decreased. The results indicate that the capacity of HLA-B27 to bind peptides with N-terminal basic residues is largely independent of the canonic interactions that stabilize the R1 side chain. Thus, the prevalence of HLA-B27 ligands with dibasic N-terminal sequences may be significantly influenced by the increased availability of these peptides resulting from their cytosolic stability. This confers to HLA-B27 a unique capacity to present antigens generated in low amounts, but resistant to intracellular degradation.