Tesis doctoral de Carmen Patricia Gomez Molina
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.
Datos académicos de la tesis doctoral «Influencia del polimorfismo molecular y del procesamiento antigénico en al selección del repertorio peptídico de hla-b27: implicaciones para la patogenia de las espondiloartropatías.«
- Título de la tesis: Influencia del polimorfismo molecular y del procesamiento antigénico en al selección del repertorio peptídico de hla-b27: implicaciones para la patogenia de las espondiloartropatías.
- Autor: Carmen Patricia Gomez Molina
- Universidad: Autónoma de Madrid
- Fecha de lectura de la tesis: 17/07/2009
Dirección y tribunal
- Director de la tesis
- José Antonio López De Castro
- Tribunal
- Presidente del tribunal: manuel Fresno escudero
- pedro Antonio Reche gallardo (vocal)
- Alberto Paradela elizalde (vocal)
- iñaki álvarez pérez (vocal)