Propiedades moleculares e inmunológicas de HLA-B14 y su papel en la espondilitis anquilosante

Abstract

The association of HLA-B27 with ankylosing spondylitis (AS) is the strongest one between an HLA class I molecule and any disease. HLA-B*1403 was strongly associated to AS in the Togolese population, where both this disease and HLA-B27 are unfrequent. B*1402, which differs from B*1403 only at residue 156 (L156R), was found only in the healthy controls. Thus, the availability of two closely related HLAB14 molecules differentially associated with AS, allowed us for the first time to look for molecular properties that may correlate with disease susceptibility in a non-B27 system. Current research on AS pathogenesis is focused on a few hypothetical mechanisms. The ones in which this thesis is focused are the arthritogenic peptide and the misfolding hypotheses. On the basis of the arthritogenic peptide hypothesis, we comparatively analyzed the peptide binding specificity of B*1402, B*1403 and B*2705. Although differing by a single residue, 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 3% of their peptide repertoires with B*2705. Shared ligands between B*1403 and B*2705 were positively identified by sequencing. Antigenic overlap analized by CTLs was similar to the peptide overlap, suggesting that shared ligands tend to maintain their antigenic features when bound to the different allotypes. In conclusion, our results indicate that B*1403 and B*2705 can present common peptides. On the basis of the misfolding hypothesis, we comparatively analyzed folding, export, and stability of B*1402, B*1403 and B*2705. B14 folding was faster and more efficient than B*2705, and similar for B*1402 and B*1403, but some unfolded heavy chain (HC) from both B14 subtypes remained in the endoplasmic reticulum with a long half life. The expor rate of B*1402 and B*1403was slow, and the heterodimers partially dissociated after exiting the endoplasmic reticulum, as revealed by significant amounts of Endo H-resistant and surface-expressed free HC. Both interaction with tapasin and thermostability decreased in the order: B*2705>B*1402>B*1403, suggesting that the B*1402 and, specially, B*1403-bound peptide repertoires were less optimized than that of B*2705. So, folding, maturation and stability of B*1403 differ more from B*2705 than from B*1402.