The South Amerindian allotype HLA-B*3909 has the largest known similarity in peptide specificity and common natural ligands with HLA-B27

HLA-B*3909 has only been found among South Amerindians, and presumably aros e locally in these populations. It differs from B*3901 by a single Tyr to S er change at position 99. To analyze the influence of this polymorphism on peptide specificity, pool sequence analysis and sequencing of multiple indi vidual ligands from B*3901 and B*3909 were carried out. Both allotypes bind peptides with Arg2 or His2 and nonpolar C-terminal residues. However, wher eas His2 is the predominant B*3901 motif, a majority of the B*3909-bound pe ptides have Arg2. In addition, B*3909 binds peptides with Pro2, and also sh ows an increased preference for Pro3. In spite of their differences, both s ubtypes bind overlapping peptide repertoires, as indicated by the identific ation of several identical ligands from their respective peptide pools. B*3 909 is significantly more similar in its peptide specificity to HLA-Bn than B*3901. This is due to the increased preference of B*3909 for Arg2 and to low suitability of HLA-B27 for His2. The similarity between HLA-B27 and B*3 909 was confirmed by identification of a natural ligand common to both allo types. In addition, multiple HLA-B27 ligands bound efficiently B*3909 in vi tro. The results indicate that, among the HLA class I allotypes of known pe ptide specificity, B*3909 is the most similar in its peptide binding proper ties to HLA-B27, which is absent in South Amerindians. This may have implic ations for the susceptibility of individuals in these populations to spondy loarthropathies.