MHC class I associations beyond HLA-B27: the peptide binding hypothesis of psoriatic arthritis and its implications...

To provide an overview of the heterogeneous human leucocyte antigen (HLA) associations of psoriatic arthritis, their relationship to particular clinical features of the disease, and how a hypothesis of binding specific peptides could provide a unifying basis for this heterogeneity.

There have been substantive advances in understanding the role of HLA molecules in binding self-peptides that select our repertoire of T cells, the specific peptide-binding properties of these HLA allotypes, and their crystallographic structure. These advances provide a means to envision the significance of the heterogeneous psoriatic arthritis HLA associations. The clinical relevance of these allotypes if heightened by emerging knowledge of their relationship to particular clinical features of the disease that serve as subphenotypes.

We propose a peptide binding hypothesis of psoriatic arthritis based on a shared pattern of negative charge in the 'B' pocket of the HLA-B and HLA-C molecules encoded by the susceptibility allotypes. This hypothesis suggests that peptides characterized by the presence of arginine at position 2 or 3 are bound to the susceptibility allotypes and drive the T-cell clones selected on them to attack molecules containing these peptides located in sites of psoriatic arthritis inflammation.