HLA class II and rheumatoid arthritis: the bumpy road of revelation

Abstract

Rheumatoid arthritis (RA) is a chronic auto-immune disease primarily targeting the joints. Approximately 1% of the population is affected by RA, and despite the improvements in therapeutic interventions, elucidation of the disease pathogenesis is still in its infancy. RA patients can be subdivided on basis of the presence of autoantibodies, especially anti-citrullinated protein antibodies (ACPA). ACPA⁺ and ACPA^- disease most likely differ in aetiology, as different genetic and environmental risk factors are associated with these two disease entities. For ACPA⁺ RA disease, the genetic factors associating with disease mainly comprised of human leukocyte antigen (HLA) class II molecules. The predisposing HLA-DR alleles have been depicted as the 'HLA Shared Epitope (SE) alleles', as these alleles encode a similar sequence, the shared epitope sequence, within the beta chain of the HLA-DR molecule. In addition to the involvement of the HLA-SE alleles in the development of ACPA⁺ RA disease, other HLA-DR molecules have been shown to confer protection against this disease entity. The protective HLA molecules have, instead of the SE-motif, a different but shared sequence at the same location in the beta chain of HLA-DR molecules, consisting of the amino acid residues DERAA. The possible contributions of the predisposing and protective HLA molecules in association with ACPA-positive RA are discussed in this review.

Keywords: ACPA+ disease; DERAA; HLA class II molecules; Rheumatoid arthritis; Shared epitope; T cells.

Fig. 1

Schematic representation of a peptide binding to a HLA-DR molecule. a Top view of the peptide binding groove. The peptide binding groove is formed by the alpha and beta chain, leaving, forming two walls to accommodate the peptide. b Side-view of the peptide-binding groove without distinguishment between the two HLA-DR chains. The peptide-binding pockets shown are anchoring points for residues of the peptide. The other residues are available for T cell receptor recognition. c Representation of how the shared epitope sequence can influence the binding of residues. Due to the presence of positively charged residues within pocket 4, arginine may be repelled and citrulline may be accepted. X represents any amino acid involved in formation of pocket 4. Position of residues within peptide-binding pocket 4 does not represent the actual position. d Representation of how the DERAA-sequence can influence the binding of residues. Due to the presence of negatively charged residues within pocket 4, both arginine and citrulline may be accepted. X represents any amino acid involved in formation of pocket 4. Position of residues within peptide-binding pocket 4 does not represent the actual position