The HLA-DRB1 shared epitope and trans-encoded HLA-DQ-heterodimers hypothesis in autoimmune Addison disease
Mikulas Pura1, Daniel Kuba2, Peter Kentos1, Silvia Chrenova2 & Peter Vanuga1
Background: The MHC is the most important susceptibility locus for human autoimmune diseases (AID). Although associations between MHC class II DRB1 alleles and Addison disease (AD) have been repeteadly proven in various populations, the biological mechanisms underlying this association remains unknown. Peptide presentation to T cells may be important in the initiation or progression of AID. Disease-linked polymorphisms map to the peptide-binding sites of MHC molecules class II pockets. The P4 pocket of HLA-DR makes an important contribution to susceptibility to AID. This is readily explained by the fact that the P4 pocket is the most polymorphic pocket of the HLA-DR binding site.
The presence of the RAA sequence at positions 7274 of the HLA-DR β-chain molecule for all HLA-DRB1 alleles known to be associated with rheumatoid arthritis led to the shared epitope (SE) hypothesis.
Aim: To evaluate the possibility that the SE hypothesis could be applicated in other autoimmune diseases, we have investigated the complete HLA-DRB1-DQA1-DQB1 haplotype status in Slovak patients with autoimmune Addison disease.
Subjects and methods: We analysed DRB1-DQA1-DQB1 haplotypes from 57 patients with autoimmune AD. Subsequently, sequences of the amino acids at positions 7074 of the HLA-DR β-chain molecule were evaluated.
Results: In 117 alleles analysed, the most frequent amino acid sequences found were as follows: QK-RGR (30×), DR-RAA (28×), QA-RAA (16×), QR-RAA (10×), DE-RAA (9×), QR-RAE (7×), QK-RAA (5×).
Conclusions: Building on the HLA genotype classification could lead to improvement in our understanding of the genetics and pathophysiology of AID, namely AD. The structural information on the P4 pocket of different DR molecules may be useful for the development of small organic molecules that inhibit peptide presentation by DR molecules associated with particular AID.