Interaction between hsp73 and rheumatoid-arthritis-associated HLA-DR alleles

Background

The QKRAA amino acid motif of HLA-DRB1*0401 helps the development of rheumatoid arthritis by an unknown mechanism. In human B cells, we have observed that the QKRAA motif carries original properties. The constitutive 70-kDa heat-shock protein hsp73 binds HLA-DRB1*0401 and targets it directly from endoplasmic reticulum to lysosomes, bypassing the normal route through golgi and endosomes.

Objective

To evaluate how well different HLA-DRB1 alleles bound hsp73, we developed quantitative assays.

Results

By precipitation assay using total and lysosomal protein extracts, we found that alleles associated with rheumatoid arthritis bound hsp73 better than alleles not associated with rheumatoid arthritis. HLA-DRB1*0401 is the best hsp73 binder. By a direct binding assay with purified protein, we confirmed that HLA-DRB1*0401 that carries the QKRAA motif is the best hsp73 binder.

Conclusion

These properties may help particular antigen processing and presentation by HLA-DRB1*0401, potentially leading to autoimmunity.