Specific HLA class II alleles are strongly associated with susceptibility to rheumatoid arthritis (RA); however, how HLA class II regulates susceptibility to RA has remained unclear. Recently, the authors found a novel function of HLA class II molecules: their ability to aberrantly transport cellular misfolded proteins to the cell surface without processing to peptides. Rheumatoid factor (RF) is an autoantibody that binds to denatured IgG or fragment crystallizable region fragments of IgG and is detected in 70.80% of RA patients but also in patients with other diseases.

The authors report that intact IgG heavy chain (IgGH) is transported to the cell surface by HLA class II via association with the peptide-binding groove and that IgGH/HLA-DR complexes are specifically recognized by autoantibodies in RF-positive sera from RA patients. In contrast, autoantibodies in RF-positive sera from non-RA individuals did not bind to IgGH/HLA-DR complexes. Of note, a strong correlation between autoantibody binding to IgG complexed with certain HLA-DR alleles and the odds ratio for that allele's associationwith RA was observed (r = 0.81; P = 4.6 × 10.5). These findings suggest that IgGH complexed with certain HLA class II alleles is a target for autoantibodies in RA, which might explain why these HLA class II alleles confer susceptibility to RA.

[Excursus] This article was reported by "Editors' Choice" in Science 344(6179), 2014.



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Contact:

Hisashi ARASE
Immunochemistry
Immunology Frontier Research Center (WPI-IFReC), Osaka University