Prime culprit behind the onset of rheumatoid arthritis identified [View all]

[kristopher]

Study: Culprit leading to rheumatoid arthritis discovered

February 26, 2014
By RYOSUKE NONAKA/ Staff Writer

An international group of researchers is offering hopes of a cure for sufferers of rheumatoid arthritis, identifying the prime culprit behind the onset of the crippling disease.

This discovery could lead to the development of a drug for the first time to cure the autoimmune disease, in which a sufferer's immune system attacks his own tissues, instead of combating invading viruses and bacteria in the body.

The scientists, including researchers at Osaka University, have found that people susceptible to contracting rheumatoid arthritis developed the disease after cellular misfolded proteins are transported to the surfaces of cells without being processed into peptides. These proteins were processed within the cells in the bodies of healthy people.

“We can expect to develop a drug that is targeted at denatured proteins to dissolve them, or a method of examination that will allow doctors to make a diagnosis of the disease at an extremely early stage,” said Hisashi Arase, professor of immunology at Osaka University, one of the researchers.

The findings were carried in the online Proceedings of the National Academy of Sciences...

Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility

Significance

Cellular misfolded proteins are transported to the cell surface by MHC class II molecules via association with the peptide-binding groove without processing to peptides. We found that IgG heavy chain is transported to the cell surface by MHC class II molecules. Furthermore, IgG heavy chain associated with MHC class II molecules is recognized by autoantibodies in rheumatoid arthritis patients. Autoantibody binding to IgG heavy chain complexed with different MHC class II alleles was strongly associated with rheumatoid arthritis susceptibility conferred by certain MHC class II alleles. These findings suggest that misfolded proteins complexed with MHC class II molecules could be targets for autoantibodies in autoimmune diseases, which might be involved in autoimmune disease susceptibility.

Abstract
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, we found a unique 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 Fc fragments of IgG and is detected in 70–80% of RA patients but also in patients with other diseases. Here, we 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 class II 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 class II 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 association with RA was observed (r = 0.81; P = 4.6 × 10−5). Our 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.

http://www.pnas.org/content/early/2014/02/19/1401105111.abstract