TY - JOUR
T1 - Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility
AU - Jin, Hui
AU - Arase, Noriko
AU - Hirayasu, Kouyuki
AU - Kohyama, Masako
AU - Suenaga, Tadahiro
AU - Saito, Fumiji
AU - Tanimura, Kenji
AU - Matsuoka, Sumiko
AU - Ebina, Kosuke
AU - Shi, Kenrin
AU - Toyama-Sorimachi, Noriko
AU - Yasuda, Shinsuke
AU - Horita, Tetsuya
AU - Hiwa, Ryosuke
AU - Takasugi, Kiyoshi
AU - Ohmura, Koichiro
AU - Yoshikawa, Hideki
AU - Saito, Takashi
AU - Atsumi, Tatsuya
AU - Sasazuki, Takehiko
AU - Katayama, Ichiro
AU - Lanier, Lewis L.
AU - Arase, Hisashi
PY - 2014/3/11
Y1 - 2014/3/11
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.1401105111
DO - 10.1073/pnas.1401105111
M3 - Article
C2 - 24567378
AN - SCOPUS:84896258752
VL - 111
SP - 3787
EP - 3792
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 10
ER -