title: Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis 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.
authors.affiliation: Laboratory of Immunochemistry, World Premier International (WPI) Immunology Frontier Research Center, Department of Immunochemistry, Research Institute for Microbial Diseases, Department of Dermatology, Graduate School of Medicine, and Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Hui
authors.initials: H
authors.lastname: Jin
authors.forename: Noriko
authors.initials: N
authors.lastname: Arase
authors.forename: Kouyuki
authors.initials: K
authors.lastname: Hirayasu
authors.forename: Masako
authors.initials: M
authors.lastname: Kohyama
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Suenaga
authors.forename: Fumiji
authors.initials: F
authors.lastname: Saito
authors.forename: Kenji
authors.initials: K
authors.lastname: Tanimura
authors.forename: Sumiko
authors.initials: S
authors.lastname: Matsuoka
authors.forename: Kosuke
authors.initials: K
authors.lastname: Ebina
authors.forename: Kenrin
authors.initials: K
authors.lastname: Shi
authors.forename: Noriko
authors.initials: N
authors.lastname: Toyama-Sorimachi
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yasuda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Horita
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Hiwa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takasugi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.forename: Hideki
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Atsumi
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Hisashi
authors.initials: H
authors.lastname: Arase
mesh_terms: D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004198:Disease Susceptibility / Q000276:immunology*; D005434:Flow Cytometry; D057809:HEK293 Cells; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000276:immunology*; D047468:Immunoprecipitation; D016017:Odds Ratio; D010957:Plasmids / Q000235:genetics; D017510:Protein Folding
chemical_list: D001323:Autoantibodies; D017931:DNA Primers; D018076:DNA, Complementary; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G
keywords: autoimmune disease; major histocompatibility complex