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.

β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome

“…32 Furthermore, intact IgG heavy chain is transported to the cell surface by HLA class II molecules via association with the peptide-binding groove, and IgG heavy chain/ HLA class II complexes are recognized by autoantibodies in rheumatoid factor-positive sera from RA patients. 33 In contrast, autoantibodies in rheumatoid factor-positive sera from non-RA individuals did not bind to IgG heavy chain/HLA class II complexes, suggesting that IgG heavy chain complexed with HLA-DR is a specific target for autoantibodies from RA patients. Of note, a strong correlation between autoantibody binding to IgG complexed with certain HLA-DR alleles and the odds ratio for association of these alleles with RA was observed.…”

“…[14][15][16][17][18] Because b2GPI is a secreted serum protein, it is not generally detected on the surface of even the cells that produce it. In order to analyze whether b2GPI is transported to the cell surface by HLA class II molecules in a manner similar to IgG heavy chain, 33 b2GPI was cotransfected into 293T cells together with GFP and HLA-DRA*01:01 and DRB1*07:01 (HLA-DR7) or HLA-DRA*01:01 and DRB1*08:01 (HLA-DR8), and cell surface expression of b2GPI on GFP-positive cells was analyzed. b2GPI was not detected on the surface of cells transfected with b2GPI alone ( Figure 1B).…”

“…Similarly, HLA-DR was coprecipitated together with b2GPI from the transfectants. Because association of full-length IgG heavy chain with HLA-DR was detected in the ER, 33 full-length b2GPI, but not fragmented b2GPI, also seems to be associated with HLA-DR in the ER and transported to the cell surface by HLA-DR ( Figure 1A).…”

“…Recently, however, we found that misfolded proteins are rescued from degradation and transported to the cell surface without processing to peptides when they associate with the peptide-binding groove of HLA class II molecules in the endoplasmic reticulum (ER). 32,33 Structural analyses of major histocompatibility complex (MHC) class II molecules have revealed that both ends of the MHC class II peptide-binding groove are open. Therefore, it is possible that MHC class II molecules might bind linear epitopes exposed on misfolded proteins.…”

“…[34][35][36] Furthermore, immunoglobulin G (IgG) heavy chains thus transported to the cell surface by HLA class II alleles associated with rheumatoid arthritis (RA) susceptibility were specifically recognized by autoantibodies from RA patients. 33 Because HLA class II expression on nonlymphoid cells, including endothelial cells, is frequently observed in various autoimmune diseased tissues, [37][38][39][40][41] we hypothesized that misfolded proteins rescued from protein degradation by HLA class II molecules might be targets for autoantibodies in autoimmune diseases. Here, we addressed whether structurally altered b2GPI is transported to the cell surface by HLA class II molecules and is recognized by autoantibodies in APS patients.…”