Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis

J Autoimmun. 2017 Nov;84:29-45. doi: 10.1016/j.jaut.2017.06.004. Epub 2017 Jun 21.

Abstract

Oxidation-associated malondialdehyde (MDA) modification of proteins can generate immunogenic neo-epitopes that are recognized by autoantibodies. In health, IgM antibodies to MDA-adducts are part of the natural antibody pool, while elevated levels of IgG anti-MDA antibodies are associated with inflammatory and autoimmune conditions. Yet, in human autoimmune disease IgG anti-MDA responses have not been well characterized and their potential contribution to disease pathogenesis is not known. Here, we investigate MDA-modifications and anti-MDA-modified protein autoreactivity in rheumatoid arthritis (RA). While RA is primarily associated with autoreactivity to citrullinated antigens, we also observed increases in serum IgG anti-MDA in RA patients compared to controls. IgG anti-MDA levels significantly correlated with disease activity by DAS28-ESR and serum TNF-alpha, IL-6, and CRP. Mass spectrometry analysis of RA synovial tissue identified MDA-modified proteins and revealed shared peptides between MDA-modified and citrullinated actin and vimentin. Furthermore, anti-MDA autoreactivity among synovial B cells was discovered when investigating recombinant monoclonal antibodies (mAbs) cloned from single B cells, and 3.5% of memory B cells and 2.3% of plasma cells were found to be anti-MDA positive. Several clones were highly specific for MDA-modification with no cross-reactivity to other antigen modifications such as citrullination, carbamylation or 4-HNE-carbonylation. The mAbs recognized MDA-adducts in a variety of proteins including albumin, histone 2B, fibrinogen and vimentin. Interestingly, the most reactive clone, originated from an IgG1-bearing memory B cell, was encoded by near germline variable genes, and showed similarity to previously reported natural IgM. Other anti-MDA clones display somatic hypermutations and lower reactivity. Importantly, these anti-MDA antibodies had significant in vitro functional properties and induced enhanced osteoclastogenesis, while the natural antibody related high-reactivity clone did not. We postulate that these may represent distinctly different facets of anti-MDA autoreactive responses.

Keywords: Autoimmunity; Malondialdehyde acetaldehyde modification; Natural autoantibodies; Oxidation; Rheumatoid arthritis.

MeSH terms

  • Actins / immunology
  • Albumins / immunology
  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / metabolism*
  • Arthritis, Rheumatoid / immunology*
  • Autoantibodies / blood
  • Autoantigens / immunology*
  • Autoantigens / metabolism
  • Autoimmunity
  • B-Lymphocytes / immunology*
  • Cells, Cultured
  • Disease Progression
  • Humans
  • Immunodominant Epitopes / immunology*
  • Immunodominant Epitopes / metabolism
  • Immunoglobulin G / blood
  • Lipid Peroxidation
  • Malondialdehyde / immunology*
  • Malondialdehyde / metabolism
  • Osteogenesis
  • Oxidation-Reduction*
  • Somatic Hypermutation, Immunoglobulin
  • Synovial Membrane / immunology*
  • Vimentin / immunology

Substances

  • Actins
  • Albumins
  • Antibodies, Monoclonal
  • Autoantibodies
  • Autoantigens
  • Immunodominant Epitopes
  • Immunoglobulin G
  • Vimentin
  • Malondialdehyde