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

Research output: Contribution to journalAbstract

Authors

  • Caroline Gronwall
  • Khaled Amara
  • Uta Hardt
  • Akilan Krishnamurthy
  • Johanna Steen
  • Marianne Engström
  • Sun Meng
  • Roman A. Zubarev
  • A. Jimmy Ytterberg
  • Jeffrey D. Greenberg
  • Lars Klareskog
  • Anca I. Catrina
  • vivianne Malmstrom
  • Gregg J. Silverman

Colleges, School and Institutes

External organisations

  • Karolinska University Hospital and Karolinska Institutet, Stockholm
  • NYU

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.

Details

Original languageEnglish
JournalJournal of Autoimmunity
Early online date21 Jun 2017
Publication statusE-pub ahead of print - 21 Jun 2017

Keywords

  • autoimmunity , oxidation , malondialdehyde acetaldehyde modification , natural autoantibodies , rheumatoid arthritis