Breach of autoreactive B cell tolerance by post-translationally modified proteins. Issue 8 (25th April 2017)

• Record Type: Journal Article
• Authors: Dekkers, Jacqueline S; Verheul, Marije K; Stoop, Jeroen N; Liu, Bisheng; Ioan-Facsinay, Andreea; van Veelen, Peter A; de Ru, Arnoud H; Janssen, George M C; Hegen, Martin; Rapecki, Steve; Huizinga, Tom W J; Trouw, Leendert A; Toes, René E M
• Is Part Of: Annals of the rheumatic diseases. Volume 76:Issue 8(2017)
• Page Start: 1449
• Page End: 1457
• Publication Date: 2017-04-25
• Subjects: Rheumatoid arthritis -- Autoantibodies -- B cell tolerance; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2016-210772
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objectives: Over 50% of patients with rheumatoid arthritis (RA) harbour a variety of anti-modified protein antibodies (AMPA) against different post-translationally modified (PTM) proteins, including anti-carbamylated protein (anti-CarP) antibodies. At present, it is unknown how AMPA are generated and how autoreactive B cell responses against PTM proteins are induced. Here we studied whether PTM foreign antigens can breach B cell tolerance towards PTM self-proteins. Methods: Serum reactivity towards five carbamylated proteins was determined for 160 patients with RA and 40 healthy individuals. Antibody cross-reactivity was studied by inhibition experiments. Mass spectrometry was performed to identify carbamylated self-proteins in human rheumatic joint tissue. Mice were immunised with carbamylated or non-modified (auto)antigens and analysed for autoantibody responses. Results: We show that anti-CarP antibodies in RA are highly cross-reactive towards multiple carbamylated proteins, including modified self-proteins and modified non-self-proteins. Studies in mice show that anti-CarP antibody responses recognising carbamylated self-proteins are induced by immunisation with carbamylated self-proteins and by immunisation with carbamylated proteins of non-self-origin. Similar to the data observed with sera from patients with RA, the murine anti-CarP antibody response was, both at the monoclonal level and the polyclonal level, highly cross-reactive towards multiple carbamylated proteins, including carbamylated self-proteins. Conclusions: Self-reactive AMPA responses can be induced by exposure to foreign proteins containing PTM. These data show how autoreactive B cell responses against PTM self-proteins can be induced by exposure to PTM foreign proteins and provide new insights on the breach of autoreactive B cell tolerance.