TY - JOUR T1 - Breach of autoreactive B cell tolerance by post-translationally modified proteins JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 1449 LP - 1457 DO - 10.1136/annrheumdis-2016-210772 VL - 76 IS - 8 AU - Jacqueline S Dekkers AU - Marije K Verheul AU - Jeroen N Stoop AU - Bisheng Liu AU - Andreea Ioan-Facsinay AU - Peter A van Veelen AU - Arnoud H de Ru AU - George M C Janssen AU - Martin Hegen AU - Steve Rapecki AU - Tom W J Huizinga AU - Leendert A Trouw AU - René E M Toes Y1 - 2017/08/01 UR - http://ard.bmj.com/content/76/8/1449.abstract N2 - 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. ER -