Breach of autoreactive B cell tolerance by post-translationally modified proteins

• Published in: Annals of the rheumatic diseases Vol. 76; no. 8; p. 1449
• Main 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
• Format: Journal Article
• Language: English
• Published: England 01-08-2017
• Subjects: Animals; Arthritis, Experimental - immunology; Arthritis, Rheumatoid - immunology; Autoantibodies - immunology; Autoantigens - immunology; Autoantigens - metabolism; B-Lymphocytes - immunology; Carbamates - immunology; Carbamates - metabolism; Case-Control Studies; Citrulline - analogs & derivatives; Citrulline - immunology; Cross Reactions - immunology; Disease Models, Animal; Humans; Mass Spectrometry; Mice; Protein Processing, Post-Translational - immunology; Self Tolerance - immunology; Synovial Membrane - metabolism; B cell tolerance; Rheumatoid arthritis; Autoantibodies
• ISSN: 1468-2060
• DOI: 10.1136/annrheumdis-2016-210772

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.
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.
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.
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.