Objectives Over 50% of rheumatoid arthritis (RA) patients harbor a variety of Anti-Modified Protein Antibodies (AMPA) against different post-translationally modified (PTM) proteins, including anti... Show moreObjectives Over 50% of rheumatoid arthritis (RA) patients harbor 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 RA-patients 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 immunized with carbamylated- or non-modified (auto)antigens and analyzed for autoantibody responses. Results We show that anti-CarP antibodies in RA are highly cross-reactive towards multiple carbamylated proteins, including modified self- as well as modified non-self proteins. Studies in mice show that anti-CarP antibody responses recognizing carbamylated self-proteins are not only induced by immunization with carbamylated self-proteins but also by immunization with carbamylated proteins of non-self origin. Similar to the data observed with sera from RA patients, the murine anti-CarP antibody response was, both at the monoclonal- and 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. Show less
Dekkers, J.; Verheul, M.K.; Stoop, J.; Liu, B.; Veelen, P.A. van; Hegen, M.; ... ; Toes, R. 2016
The development of novel treatments for rheumatoid arthritis (RA) requires the interplay between clinical observations and studies in animal models. Given the complex molecular pathogenesis and... Show moreThe development of novel treatments for rheumatoid arthritis (RA) requires the interplay between clinical observations and studies in animal models. Given the complex molecular pathogenesis and highly heterogeneous clinical picture of RA, there is an urgent need to dissect its multifactorial nature and to propose new strategies for preventive, early and curative treatments. Research on animal models has generated new knowledge on RA pathophysiology and aetiology and has provided highly successful paradigms for innovative drug development. Recent focus has shifted towards the discovery of novel biomarkers, with emphasis on presymptomatic and emerging stages of human RA, and towards addressing the pathophysiological mechanisms and subsequent effi cacy of interventions that underlie different disease variants. Shifts in the current paradigms underlying RA pathogenesis have also led to increased demand for new (including humanised) animal models. There is therefore an urgent need to integrate the knowledge on human and animal models with the ultimate goal of creating a comprehensive 'pathogenesis map' that will guide alignment of existing and new animal models to the subset of disease they mimic. This requires full and standardised characterisation of all models at the genotypic, phenotypic and biomarker level, exploiting recent technological developments in '-omics' profiling and computational biology as well as state of the art bioimaging. Efficient integration and dissemination of information and resources as well as outreach to the public will be necessary to manage the plethora of data accumulated and to increase community awareness and support for innovative animal model research in rheumatology. Show less
