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Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons

Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypers...

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Published in:arXiv.org 2019-08
Main Authors: Alex Bersellini Farinotti, Wigerblad, Gustaf, Nascimento, Diana, Bas, Duygu B, Carlos Morado Urbina, Kutty Selva Nandakumar, Sandor, Katalin, Xu, Bingze, Abdelmoaty, Sally, Hunt, Matthew A, Kristina Ängeby Möller, Baharpoor, Azar, Sinclair, Jon, Jardemark, Kent, Lanner, Johanna T, Khmaladze, Ia, Borm, Lars E, Zhang, Lu, Wermeling, Fredrik, Cragg, Mark S, Lengqvist, Johan, Chabot-Doré, Anne-Julie, Diatchenko, Luda, Belfer, Inna, Collin, Mattias, Kultima, Kim, Heyman, Birgitta, Jimenez-Andrade, Juan M, Codeluppi, Simone, Holmdahl, Rikard, Svensson, Camilla I
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Language:English
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Summary:Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcR{\gamma} chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcR{\gamma} chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcR{\gamma} chain-deficient mice or mice lacking activating Fc{\gamma}Rs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.
ISSN:2331-8422
DOI:10.48550/arxiv.1908.05298