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

• Published in: The Journal of experimental medicine Vol. 216; no. 8; pp. 1904 - 1924
• Main Authors: Bersellini Farinotti, Alex, Wigerblad, Gustaf, Nascimento, Diana, Bas, Duygu B, Morado Urbina, Carlos, Nandakumar, Kutty Selva, Sandor, Katalin, Xu, Bingze, Abdelmoaty, Sally, Hunt, Matthew A, Ängeby Möller, Kristina, 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 Miguel, Codeluppi, Simone, Holmdahl, Rikard, Svensson, Camilla I
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 05.08.2019
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antigen-Antibody Complex - metabolism; Arthralgia - drug therapy; Arthralgia - immunology; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Autoantibodies - immunology; Autoantibodies - therapeutic use; Basic Medicine; Behavior, Animal - drug effects; Cartilage - immunology; Cartilage Oligomeric Matrix Protein - immunology; Collagen Type II - immunology; Disease Models, Animal; Female; Immunologi inom det medicinska området; Immunology in the medical area; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Neurons - metabolism; Neurosciences; Neurovetenskaper; Receptors, IgG - deficiency; Receptors, IgG - genetics
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20181657

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 and mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs 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.