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

Abstract

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 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.

• Authors: Alex Bersellini Farinotti, Gustaf Wigerblad, Diana Nascimento, Duygu B Bas, Carlos Morado Urbina, Kutty Selva Nandakumar, Katalin Sandor, Bingze Xu, Sally Abdelmoaty, Matthew A Hunt, Kristina Ängeby Möller, Azar Baharpoor, Jon Sinclair, Kent Jardemark, Johanna T Lanner, Ia Khmaladze, Lars E Borm, Lu Zhang, Fredrik Wermeling, Mark S Cragg, Johan Lengqvist, Anne-Julie Chabot-Doré, Luda Diatchenko, Inna Belfer, Mattias Collin, Kim Kultima, Birgitta Heyman, Juan Miguel Jimenez-Andrade, Simone Codeluppi, Rikard Holmdahl, Camilla I Svensson
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 216 Issue 8 Pg. 1904-1924 (08 05 2019) ISSN: 1540-9538 [Electronic] United States
• PMID: 31196979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Bersellini Farinotti et al.

Chemical References

• Antibodies, Monoclonal
• Antigen-Antibody Complex
• Autoantibodies
• Cartilage Oligomeric Matrix Protein
• Collagen Type II
• Comp protein, mouse
• Receptors, IgG

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• Antigen-Antibody Complex (metabolism)
• Arthralgia (drug therapy, immunology)
• Arthritis, Rheumatoid (drug therapy, immunology)
• Autoantibodies (immunology, therapeutic use)
• Behavior, Animal (drug effects)
• Cartilage (immunology)
• Cartilage Oligomeric Matrix Protein (immunology)
• Collagen Type II (immunology)
• Disease Models, Animal
• Female
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Mice, Transgenic
• Neurons (metabolism)
• Receptors, IgG (deficiency, genetics)