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

• DOI: 10.1084/jem.20181657
• Publication Date: 2019-06-13T18:45:16Z
• Authors: Alex Bersellini F...; Gustaf Wigerblad; Diana Nascimento; Duygu B. Bas; Carlos Morado Urbina; Kutty Selva Nanda...; Katalin Sandor; Bingze Xu; Sally Abdelmoaty; Matthew A. Hunt; Kristina Ängeby M...; 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...; Luda Diatchenko; Inna Belfer; Mattias Collin; Kim Kultima; Birgitta Heyman; Juan Miguel Jimen...; Simone Codeluppi; Rikard Holmdahl; Camilla I. Svensson
• Keywords: Male; 570; 610; Mice, Transgenic; Antigen-Antibody Complex; Cartilage Oligomeric Matrix Protein; Arthritis, Rheumatoid; Mice; 03 medical and health sciences; Immunology in the Medical Area (including Cell and Immunotherapy); Animals; Tissues and Organs (q-bio.TO); Collagen Type II; Research Articles; Autoantibodies; Neurons; Mice, Inbred BALB C; 0303 health sciences; Behavior, Animal; Receptors, IgG; Klinisk medicin; Neurosciences; Immunology in the medical area; Antibodies, Monoclonal; Quantitative Biology - Tissues and Organs; Arthralgia; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Cartilage; Immunologi inom det medicinska området; Quantitative Biology - Neurons and Cognition; FOS: Biological sciences; Mice, Inbred CBA; Female; Neurons and Cognition (q-bio.NC); Clinical Medicine

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.