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

Bersellini Farinotti, Alex; Wigerblad, Gustaf; Nascimento, Diana; Bas, Duygu B; Morado Urbina, Carlos; Nandakumar, Kutty Selva; Sandor, Katalin; Xu, Bingze; Abdelmoaty, Sally and Hunt, Matthew A, et al. (2019) In Journal of Experimental Medicine 216(8). p.1904-1924
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... (More)

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.

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@article{db750eef-ffdf-4e68-b06a-6efe9f60b7cd,
  abstract     = {<p>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.</p>},
  author       = {Bersellini Farinotti, Alex and Wigerblad, Gustaf and Nascimento, Diana and Bas, Duygu B and Morado Urbina, Carlos and Nandakumar, Kutty Selva and Sandor, Katalin and Xu, Bingze and Abdelmoaty, Sally and Hunt, Matthew A and Ängeby Möller, Kristina and Baharpoor, Azar and Sinclair, Jon and Jardemark, Kent and Lanner, Johanna T and Khmaladze, Ia and Borm, Lars E and Zhang, Lu and Wermeling, Fredrik and Cragg, Mark S and Lengqvist, Johan and Chabot-Doré, Anne-Julie and Diatchenko, Luda and Belfer, Inna and Collin, Mattias and Kultima, Kim and Heyman, Birgitta and Jimenez-Andrade, Juan Miguel and Codeluppi, Simone and Holmdahl, Rikard and Svensson, Camilla I},
  issn         = {1540-9538},
  language     = {eng},
  month        = {06},
  number       = {8},
  pages        = {1904--1924},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Experimental Medicine},
  title        = {Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons},
  url          = {http://dx.doi.org/10.1084/jem.20181657},
  volume       = {216},
  year         = {2019},
}