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

Cartilage binding antibodies induce pain through immune complex mediated activation of neurons
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 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.
0022-1007
1904-1924
Bersellini Farinotti, Alex
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Wigerblad, Gustaf
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Nascimento, Diana
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Bas, Duygu B.
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Morado Urbina, Carlos
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Nandakumar, Kutty Selva
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Sandor, Katalin
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Xu, Bingze
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Abdelmoaty, Sally
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Hunt, Matthew A.
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Angeby Moller, Kristina
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Baharpoor, Azar
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Sinclair, Jon
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Jardemark, Kent
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Lanner, Johanna T.
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Khmaladze, Ia
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Borm, Lars E.
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Zhang, Lu
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Wermeling, Fredrik
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Cragg, Mark
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Lengqvist, Johan
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Chabot-Dore, Anne-Julie
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Diatchenko, Luda
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Belfer, Inna
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Collin, Mattias
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Kultima, Kim
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Heyman, Birgitta
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Andrade Jimenez, Juan M.
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Codeluppi, Simone
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Holmdahl, Rikard
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Svensson, Camilla I.
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Bersellini Farinotti, Alex
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Wigerblad, Gustaf
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Nascimento, Diana
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Bas, Duygu B.
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Morado Urbina, Carlos
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Nandakumar, Kutty Selva
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Sandor, Katalin
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Xu, Bingze
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Abdelmoaty, Sally
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Hunt, Matthew A.
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Angeby Moller, Kristina
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Baharpoor, Azar
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Sinclair, Jon
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Jardemark, Kent
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Lanner, Johanna T.
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Khmaladze, Ia
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Borm, Lars E.
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Zhang, Lu
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Wermeling, Fredrik
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Cragg, Mark
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Lengqvist, Johan
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Chabot-Dore, Anne-Julie
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Diatchenko, Luda
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Belfer, Inna
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Collin, Mattias
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Kultima, Kim
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Heyman, Birgitta
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Andrade Jimenez, Juan M.
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Codeluppi, Simone
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Holmdahl, Rikard
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Svensson, Camilla I.
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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., Angeby Moller, Kristina, Baharpoor, Azar, Sinclair, Jon, Jardemark, Kent, Lanner, Johanna T., Khmaladze, Ia, Borm, Lars E., Zhang, Lu, Wermeling, Fredrik, Cragg, Mark, Lengqvist, Johan, Chabot-Dore, Anne-Julie, Diatchenko, Luda, Belfer, Inna, Collin, Mattias, Kultima, Kim, Heyman, Birgitta, Andrade Jimenez, Juan M., Codeluppi, Simone, Holmdahl, Rikard and Svensson, Camilla I. (2019) Cartilage binding antibodies induce pain through immune complex mediated activation of neurons. Journal of Experimental Medicine, 216 (8), 1904-1924. (doi:10.1084/jem.20181657).

Record type: Article

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.

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Accepted/In Press date: 24 April 2019
e-pub ahead of print date: 13 June 2019
Published date: 5 August 2019

Identifiers

Local EPrints ID: 431503
URI: http://eprints.soton.ac.uk/id/eprint/431503
ISSN: 0022-1007
PURE UUID: 3f25ea3a-174f-4a2b-baa4-04e5e47f75b2
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 06 Jun 2019 16:30
Last modified: 26 Nov 2021 05:33

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Contributors

Author: Alex Bersellini Farinotti
Author: Gustaf Wigerblad
Author: Diana Nascimento
Author: Duygu B. Bas
Author: Carlos Morado Urbina
Author: Kutty Selva Nandakumar
Author: Katalin Sandor
Author: Bingze Xu
Author: Sally Abdelmoaty
Author: Matthew A. Hunt
Author: Kristina Angeby Moller
Author: Azar Baharpoor
Author: Jon Sinclair
Author: Kent Jardemark
Author: Johanna T. Lanner
Author: Ia Khmaladze
Author: Lars E. Borm
Author: Lu Zhang
Author: Fredrik Wermeling
Author: Mark Cragg ORCID iD
Author: Johan Lengqvist
Author: Anne-Julie Chabot-Dore
Author: Luda Diatchenko
Author: Inna Belfer
Author: Mattias Collin
Author: Kim Kultima
Author: Birgitta Heyman
Author: Juan M. Andrade Jimenez
Author: Simone Codeluppi
Author: Rikard Holmdahl
Author: Camilla I. Svensson

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