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J Exp Med. 2019 Aug 5;216(8):1904-1924. doi: 10.1084/jem.20181657. Epub 2019 Jun 13.

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

Author information

1
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
2
Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
3
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
4
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
5
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
6
Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
7
Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
8
Alan Edwards Centre for Research on Pain, McGill University, Montréal, Quebec, Canada.
9
Office of Research on Women's Health, National Institutes of Health, Bethesda, MD.
10
Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.
11
Department of Medical Science, Uppsala University, Uppsala, Sweden.
12
Department of Unidad Academica Multidisciplinaria Reynosa Aztlan, Universidad Autonoma de Tamaulipas, Reynosa, Tamaulipas, Mexico.
13
Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden rikard.holmdahl@ki.se.
14
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden camilla.svensson@ki.se.
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Contributed equally

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.

PMID:
31196979
PMCID:
PMC6683987
[Available on 2020-02-05]
DOI:
10.1084/jem.20181657

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