title: Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism.
abstract: OBJECTIVE
  An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation.
  
  
  METHODS
  Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin.
  
  
  RESULTS
  Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin.
  
  
  CONCLUSIONS
  The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.
authors.affiliation: Molecular Pain Research, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gustaf
authors.initials: G
authors.lastname: Wigerblad
authors.affiliation: Molecular Pain Research, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Duygu B
authors.initials: DB
authors.lastname: Bas
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Cátia
authors.initials: C
authors.lastname: Fernades-Cerqueira
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Akilan
authors.initials: A
authors.lastname: Krishnamurthy
authors.affiliation: Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kutty Selva
authors.identifier: http://orcid.org/0000-0001-7790-8197
authors.initials: KS
authors.lastname: Nandakumar
authors.affiliation: Molecular Pain Research, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Rogoz
authors.affiliation: Molecular Pain Research, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jungo
authors.initials: J
authors.lastname: Kato
authors.affiliation: Molecular Pain Research, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Katalin
authors.initials: K
authors.lastname: Sandor
authors.affiliation: Molecular Pain Research, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Unidad Academica Multidisciplinaria Reynosa Aztlan, Universidad Autonoma de Tamaulipas, Reynosa, Tamaulipas, Mexico.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Jimenez-Andrade
authors.affiliation: Molecular Pain Research, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anja
authors.initials: A
authors.lastname: Finn
authors.affiliation: Molecular Pain Research, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Alex
authors.initials: A
authors.lastname: Bersellini Farinotti
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Khaled
authors.initials: K
authors.lastname: Amara
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Lundberg
authors.affiliation: Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Vivianne
authors.initials: V
authors.lastname: Malmström
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Anca I
authors.initials: AI
authors.lastname: Catrina
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Molecular Pain Research, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Camilla I
authors.initials: CI
authors.lastname: Svensson
mesh_terms: D000818:Animals; D018771:Arthralgia / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D016022:Case-Control Studies; D054360:Chemokine CXCL1 / Q000187:drug effects / Q000276:immunology*; D018925:Chemokines; D002956:Citrulline / Q000276:immunology*; D007249:Inflammation; D016209:Interleukin-8 / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology*; D053700:Receptors, Interleukin-8 / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; D054360:Chemokine CXCL1; D018925:Chemokines; C475895:Cxcl1 protein, mouse; D016209:Interleukin-8; D053700:Receptors, Interleukin-8; D013449:Sulfonamides; D002956:Citrulline; C490707:reparixin
keywords: Ant-CCP; Autoantibodies; Fibromyalgis/Pain Syndromes; Rheumatoid Arthritis