Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism
Gustaf Wigerblad, Duygu B Bas, Cátia Fernades-Cerqueira, Akilan Krishnamurthy, Kutty Selva Nandakumar, Katarzyna Rogoz, Jungo Kato, Katalin Sandor, Jie Su, Juan Miguel Jimenez-Andrade, Anja Finn, Alex Bersellini Farinotti, Khaled Amara, Karin Lundberg, Rikard Holmdahl, Per-Johan Jakobsson, Vivianne Malmström, Anca I Catrina, Lars Klareskog, Camilla I Svensson, Gustaf Wigerblad, Duygu B Bas, Cátia Fernades-Cerqueira, Akilan Krishnamurthy, Kutty Selva Nandakumar, Katarzyna Rogoz, Jungo Kato, Katalin Sandor, Jie Su, Juan Miguel Jimenez-Andrade, Anja Finn, Alex Bersellini Farinotti, Khaled Amara, Karin Lundberg, Rikard Holmdahl, Per-Johan Jakobsson, Vivianne Malmström, Anca I Catrina, Lars Klareskog, Camilla I Svensson
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.
Keywords: Ant-CCP; Autoantibodies; Fibromyalgis/Pain Syndromes; Rheumatoid Arthritis.
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References
- Heiberg T, Kvien TK. Preferences for improved health examined in 1,024 patients with rheumatoid arthritis: pain has highest priority. Arthritis Rheum 2002;47:391–7. 10.1002/art.10515
- Rantapää-Dahlqvist S, de Jong BAW, Berglin E, et al. . Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003;48:2741–9. 10.1002/art.11223
- Bos WH, Wolbink GJ, Boers M, et al. . Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann Rheum Dis 2010;69:490–4. 10.1136/ard.2008.105759
- van Steenbergen HW, van Nies JAB, Huizinga TWJ, et al. . Characterising arthralgia in the preclinical phase of rheumatoid arthritis using MRI. Ann Rheum Dis 2015;74:1225–32. 10.1136/annrheumdis-2014-205522
- McWilliams DF, Zhang W, Mansell JS, et al. . Predictors of change in bodily pain in early rheumatoid arthritis: an inception cohort study. Arthritis Care Res (Hoboken) 2012;64:1505–13. 10.1002/acr.21723
- American College of Rheumatology Pain Management Task Force. Report of the American College of Rheumatology Pain Management Task Force. Arthritis Care Res (Hoboken) 2010;62:590–9. 10.1002/acr.20005
- Kojima M, Kojima T, Suzuki S, et al. . Depression, inflammation, and pain in patients with rheumatoid arthritis. Arthritis Rheum 2009;61:1018–24. 10.1002/art.24647
- Lee YC, Cui J, Lu B, et al. . Pain persists in DAS28 rheumatoid arthritis remission but not in ACR/EULAR remission: a longitudinal observational study. Arthritis Res Ther 2011;13:R83 10.1186/ar3353
- Schellekens GA, de Jong BA, van den Hoogen FH, et al. . Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998;101:273–81. 10.1172/JCI1316
- Klareskog L, Lundberg K, Malmström V. Autoimmunity in rheumatoid arthritis: citrulline immunity and beyond. Adv Immunol 2013;118:129–58. 10.1016/B978-0-12-407708-9.00003-0
- van de Sande MGH, de Hair MJH, van der Leij C, et al. . Different stages of rheumatoid arthritis: features of the synovium in the preclinical phase. Ann Rheum Dis 2011;70:772–7. 10.1136/ard.2010.139527
- Kuhn KA, Kulik L, Tomooka B, et al. . Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 2006;116:961–73. 10.1172/JCI25422
- Uysal H, Bockermann R, Nandakumar KS, et al. . Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis. J Exp Med 2009;206:449–62. 10.1084/jem.20081862
- Harre U, Georgess D, Bang H, et al. . Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest 2012;122:1791–802. 10.1172/JCI60975
- Klein CJ, Lennon VA, Aston PA, et al. . Chronic pain as a manifestation of potassium channel-complex autoimmunity. Neurology 2012;79:1136–44. 10.1212/WNL.0b013e3182698cab
- Arnett FC, Edworthy SM, Bloch DA, et al. . The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. 10.1002/art.1780310302
- Ossipova E, Cerqueira CF, Reed E, et al. . Affinity purified anti-citrullinated protein/peptide antibodies target antigens expressed in the rheumatoid joint. Arthritis Res Ther 2014;16:R167 10.1186/ar4683
- Amara K, Steen J, Murray F, et al. . Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J Exp Med 2013;210:445–55. 10.1084/jem.20121486
- Bas DB, Su J, Sandor K, et al. . Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis Rheum 2012;64:3886–96. 10.1002/art.37686
- Chaplan SR, Bach FW, Pogrel JW, et al. . Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994;53:55–63. 10.1016/0165-0270(94)90144-9
- Dirig DM, Salami A, Rathbun ML, et al. . Characterization of variables defining hindpaw withdrawal latency evoked by radiant thermal stimuli. J Neurosci Methods 1997;76:183–91. 10.1016/S0165-0270(97)00097-6
- Cobos EJ, Ghasemlou N, Araldi D, et al. . Inflammation-induced decrease in voluntary wheel running in mice: a nonreflexive test for evaluating inflammatory pain and analgesia. Pain 2012;153:876–84. 10.1016/j.pain.2012.01.016
- Athanasou NA, Puddle B, Quinn J, et al. . Use of monoclonal antibodies to recognise osteoclasts in routinely processed bone biopsy specimens. J Clin Pathol 1991;44: 664–6. 10.1136/jcp.44.8.664
- Wu J, Glimcher LH, Aliprantis AO. HCO3-/Cl- anion exchanger SLC4A2 is required for proper osteoclast differentiation and function. Proc Natl Acad Sci USA 2008;105:16934–9. 10.1073/pnas.0808763105
- Krishnamurthy A, Vijay J, Hensvold H, et al. . Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone destruction. Ann Rheum Dis 2016;75:721–9..
- Cunha TM, Verri WA, Silva JS, et al. . A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc Natl Acad Sci USA 2005;102:1755–60. 10.1073/pnas.0409225102
- Guerrero ATG, Cunha TM, Verri WA, et al. . Toll-like receptor 2/MyD88 signaling mediates zymosan-induced joint hypernociception in mice: participation of TNF-α, IL-1β and CXCL1/KC. Eur J Pharmacol 2012;674:51–7. 10.1016/j.ejphar.2011.10.023
- Zhang Z-J, Cao D-L, Zhang X, et al. . Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain 2013;154:2185–97. 10.1016/j.pain.2013.07.002
- Qin X, Wan Y, Wang X. CCL2 and CXCL1 trigger calcitonin gene-related peptide release by exciting primary nociceptive neurons. J Neurosci Res 2005;82:51–62. 10.1002/jnr.20612
- Wang J-G, Strong JA, Xie W, et al. . The chemokine CXCL1/growth related oncogene increases sodium currents and neuronal excitability in small diameter sensory neurons. Mol Pain 2008;4:38 10.1186/1744-8069-4-38
- Yang R-H, Strong JA, Zhang J-M. NF-kappa B mediated enhancement of potassium currents by the chemokine CXCL1/growth related oncogene in small diameter rat sensory neurons. Mol Pain 2009;5:26 10.1186/1744-8069-5-26
- Dong F, Du Y-R, Xie W, et al. . Increased function of the TRPV1 channel in small sensory neurons after local inflammation or in vitro exposure to the pro-inflammatory cytokine GRO/KC. Neurosci Bull 2012;28:155–64. 10.1007/s12264-012-1208-8
- Harre U, Lang SC, Pfeifle R, et al. . Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun 2015;6:6651 10.1038/ncomms7651
- Negishi-Koga T, Gober H-J, Sumiya E, et al. . Immune complexes regulate bone metabolism through FcRγ signalling. Nat Commun 2015;6:6637 10.1038/ncomms7637
- Rönnelid J, Wick MC, Lampa J, et al. . Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression. Ann Rheum Dis 2005;64:1744–9. 10.1136/ard.2004.033571
- Bos WH, Bartelds GM, Wolbink GJ, et al. . Differential response of the rheumatoid factor and anticitrullinated protein antibodies during adalimumab treatment in patients with rheumatoid arthritis. J Rheumatol 2008;35:1972–7.
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