Passive transfer of fibromyalgia symptoms from patients to mice

TY - JOUR

T1 - Passive transfer of fibromyalgia symptoms from patients to mice

AU - Goebel, Andreas

AU - Krock, Emerson

AU - Gentry, Clive

AU - Israel, Mathilde R.

AU - Jurczak, Alexandra

AU - Morado Urbina, Carlos

AU - Sandor, Katalin

AU - Vastani, Nisha

AU - Maurer, Margot

AU - Cuhadar, Ulku

AU - Sensi, Serena

AU - Nomura, Yuki

AU - Menezes, Joana

AU - Baharpoor, Azar

AU - Brieskorn, Louisa

AU - Sandström, Angelica

AU - Tour, Jeanette

AU - Kadetoff, Diana

AU - Haglund, Lisbet

AU - Kosek, Eva

AU - Bevan, Stuart

AU - Svensson, Camilla I.

AU - Andersson, David A.

N1 - Funding Information: This work was supported by the Medical Research Council grant MR/S003428/1 (to DAA, SB, and AG), Versus Arthritis grants 21544 (to DAA and AG) and 21543 (to SB), the Pain Relief Foundation Liverpool (to DAA, SS, and AG), Eli Lilly & Co (to DAA), Swedish Research Council grant 542-2013-8373 (to CIS), the Knut and Alice Wallenberg Foundation (018.0161 to CIS), the Karolinska Institute Foundations (to CMU), the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement number 602919 (to CIS and E Kosek), European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement number 764860 (to CIS and E Kosek), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under the grant agreement no. 866075 (to CIS), by a generous donation from Leif Lundblad and family (to CIS and E Kosek), Stockholm County Council (grant ALF-20190039 to E Kosek), the IASP John J. Bonica fellowship (to E Krock), a CIHR postdoctoral fellowship (MFE-171299 to E Krock), and the Konung Gustaf V:s 80-årsfond (to E Krock). The authors are grateful to Domenico Cozzetto from the Translational Bioinformatics Platform at the NIHR Biomedical Research Centre at Guy’s and St. Thomas’s NHS Foundation Trust and King’s College London for bioinformatics advice. The graphical abstract was created with BioRender and the Strategic Research Programme in Diabetes at Karolinska Institutet provided access to the CLAMS system. Publisher Copyright: © 2021, Goebel et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/7/1

Y1 - 2021/7/1

N2 - Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.

AB - Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.

KW - FIBROMYALGIA

KW - Pain

KW - AUTOANTIBODIES

KW - FIBROMYALGIA SYNDROME

UR - http://www.scopus.com/inward/record.url?scp=85108991502&partnerID=8YFLogxK

U2 - 10.1172/JCI144201

DO - 10.1172/JCI144201

M3 - Article

SN - 1558-8238

VL - 131

JO - The Journal of clinical investigation

JF - The Journal of clinical investigation

IS - 13

M1 - e144201

ER -