Passive transfer of fibromyalgia symptoms from patients to mice
Andreas Goebel, Emerson Krock, Clive Gentry, Mathilde R. Israel, Alexandra Jurczak, Carlos Morado Urbina, Katalin Sandor, Nisha Vastani, Margot Maurer, Ulku Cuhadar, Serena Sensi, Yuki Nomura, Joana Menezes, Azar Baharpoor, Louisa Brieskorn, Angelica Sandström, Jeanette Tour, Diana Kadetoff, Lisbet Haglund, Eva Kosek, Stuart Bevan, Camilla I. Svensson, David A. Andersson
Andreas Goebel, Emerson Krock, Clive Gentry, Mathilde R. Israel, Alexandra Jurczak, Carlos Morado Urbina, Katalin Sandor, Nisha Vastani, Margot Maurer, Ulku Cuhadar, Serena Sensi, Yuki Nomura, Joana Menezes, Azar Baharpoor, Louisa Brieskorn, Angelica Sandström, Jeanette Tour, Diana Kadetoff, Lisbet Haglund, Eva Kosek, Stuart Bevan, Camilla I. Svensson, David A. Andersson
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Research Article Neuroscience

Passive transfer of fibromyalgia symptoms from patients to mice

Abstract

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.

Authors

Andreas Goebel, Emerson Krock, Clive Gentry, Mathilde R. Israel, Alexandra Jurczak, Carlos Morado Urbina, Katalin Sandor, Nisha Vastani, Margot Maurer, Ulku Cuhadar, Serena Sensi, Yuki Nomura, Joana Menezes, Azar Baharpoor, Louisa Brieskorn, Angelica Sandström, Jeanette Tour, Diana Kadetoff, Lisbet Haglund, Eva Kosek, Stuart Bevan, Camilla I. Svensson, David A. Andersson

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Figure 8

FMS IgG increases signs of satellite glial cell activity in vivo but does not drive systemic inflammation.

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FMS IgG increases signs of satellite glial cell activity in vivo but doe...
DRG from FMS IgG–injected mice have increased GFAP immunoreactivity (A), which is indicative of increased satellite glial cell activity, compared with HC IgG injected mice when the percentage area of GFAP immunoreactivity and GFAP mean pixel intensity are quantified and normalized to the DAPI signal (B). Gfap and s100b gene expression is elevated in the DRG of mice injected with FMS IgG compared with HC IgG (C). The number of Iba1-immunoreactive macrophages was unchanged, as was the percentage area of Iba1 immunoreactivity, when comparing HC IgG– and FMS IgG–injected mice (D and E). Gene expression of Aif1 (Iba1 gene) and Itagm (gene for CD11b, another macrophage marker) was elevated in FMS IgG–injected mice compared with HC IgG–injected mice (F). Scale bars: 50 μm. qPCR data were normalized to Hprt1 expression analyzed using the 2–ΔΔCt method. Serum levels of TNF (G), CXCL1 (H), IL-2 (I), IL-5 (J), IL-6 (K), IL-10 (L), and IFN-γ (M) were measured and there were no differences between groups. The dashed lines indicate the lower limit of quantification (LLOQ) and the dotted lines indicate the lower limit of detection (G–M). Line and whiskers indicate mean ± SEM (n = 4–6). Differences between FMS IgG and HC IgG were analyzed with Mann-Whitney U test (B–F). Cytokine levels were compared between saline, HC, and FMS with 1-way ANOVA followed by Tukey’s post hoc test for each analyte (G–M) except IL-6, which was not analyzed statistically because most values were below the LLOQ. *P < 0.05, **P < 0.01, ***P < 0.001.