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
View: Text | PDF
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

×

Figure 7

FMS IgG accumulates in the DRG and binds satellite glial cells.

Options: View larger image (or click on image) Download as PowerPoint
FMS IgG accumulates in the DRG and binds satellite glial cells. Followin...
Following IgG injection into mice, Western blot analysis detected FMS IgG in the DRG but little to no IgG in spinal cords (SC) or brains (A) (pooled IgG, 8 mg per day for 4 consecutive days, tissue collected after last injection). FMS IgG, but not HC IgG, accumulates in the DRG 14 days after the first IgG injection (B and C). Human IgG is red and DAPI is blue. Human IgG immunoreactivity in the neuron-rich area was quantified by assessing the percentage area that was immunoreactive for human IgG and the mean pixel intensity of human IgG. Percentage area and pixel intensity were normalized to the DAPI signal (n = 9–10; data points are median ± 95% CI). **P < 0.01, ***P < 0.001 by 1-way ANOVA followed by Tukey’s post hoc test. FMS IgG immunoreactivity does not colocalize with neuronal NeuN staining but does colocalize with satellite glial cells (SGCs) (glutamate synthase–expressing [GS-expressing] cells), some macrophages (Iba1-expressing cells) and blood vessels (CD31-expressing cells), and myelinated fiber tracts (myelin basic protein [MBP] staining), but not to myelinated fibers in the DRG (D). To further delineate between SGCs and neuronal membranes, FMS IgG immunoreactivity colocalization was compared with GS and TrkA (a membrane receptor expressed by a subset of nociceptors). FMS IgG colocalizes with GS-expressing SGCs (white arrows) but may also infrequently bind to TrkA-positive neuronal cell membranes (white triangles) (E). Scale bars indicate 50 μm, except the high-magnification image scale bar and scale bar in E, which indicate 25 μm.