Fibromyalgia syndrome (FMS) is characterized by elevated levels of immunoglobulin G (IgG), altered bowel habits, and increased pain sensitivity, suggesting immune dysregulation, but the exact mechanism remains unclear. Here, we found that FMS-IgG binds to mast cells in a MRGPRX2/b2-dependent manner, leading to mast cell recruitment and IL-6 secretion. Transferring serum-IgG from FMS patients to mice induced FMS-like symptoms and increased skin mast cells, indicating that FMS-IgG acts through mast cell activation. The ablation of mice Mrgprb2 mast cells or deleting Mrgprb2 receptors prevented IgG-induced heightened sensitivity to mechanical and cold stimuli. Stimulating human LAD2 cells with FMS IgG elicited MRGPRX2-dependent IL-6 production. Consistent with mice findings, mast cell density and tryptase levels increased in human FMS skin samples compared to healthy controls. Taken together our results suggests that FMS IgG mediates hypersensitivity via activation of mast cells bearing the MRGPRX2 receptor and that these cells are a potential therapeutic target. ### Competing Interest Statement X.D. is the scientific founder of and consultant for Escient Pharmaceuticals, a pharmaceutical company developing drugs targeting Mrgprs. X.D. collaborates with GlaxoSmithKline (GSK) on Mrgpr-related projects unrelated to this manuscript. Other authors declare no competing interests. Howard Hughes Medical Institute, https://ror.org/006w34k90 Pain Relief Foundation, https://ror.org/0017mh436 Versus Arthritis, https://ror.org/02jkpm469, 22471

Approximately 30% of long COVID patients still experience neurological symptoms (brain fog, pain, chronic fatigue) more than 4 months after the onset of COVID-19. This condition, known as neurological long COVID, remains poorly understood and might be explained by a persisting autoimmune response against nervous-derived self-antigens. The aim of this study is to determine whether IgG autoantibodies from long COVID patients with neurological sequelae can bind to central or peripheral nervous system epitopes and triggers neuropsychiatric symptoms upon passive transfer into mice, thereby mirroring patient-reported manifestations. Long COVID patients meeting the 2021 consensus WHO definition were included following a standardized neuropsychological assessment, while excluding patients with a medical history of autoimmune and neurological disorders. Age- and sex-matched asymptomatic individuals were used as healthy controls. Total IgGs were isolated using protein G purification and injected intraperitoneally into C57Bl6/J mice for four consecutive days. During the two weeks post-injections, behavioral tests assessed mechanical allodynia, thermal hyperalgesia, spatial working memory, depression, and anxiety. Mice injected with IgG from long COVID patients showed no difference with the control group in terms of anxiety or depression behaviors, as well as no impairment of short- or long-term spatial memories and thermal hyperalgesia. However, they displayed a transient decrease of paw withdrawal threshold during the first week. This effect was abolished when IgG-depleted serum or papain-digested IgGs were transferred. IgG from long COVID patients accumulated in the lumbar dorsal root ganglia of injected mice and colocalized with proprioceptive and nociceptive sensory neurons, without inducing local neuroinflammation or astrogliosis. These data demonstrate that IgGs from long COVID patients bind to peripheral sensory neurons and induce pain-related symptoms in mice. Our findings also support the hypothesis that autoantibodies mediate pain-related pathophysiology in the spectrum of long COVID symptoms. ### Competing Interest Statement The authors have declared no competing interest. FNRS, CDR J.0147.22 FNRS/FRIA

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