Pathogenic Role of FGFR3 Autoantibodies in Small Fiber Neuropathy

Abstract Sensory neuronopathies (SNN) and small fiber neuropathies (SFN) are debilitating disorders associated with neuropathic pain, yet their underlying mechanisms remain poorly understood. Autoantibodies against fibroblast growth factor receptor 3 (FGFR3-Abs) define a subset of patients with consistent reports of neuropathic pain harboring a distinct clinical phenotype characterized by small-fiber and non-length-dependent neuropathy, suggesting dorsal root ganglia (DRG) dysfunction. FGFR3-Abs bind to sensory neurons within dorsal root ganglia (DRG). The target of autoantibodies FGFR3 is expressed at the transcript and protein level in human sensory neurons, suggesting that FGFR3-Abs could find their target in primary afferents. DRG neurons exposed to FGFR3-Abs rapidly acquired a hyperexcitability phenotype which was linked to mechanical hypersensitivity, mirroring patient-reported pain symptoms. CRISPR mediated gene editing of FGFR3 in sensory neuron prevented FGFR3-Abs induced sensitization of sensory neurons and mechanical hypersensitivity. In parallel, Epitope mapping reveals extracellular FGFR3 epitopes essential for antibody-induced sensitization and pain hypersensitivity. Together this work suggests that beyond their role as biomarkers, FGFR3-Abs are pathogenic in small fiber neuropathy by acting directly on DRG neurons. This positions both FGFR3-Abs and FGFR3 signaling as actionable therapeutic targets for modulating sensory neuron excitability and treating autoimmune painful neuropathies.