Work

Pathogenic Role of FGFR3 Autoantibodies in Small Fiber Neuropathy

Year: 2026

Type: article

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 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-autoantibody-positive sera (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.

Source: Advanced Science

DOI: 10.1002/advs.202511413