Pathogenic Role of FGFR3 Autoantibodies in Small Fiber Neuropathy

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Sensory neuronopathies (SNN) and small fiber neuropathies (SFN) cause neuropathic pain with unclear mechanisms.
• Autoantibodies against fibroblast growth factor receptor 3 (FGFR3) are linked to a specific SNN/SFN phenotype and dorsal root ganglia (DRG) dysfunction.

Purpose of the Study:

• To investigate the pathogenic role of FGFR3 autoantibodies in SNN/SFN.
• To explore FGFR3 as a potential therapeutic target for autoimmune neuropathies.

Main Methods:

• Analysis of patient sera (FGFR3-autoantibody-positive sera, FGFR3-AbS) binding to sensory neurons.
• Assessment of DRG neuron excitability and hypersensitivity after FGFR3-AbS exposure.
• CRISPR gene editing of FGFR3 in sensory neurons.
• Epitope mapping of FGFR3.

Main Results:

• FGFR3-AbS bind to sensory neurons in human DRG.
• FGFR3-AbS exposure induces DRG neuron hyperexcitability and mechanical hypersensitivity.
• CRISPR-mediated FGFR3 gene editing prevents FGFR3-AbS-induced sensitization and hypersensitivity.
• Specific extracellular FGFR3 epitopes are crucial for antibody-induced sensitization.

Conclusions:

• FGFR3 autoantibodies are pathogenic in SNN/SFN, acting directly on DRG neurons.
• FGFR3 autoantibodies and FGFR3 signaling represent viable therapeutic targets for autoimmune painful neuropathies.