Autoantibody-induced novel pathophysiology of neuropathic pain

Abstract

　Autoantibodies can cause neuropathic pain by binding to sensory neurons and inducing neuronal hyperexcitability. Underlying mechanisms include disruption of ion channel complexes, activation of intracellular signaling pathways, formation of immune complexes, and stimulation of glial cells. This form of neuropathic pain, known as “autoantibody-mediated neuropathic pain”, represents a distinct immunological subtype within the broader category of neuropathic pain disorders. Several autoantibodies have been identified to date, including anti‑Plexin D1, anti‑Annexin A2, and anti‑MX1 antibodies, and their involvement has been suggested particularly in patients with otherwise unexplained neuropathic pain, such as those with small fiber neuropathy (SFN) . Although case reports and small series have described favorable responses to immunotherapies in some antibody‑positive patients, high‑quality clinical trials demonstrating clear therapeutic efficacy remain limited.
　Future challenges include the identification of uncharacterized target antigens, elucidation of the detailed pathogenic mechanisms by which these antibodies alter neuronal or glial function, and the establishment of criteria for selecting patients who are most likely to benefit from immunomodulatory treatment. Measurement of autoantibodies holds promise as a clinically meaningful tool for stratifying patients and guiding therapeutic decisions. In particular, antibody testing may help identify individuals whose neuropathic pain shows limited response to analgesics and who may benefit from immunotherapy, thereby expanding therapeutic options beyond current treatment approaches. As research advances, autoantibody profiling is expected to contribute to a more precise understanding of disease mechanisms and to the development of personalized treatment strategies for patients with chronic, difficult‑to‑treat neuropathic pain.