Anti-plexin D1 antibody–mediated neuropathic pain

Neuropathic pain (NeP) is an intractable pain caused by a lesion or disease of the somatosensory nervous system. NeP is often challenging to manage because most of the mechanisms remain to be elucidated. Recent investigations in the field of autoimmune neurology have demonstrated that specific autoantibodies against antigens in the somatosensory pathway can cause NeP. Detection of pathogenic autoantibodies in NeP adds to the understanding of the mechanism of pain, which might aid in the development of novel immunotherapies. Therefore, it is necessary to explore novel NeP-related autoantibodies to improve the management of intractable pain. Recently, we screened serum autoantibodies that bound to pain-conducting small dorsal root ganglion (DRG) neurons and their nerve terminals in the dorsal horns of NeP patients. We detected a novel autoantibody that bound to unmyelinated C-fiber–type small DRG neurons. The positive rate in patients with NeP was 10%. We identified plexin D1 as the target antigen. NeP patients with plexin D1-IgG developed burning pain and thermal hyperalgesia. The main comorbidities were allergy, collagen vascular disease, and cancer. Plasma exchange and intravenous methylprednisolone pulse therapy are effective for NeP in patients with plexin D1-IgG, indicating that these autoantibodies might be pathogenic in NeP. Indeed, our in vitro study demonstrated that plexin D1-IgG induced the membrane hyperpermeability of DRG neurons. In this review, we describe the discovery of plexin D1-IgG and discuss the association between plexin D1 and pain, allergy, and cancer.