A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain

Abstract

Anti-plexin D1 antibodies are a novel biomarker for immunotherapy-responsive NeP. Ann Neurol 2018;84:208-224.

Anti‐plexin D1 antibodies are a novel biomarker for immune‐mediated neuropathic pain

“…We screened serum autoantibodies that specifically bound to the DRG and dorsal horns of the spinal cord in the somatosensory pathway using a mouse tissue‐based indirect immunofluorescence assay (IFA) with serum samples from 110 patients with NeP and 50 subjects without NeP 10 . As a result, specific IgG against small DRG neurons and their nerve terminals in the dorsal horn of the spinal cord were found in patients with NeP, whereas control subjects without NeP had no specific IgG against small DRG neurons.…”

“…The positivity rates of anti‐small DRG neuron autoantibodies were significantly higher in patients with NeP than in non‐NeP subjects (10% vs 0%; P < .05). The positivity rates in 15 relapsing‐remitting multiple sclerosis patients, 17 neuromyelitis optica spectrum disorders patients, and 22 atopic myelitis (AM) patients were 6.7%, 11.8%, and 27.3%, respectively 10 . AM patients showed a relatively high frequency of anti‐small DRG neuron autoantibodies compared with patients with other immune‐mediated neurological diseases.…”

“…The main IgG subclass was IgG2, which usually recognizes carbohydrate antigens and only weakly activates complement 13 . To identify which DRG neuron subtypes patient IgG bound to, we performed dual immunostaining with patient IgG and DRG neuron markers 10 . Anti‐small DRG neuron autoantibodies mostly colocalized with isolectin B4 (IB4)‐positive and P2X purinoceptor 3 (P2X3)‐positive unmyelinated C‐fiber–type small DRG neurons and partly with calcitonin gene‐related peptide (CGRP)‐positive and transient receptor potential vanilloid 1 (TRPV1)‐positive neurons.…”

“…Western blotting (WB) with mouse DRG and IgG from patients with anti‐small DRG neuron antibodies revealed a common 220‐kDa band. Liquid chromatography–tandem mass spectrometry of the immunoprecipitates demonstrated that plexin D1 was the target autoantigen 10 . To confirm plexin D1 as the target antigen, we performed an immunoadsorption assay with a recombinant human plexin D1 extracellular domain using mouse DRG tissue‐based IFA and WB 10 .…”

“…We recently discovered a unique IgG autoantibody that binds to pain‐conducting small dorsal root ganglion (DRG) neurons (primary sensory neurons) and their nerve terminals in the spinal dorsal horn of patients with NeP 10 . Its antigen, plexin D1, is a large transmembrane glycoprotein (approximately 212 kDa) belonging to the plexin family, which is associated with neuronal axon guidance 11,12 …”