PT  - JOURNAL ARTICLE
AU  - Fujii, Takayuki
AU  - Lee, Eun-Jae
AU  - Miyachi, Yukino
AU  - Yamasaki, Ryo
AU  - Lim, Young-Min
AU  - Iinuma, Kyoko
AU  - Sakoda, Ayako
AU  - Kim, Kwang-Kuk
AU  - Kira, Jun-ichi
TI  - Antiplexin D1 Antibodies Relate to Small Fiber Neuropathy and Induce Neuropathic Pain in Animals
AID  - 10.1212/NXI.0000000000001028
DP  - 2021 Sep 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e1028
VI  - 8
IP  - 5
4099  - http://nn.neurology.org/content/8/5/e1028.short
4100  - http://nn.neurology.org/content/8/5/e1028.full
SO  - Neurol Neuroimmunol Neuroinflamm2021 Sep 01; 8
AB  - Objectives To assess the prevalence of antiplexin D1 antibodies (plexin D1-immunoglobulin G [IgG]) in small fiber neuropathy (SFN) and the effects of these antibodies in vivo.Methods We developed an ELISA for plexin D1-IgG using a recombinant extracellular domain of human plexin D1 containing the major epitope and sera from 58 subjects previously studied with a standard tissue-based indirect immunofluorescence assay (TBA). We screened 63 patients with probable SFN and 55 healthy controls (HCs) for serum plexin D1-IgG using ELISA. The results were confirmed by TBA. IgG from 3 plexin D1-IgG-positive patients, 2 plexin D1-IgG-negative inflammatory disease controls, and 2 HCs was intrathecally injected into mice, which were assessed for mechanical and thermal hypersensitivity 24 and 48 hours after injection.Results The ELISA had 75% sensitivity and 100% specificity using the TBA as a standard, and the coincidence rate of ELISA to TBA was 96.6% (56/58). The frequency of plexin D1-IgG was higher in patients with SFN than in HCs (12.7% [8/63] vs 0.0% [0/55], p = 0.007). Purified IgG from all 3 plexin D1-IgG-positive patients, but not 2 plexin D1-IgG-negative patients, induced significant mechanical and/or thermal hypersensitivity compared with IgG from HCs. In mice injected with plexin D1-IgG-positive but not D1-IgG-negative patient IgG, phosphorylated extracellular signal-regulated protein kinase immunoreactivity, an activation marker, was confined to small dorsal root ganglion neurons and was significantly more abundant than in mice injected with HC IgG.Conclusions Plexin D1-IgG is pathogenic but with low prevalence and is a potential biomarker for immunotherapy in SFN.ALS=amyotrophic lateral sclerosis; ANOVA=analysis of variance; CV=coefficient of variation; DM=diabetes mellitus; DRG=dorsal root ganglia; FGFR3=fibroblast growth factor receptor 3; HC=healthy control; IDC=inflammatory disease control; IgG=immunoglobulin G; iSFN=idiopathic SFN; NeP=neuropathic pain; OD=optical density; PBS=phosphate-buffered saline; pERK=phosphorylated extracellular signal-regulated protein kinase; rhPlexin D1=recombinant human plexin D1 extracellular domain; RT=room temperature; SFN=small fiber neuropathy; SFN-SIQ=SFN Symptom Inventory Questionnaire; sSFN=secondary SFN; TBA=tissue-based indirect immunofluorescence assay; TS-HDS=trisulfated heparin disaccharide