Painful trigeminal neuropathy associated with anti-Plexin D1 antibody

Abstract

ObjectiveTo determine whether anti-Plexin D1 antibody (Plexin D1-immunoglobulin G [IgG]), which is associated with limb and trunk neuropathic pain (NP) and binds to pain-conducting small unmyelinated dorsal root ganglion (DRG) neurons, exists in patients with idiopathic painful trigeminal neuropathy (IPTN) and whether Plexin D1-IgG binds to trigeminal ganglion (TG) neurons.MethodsWe enrolled 21 consecutive patients with IPTN and 35 age- and sex-matched controls without NP (25 healthy persons and 10 with neurodegenerative diseases). We measured serum Plexin D1-IgG using a mouse DRG tissue–based indirect immunofluorescence assay (IFA) and by Western blotting (WB) using a recombinant human Plexin D1 (rhPlexin D1) accompanied by immunoadsorption tests with rhPlexin D1. The reactivity of Plexin D1-IgG toward mouse TG, brain, heart, and kidney was assessed by tissue-based IFAs.ResultsSerum Plexin D1-IgG was detected more frequently in IPTN than in controls by both IFA and WB (14.3% vs 0%, p = 0.048). Three Plexin D1-IgG–positive patients also had limb or trunk NP and commonly showed tongue pain. In tissue-based IFAs, IgG from 2 Plexin D1-IgG–positive patients immunostained small TG neurons, which was prevented by preincubation with rhPlexin D1. Moreover, Plexin D1-IgG immunostaining mostly colocalized with isolectin B4-positive pain-conducting unmyelinated TG neurons. IFAs of other tissues with the same IgG revealed weak immunoreactivity only in endothelial cells, which was prevented by preincubation with rhPlexin D1.ConclusionsPlexin D1-IgG, which binds to pain-conducting small TG neurons in addition to DRG neurons, can be present in IPTN as well as limb and trunk NP.

Antiplexin D1 Antibodies Relate to Small Fiber Neuropathy and Induce Neuropathic Pain in Animals

“…The passive transfer to mice of mechanical pain associated with activation of small pain-conducting DRG neurons by plexin D1-IgG and abrogation of these effects by preadsorption of purified IgG with the extracellular domain of plexin D1 indicates the mechanical pain-provoking effects of plexin D1-IgG in vivo. This is consistent with the previous finding that NeP patient-derived plexin D1-IgG selectively binds to isolectin B4-positive unmyelinated C-fiber type small DRG neurons 8 , 10 that sense mechanical pain. 31 , 32 Accordingly, plexin D1-IgG is considered to be pathogenic.…”

“…TBA, the current gold standard for plexin D1-IgG identification, 8 , 10 is unsuitable for large-scale screening studies because of low sensitivity, despite its high specificity. Therefore, we developed an indirect ELISA for plexin D1-IgG.…”

“…To confirm the antibody specificity to plexin D1, immunoadsorption tests were performed with rhPlexin D1 by TBA. 10 In the SFN cohort study, we applied TBA as a confirmatory test for ELISA plexin D1-IgG positivity. 8 , 10 …”

“… 9 Plexin D1-IgG was also detected in patients with idiopathic painful trigeminal neuropathy presenting facial pain and bound to trigeminal ganglion neurons. 10 These observations prompted us to assess the prevalence of plexin D1-IgG in patients with SFN and to evaluate the pain-provoking effects of intrathecally-injected plexin D1-IgG in mice.…”

N2 in the time of COVID-19

“…In another study, Fujii et al 3 investigated whether patients with idiopathic painful trigeminal neuropathy (IPTN) had antibodies against Plexin D1 and whether the antibodies were able to bind trigeminal ganglion neurons. The rationale for this study is based in previous work of the same authors showing that about 10% of patients with neuropathic pain had antibodies against Plexin D1, which is a member of a family of transmembrane protein receptors that bind semaphorins as ligands.…”