The role of antiplexin D1 antibodies in small fiber neuropathy

The antiplexin-D1 antibody has been associated with typical manifestations of small fiber neuropathy (SFN) and could be a useful tool in identifying patients who are more likely to respond to immunotherapy, according to study results published in Neurology.

Symptoms of SFN can include neuropathic pain, allodynia, paresthesia, and loss of needlestick and warmth sensations, as well as autonomic symptoms. Antiplexin D1 antibodies have been identified in patients with neuropathic pain with neuroinflammatory diseases and in patients with idiopathic painful trigeminal neuropathy.

The aim of the current study was to determine the prevalence of antiplexin D1 antibodies in patients with SFN and to assess the pain-inducing effects of intrathecally injected D1 immunoglobulin G (IgG) in mice.

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To develop an ELISA for antiplexin D1 antibodies, the study researchers used sera from 8 patients with neuropathic pain with antiplexin D1 antibodies and sera from 50 controls without neuropathic pain or antiplexin D1 antibodies. These were previously examined in a standard tissue-based indirect immunofluorescence assay (TBA).

The study cohort comprised 63 patients with SFN (women 32, mean age 58.0 years) and 55 healthy controls (women 37, mean age 57.0 years). The positive ELISA rate was 12.7% (8 of 63 patients) in those with SFN and 3.6% (2 of 55 patients) in the healthy controls. Positive rates for ELISA plus TBA were 12.7% (8 of 63 patients) and 0% (P = 0.007), respectively.

Using TBA as the standard evaluation method, the ELISA had a sensitivity of 75% in patients with antiplexin D1 antibodies and a specificity of 100% in seronegative patients. The overall coincidence rate of the ELISA on TBA was 96.6% (56 of 58 patients).

Study researchers injected mice intrathecally with IgG from 3 antiplexin D1 positive patients, 2 antiplexin D1 negative controls for inflammatory diseases, and 2 healthy controls. They then assessed the mechanical and thermal hypersensitivity 24 and 48 hours after the injection. To study hypersensitivity to thermal pain, mice were placed on a digital hot plate; Mechanical hypersensitivity to pain was assessed using calibrated von Frey filaments.

Injection of antiplexin D1 antibody was associated with significantly higher response rates to each stimulus compared to injection of IgG from healthy controls.

At 24 hours after injection, the average percentages of phosphorylated extracellular signal-regulated protein kinase-labeled neurons among the spinal ganglion neurons in mice treated with IgG from antiplexin-D1 antibody-positive individuals were significantly higher than in mice receiving immunoglobulin from antiplexin -D1 IgG. was injected – negative patient. The phosphorylated extracellular signal-regulated protein kinase immunoreactivity was significantly more abundant than in mice injected with IgG from healthy controls.

The study had several limitations, including inclusion of patients without histopathological confirmation of SFN, limited amounts of patient sera, and inclusion limited to patients with length-dependent clinical manifestations.

“Plexin D1-IgG is pathogenic but with a low prevalence and a potential biomarker for immunotherapy in SFN,” the study researchers concluded.

Disclosure: Some study authors stated links with biotech, pharmaceutical, and / or device companies. For a full list of the author’s disclosures, see the original reference.


Fujii T, Lee EJ, Miyachi Y, et al. Antiplexin D1 antibodies are related to small fiber neuropathy and induce neuropathic pain in animals. Neurol Neuroimmunol Neuroinflamm. Published online June 7, 2021. doi: 10.1212 / NXI.0000000000001028

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