The Role of Antiplexin D1 Antibodies in Small Fiber Neuropathy

Investigators sought to evaluate the prevalence of antiplexin D1 antibodies in small fiber neuropathy, as well as their effects in vivo.

Antiplexin D1 antibody is associated with typical small fiber neuropathy (SFN) manifestations and may be a useful tool to identify patients more likely to respond to immunotherapy, according to study results published in Neurology.

The symptoms of SFN may include neuropathic pain, allodynia, paresthesia, and loss of pinprick and thermal sensation, as well as autonomic symptoms. Antiplexin D1 antibody was identified in patients with neuropathic pain with neuroinflammatory diseases and in patients with idiopathic painful trigeminal neuropathy.

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

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

The study cohort included 63 patients with SFN (women, 32; mean age, 58.0 years) and 55 healthy controls (women, 37; mean age, 57.0 years). Positive rate of ELISA was 12.7% (8 of 63 patients) among those with SFN and 3.6% (2 of 55 patients) among healthy controls. Positive rates of ELISA plus TBA were 12.7% (8 of 63 patients) and 0% respectively (P =.007).

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

The study researchers intrathecally injected IgG from 3 antiplexin D1 positive patients, 2 antiplexin-D1 negative inflammatory disease controls, and 2 healthy controls into mice. They then assessed mechanical and thermal hypersensitivity 24 and 48 hours following injection. To examine thermal pain hypersensitivity, mice were placed on a digital hot plate; mechanical pain hypersensitivity was evaluated using calibrated von Frey filaments.

Injection of antiplexin D1 antibody was associated with a significantly higher reaction rates to each stimuli, compared with injection from of IgG from healthy controls.

At 24 hours after injection, the average percentages of phosphorylated extracellular signal-regulated protein kinase-labeled neurons among dorsal root ganglion neurons were significantly greater in mice treated with IgG from antiplexin D1 antibody positive individuals, compared to those injected with immunoglobulin from antiplexin D1 IgG-negative patient. 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 a histopathology confirmation of SFN, limited amounts of patients’ sera, and inclusion limited to patients with length-dependent clinical manifestations.

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

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


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