アトピー性脊髄炎

OBJECTIVE: To elucidate the features of plexin D1-immunoglobulin (Ig)G-associated neuropathic pain and its relationship to atopic myelitis (AM) in a nationwide Japanese survey. METHODS: A preliminary survey questionnaire was sent to 1574 selected departments (neurology and pediatrics/pediatric neurology) to explore the numbers of AM and plexin D1-IgG-positive patients between 2018 and 2022. A secondary survey collected detailed patient data via a questionnaire. RESULTS: In the preliminary survey, 987 (62.7%) institutions responded, reporting 87 AM patients (49 women) and 11 plexin D1-IgG-positive non-AM patients (8 women). The secondary survey collected 71 AM (plexin D1-IgG-positive: 6/31) and 11 plexin D1-IgG-positive non-AM patients (83.7% recovery rate). In AM, paresthesia/dysesthesia was most frequently experienced (> 90%), followed by pain (> 70%). The underlying diseases in 17 plexin D1-IgG-positive patients, all of whom had neuropathic pain, were AM and small fiber neuropathy in 6 each, neuromyelitis optica spectrum disorder with aquaporin-4-IgG in 2, and painful trigeminal neuropathy, erythromelalgia, and multiple sclerosis in 1 each. When 14 plexin D1-IgG-positive patients (excluding 3 patients with established demyelinating diseases) were compared with 25 plexin D1-IgG-negative AM patients, onset ≥ 50 years old, pain at onset, and allodynia/erythromelalgia/facial pain during the entire disease course were significantly more common in the plexin D1-IgG-positive group. Conversely, atopic disorders and hyperIgEemia were associated with plexin D1-IgG-negative AM but not plexin D1-IgG-positive patients. INTERPRETATION: Both AM and plexin D1-IgG-positive patients present long-standing neuropathic pain, whereas plexin D1-IgG is particularly associated with aged-onset neuropathic pain, allodynia, erythromelalgia, and facial pain, but not atopy.

BACKGROUND: The aim of this study was to evaluate the long-term outcome of our series of narcolepsy type 1 (NT1) patients with comorbid autoimmune diseases (ADs) and other immunopathological diseases (IDs), focusing on the incidence of new ADs and IDs in this sample. METHODS: A longitudinal observational study was conducted over 6 years (2014 - 2020) in a series of 158 Caucasians NT1 patients (96 males; mean age: 50.1 ± 19.0 years) from the previous study. All but one case (familial case) were HLA-DQB1*06:02-positive. The diagnosis of narcolepsy was made according to the International Classification of Sleep Disorders (ICSD-3). RESULTS: Twenty-one patients have been diagnosed with a new ID, 10 of them with an AD (autoimmune thyroid disease, psoriasis, rheumatoid arthritis, transverse myelitis, granuloma annulare, primary biliary cirrhosis, alopecia areata and antiphospholipid syndrome), and 11 with other IDs (allergic rhinitis, allergic asthma, atopic dermatitis, food allergy, contact dermatitis and drug allergy). One patient was diagnosed with two new ADs. We found IDs in 46 patients (24 females and 22 males) and the overall prevalence in this series is actually 29.11%; 22 of them (13.92%) had an AD, with a percentage higher than estimated in the general population. CONCLUSIONS: The prevalence of AD/ID is high in our series, suggesting that NT1 might arise on a background of generalized susceptibility to immune-mediated processes. The occurrence of an ID can in turn influence the development of others in genetically predisposed individuals, which explains the increased associations observed in this long-term study.

Allergic diseases are associated with central and peripheral nervous system diseases such as autism spectrum disorders and eosinophilic granulomatosis with polyangiitis, which frequently causes mononeuritis multiplex. Thus, it is possible that patients with an atopic constitution might develop multifocal inflammation in central and peripheral nervous system tissues. In a previous study in Japan, we reported a rare form of myelitis with persistent neuropathic pain (NeP) in patients with allergic disorders. However, the underlying mechanism of allergic inflammation-related NeP remains to be elucidated. First, we analyzed the effect of allergic inflammation on the nociceptive system in the spinal cord. Mice with atopy showed microglial and astroglial activation in the spinal cord and tactile allodynia. In a microarray analysis of isolated microglia from the spinal cord, endothelin receptor type B (EDNRB) was the most upregulated cell surface receptor in mice with atopy. Immunohistochemical analysis demonstrated EDNRB expression was upregulated in microglia and astroglia. The EDNRB antagonist BQ788 abolished glial activation and allodynia. These findings indicated that allergic inflammation induced widespread glial activation through the EDNRB pathway and NeP. Second, we investigated whether autoantibody-mediated pathogenesis underlies allergic inflammation-related NeP. We detected specific autoantibodies to small dorsal root ganglion (DRG) neurons and their nerve terminals in the dorsal horns of NeP patients with allergic disorders. An analysis of IgG subclasses revealed a predominance of IgG2. These autoantibodies were mostly colocalized with isolectin B4- and P2X3-positive unmyelinated C-fiber type small DRG neurons. By contrast, immunostaining for S100β, a myelinated DRG neuron marker, showed no colocalization with patient IgG. Immunoprecipitation and liquid chromatography-tandem mass spectrometry identified plexin D1 as a target autoantigen. Patients with anti-plexin D1 antibodies often present with burning pain and thermal hyperalgesia. Immunotherapies, including plasma exchange, are effective for NeP management. Therefore, anti-plexin D1 antibodies may be pathogenic for immune-mediated NeP, especially under allergic inflammation conditions. Thus, allergic inflammation may induce NeP through glial inflammation in the spinal cord and the anti-plexin D1 antibody-mediated impairment of small DRG neurons.