Interleukin-37 (IL-37) Suppresses Pertussis Toxin-Induced Inflammatory Myopathy in a Rat Model.

BACKGROUND Recent data have demonstrated the potential immunosuppressive roles of interleukin-37 (IL-37) in several diseases, but whether it is involved in the pathogenesis of inflammatory myopathy has not been elucidated. MATERIAL AND METHODS An experimental autoimmune myositis (EAM) model was built by subcutaneous injections of pertussis toxin (PTX) and purified rabbit myosin (10mg/kg) emulsified with an equal volume of conventional complete Freund's adjuvant (CFA) in a Lewis model. Autoimmune myositis Lewis model rats were divided into 3 groups: group A rats (control group) were injected with CFA in saline weekly; group B (IL-37 group) rats were injected with saline with IL-37 and CFA in saline weekly; and group C (IL-37 + SIS3 group) rats were injected with IL-37, CFA, and SIS3. ELISA was also used to assess the expressions of TNF-α, IL-6, IL-1ß, TGF-ß1, and CK. HE staining was performed to assess pathological changes in lung and muscle tissues. RESULTS The expressions of TNF-α, IL-6, IL-1ß, TGF-ß1, and CK significantly increased in autoimmune myositis Lewis model rats. After IL-37 treatment, the expression of TNF-α, IL-6, IL-1ß, TGF-ß1, and CK was significantly reduced, as were the inflammatory responses of lung and muscle. However, SIS3 reduced the effects of IL-37 on the autoimmune myositis Lewis model rats. CONCLUSIONS These findings indicate that IL-37 protects against inflammatory response via regulating Smad3 in autoimmune myositis Lewis model rats.

Catastrophic relapses following initiation of dimethyl fumarate in two patients with neuromyelitis optica spectrum disorder.

We report two cases of neuromyelitis optica spectrum disorder (NMOSD) who were misdiagnosed as multiple sclerosis (MS) and developed catastrophic relapses following initiation of dimethyl fumarate. Both patients developed a severe myelitis extending from the cervical cord to the medulla with significant cord swelling, resulting in complete quadriplegia and respiratory difficulties, in addition to severe bilateral visual loss in one patient. It is of note that both catastrophic relapses occurred 2 and 3 months following initiation of dimethyl fumarate.

Inhibitors of protein arginine deiminases and their efficacy in animal models of multiple sclerosis.

Protein arginine deiminases (PAD) are implicated in a variety of inflammatory and neurodegenerative diseases including multiple sclerosis (MS). Following the discovery of an in silico hit containing hydantoin and a piperidine moiety, we hypothesized that a 2-carbon linker on the hydantoin would be necessary for a 5-membered heterocycle for optimal PAD inhibitory activity. We designed thirteen compounds as potential inhibitors of PAD2 and PAD4 enzymes-two important PAD enzymes implicated in MS. Two compounds, one with an imidazole moiety (22) and the other with a tetrazole moiety (24) showed good inhibition of PAD isozymes in vitro and in the EAE mouse model of MS in vivo. Further experiments suggested that compound 22, a non-covalent inhibitor of PAD2 and PAD4, exhibits dose-dependent efficacy in the EAE mouse model and in the cuprizone-mediated demyelination model.

Clioquinol increases the expression of VGF, a neuropeptide precursor, through induction of c-Fos expression.

Clioquinol was used extensively in the mid-1900s as an amebicide to treat indigestion and diarrhea. It was eventually withdrawn from the market because it was linked to subacute myelo-optic neuropathy (SMON) in Japan. However, the pathogenesis of SMON has not yet been elucidated in detail. As reported previously, we performed a global analysis on human neuroblastoma cells using DNA chips. The global analysis and quantitative PCR demonstrated that the mRNA level of VGF (nonacronymic), the precursor of neuropeptides involved in pain reactions, was significantly increased when SH-SY5Y and IMR-32 neuroblastoma cells were treated with clioquinol. Promoter analyses in SH-SY5Y cells revealed that a region responsive to clioquinol exists between -1381 and -1349 of the human VGF gene, which contains an activator protein (AP)-1 site-like sequence. The introduction of mutations at this site significantly reduced clioquinol-induced transcriptional activation. Clioquinol induced the expression of the AP-1 family transcription factors, c-Jun and c-Fos. Electrophoresis mobility shift assays demonstrated that c-Jun and c-Fos could bind to the AP-1 site at -1374/-1368 in SH-SY5Y cells treated with clioquinol. RNA interference against c-Fos significantly suppressed clioquinol-induced VGF mRNA expression. These results suggest that the clioquinol-induced expression of c-Fos mediates the induction of VGF expression.

[TNF inhibitors and myelitis: think about it, even lately]. / Myélite sous anti-TNFα : y penser, même tardivement.

Anti-TNF medications have been widely used for the treatment of auto-immune disease and new drugs are regularly approved. We report here a case of late myelitis after more than 6 years of adalimumab in a 74-year-old woman treated for rheumatoid polyarthritis.

Anti-inflammatory role of microsomal prostaglandin E synthase-1 in a model of neuroinflammation.

A major immunological response during neuroinflammation is the activation of microglia, which subsequently release proinflammatory mediators such as prostaglandin E(2) (PGE(2)). Besides its proinflammatory properties, cyclooxygenase-2 (COX-2)-derived PGE(2) has been shown to exhibit anti-inflammatory effects on innate immune responses. Here, we investigated the role of microsomal PGE(2) synthase-1 (mPGES-1), which is functionally coupled to COX-2, in immune responses using a model of lipopolysaccharide (LPS)-induced spinal neuroinflammation. Interestingly, we found that activation of E-prostanoid (EP)2 and EP4 receptors, but not EP1, EP3, PGI(2) receptor (IP), thromboxane A(2) receptor (TP), PGD(2) receptor (DP), and PGF(2) receptor (FP), efficiently blocked LPS-induced tumor necrosis factor α (TNFα) synthesis and COX-2 and mPGES-1 induction as well as prostaglandin synthesis in spinal cultures. In vivo, spinal EP2 receptors were up-regulated in microglia in response to intrathecally injected LPS. Accordingly, LPS priming reduced spinal synthesis of TNFα, interleukin 1ß (IL-1ß), and prostaglandins in response to a second intrathecal LPS injection. Importantly, this reduction was only seen in wild-type but not in mPGES-1-deficient mice. Furthermore, intrathecal application of EP2 and EP4 agonists as well as genetic deletion of EP2 significantly reduced spinal TNFα and IL-1ß synthesis in mPGES-1 knock-out mice after LPS priming. These data suggest that initial inflammation prepares the spinal cord for a negative feedback regulation by mPGES-1-derived PGE(2) followed by EP2 activation, which limits the synthesis of inflammatory mediators during chronic inflammation. Thus, our data suggest a role of mPGES-1-derived PGE(2) in resolution of neuroinflammation.

[Myelitis following vaccination against tick-borne encephalitis]. / Puutiaisaivokuumerokotuksen jälkeinen myeliitti.

Tick-borne encephalitis is a significant concern in endemic regions, and in rare cases it may even be fatal. There is no specific treatment for the disease. Vaccines from two manufacturers are available against tick-borne encephalitis, both considered effective and safe. Severe adverse effects due to tick-borne encephalitis vaccine are rare. We describe the first severe myelitis detected in Finland following vaccination against tick-borne encephalitis.

Changes in membrane excitability and potassium currents in sensitized dorsal horn neurons of mice pups.

Rationally, an increased intrinsic excitability of dorsal horn neurons could be a factor contributing to alter the gain of the nociceptive system during central sensitization, however direct evidence is scarce. Here we have examined this hypothesis using current and voltage-clamp recordings from dorsal horn neurons in the spinal cord in vitro preparation obtained from mice pups of either sex. Cords were extracted from carrageenan-pretreated and control animals to allow for comparison. Dorsal horn neurons from treated animals showed significantly larger and faster synaptic responses. Synaptic changes started developing shortly after inflammation (1 h) and developed further after a longer-term inflammation (20 h). However, these neurons showed biphasic changes in membrane excitability with an increase shortly after inflammation and a decrease in the longer term. Concomitant changes were observed in transient (I(A)) and sustained potassium currents (I(DR)). Prolonged superfusion of naive spinal cords with NMDA led to a decreased neuronal excitability and to increased potassium currents. Results suggest that excitability plays a role more complex than expected during the process of central sensitization of dorsal horn neurons and that modulation of potassium currents may contribute to shape the changing states of excitability. The decreased excitability observed after long-term inflammation is interpreted as a homeostatic correction to an abnormal state of synaptic activity.

Isolated myelitis in a patient with Behcet's disease during golimumab therapy.

Tumor necrosis factor-alpha (TNF-α) inhibitors are increasingly used for various autoimmune diseases. Demyelinating events in the CNS, including myelitis, are reportedly associated with TNF-α inhibitor exposure. Behcet's disease rarely involves the spinal cord. A 51-year-old Japanese woman presented with back pain, leg weakness, and numbness during golimumab administration, a TNF-α inhibitor, for Behcet's disease. Magnetic resonance imaging revealed multifocal myelitis in the cervical and thoracic spinal cords. Discontinuation of golimumab and steroid therapy were effective and the symptoms have not relapsed. Although it is possible that the patient's myelitis was part of the symptoms of neuro-Behcet's disease, we believe that golimumab likely played a role in the myelitis development.

Acute myelitis and ChAdOx1 nCoV-19 vaccine: Casual or causal association?

A 44-year-old previously healthy woman developed acute myelitis in close temporal relationship with ChAdOx1 nCoV-19 vaccine first-dose administration. The neurological involvement was mainly sensory with neuroimaging showing two mono-metameric lesions involving the posterior and lateral cord at dorsal level. Significant improvement was promptly recorded with high-dose intravenous steroids, with complete recovery within one month. The strict temporal relationship between vaccination and myelitis, together with the absence of clues pointing to alternative diagnoses, might suggest a conceivable role for anti-SARS-CoV-2 vaccine as immunological trigger, although a causal relationship has yet to be established and our preliminary observation suggests caution.

[Fifity years after the identification of the cause of SMON].

SMON (subacute myelo-optico-neuropathy) is toxic neurological disease which had a profound impact on the population in Japan in 1960's. The clinical characteristics of SMON includes an ascending sensory disturbance, spasticity, and visual impairment typically following abdominal symptoms. Infection was first suspected as an underlying cause of this epidemic. The disorder was ultimately attributed to the overuse of clioquinol, based on the analysis of green urine from affected patients and confirmed by the epidemiological surveys and experimental animal studies. The factors that contributed to the prevalence of SMON which remains the worst example of drug-associated toxicity in Japan to date include the conversion of clioquinol from a purely topical agent to an orally-administered drug, dogma associated with drug safety, relatively limited regulation of drug use, an increase in the number of prescriptions due to the availability of universal insurance, as well as the complexity of the associated abdominal symptoms. Periodical examination of the patients diagnosed with SMON continues to this day. As such, it is important to have a better understanding of clioquinol-induced neurotoxicity together with the mechanisms underlying drug susceptibility; we should not permit the memory of this severe and prominent drug-associated toxicity fade from view.

Ixekizumab exposure associated with myelitis: A case report and a literature review.

We describe a case of a 28-year-old man who developed a cervical myelitis while exposed to ixekizumab (IL-17 inhibitor) for psoriatic arthritis. Spinal MRI showed a T2 hyperintense lesion at the C4-C5 level while brain MRI was unspecific. Oligoclonal bands were absent and extensive screening for autoimmunity was negative. Rechallenge with ixekizumab was positive corroborating a relation between drug exposure and the neurological event. To the best of our knowledge, this is the first case of CNS inflammatory adverse event associated with ixekizumab. We also provide a review of case reports of demyelinating disorders associated with the use of biologic drugs for the treatment of psoriasis and psoriatic arthritis.

[Spinal anesthesia in a patient with SMON disease].

We report a patient with subacute myelo-optico-neuropathy (SMON) in whom spinal anesthesia was employed to treat fracture of the femur neck. An 87-year-old woman was diagnosed as having SMON at the age of 45. The patient was admitted to our hospital with fracture of the femur neck. Aspiration pneumonia was also suspected with shadow in the right lung on the chest X-P The percutaneous oxygen saturation (Spo2) with room air was 77%. Spinal anesthesia with 5 mg of 0.5% hyperbaric bupivacaine and 20 mcg of fentanyl was performed at L3-4. The level of anesthesia was T4. During surgery, no severe pain in the lower limbs was observed. Three hours after the end of surgery, the level of anesthesia was T9. On the day after surgery, the extent of dysesthesia and reflex were similar to those before surgery. General anesthesia has been chosen in SMON patients, because there was a report of severe pain of the lower limbs after spinal anesthesia with dibucaine. In our patient, general anesthesia was considered inappropriate due to hypoxemia. We used a mixture of bupivacaine and fentanyl for spinal anesthesia, because the neurotoxicity of bupivacaine is weaker than that of dibucaine.

[Evaluation of neurological symptoms related to hip fracture in a 29-year longitudinal study of subacute myelo-optic-neuropathy (SMON)].

AIM: Hip fracture in elderly people is a major risk factor in the deterioration of activities of daily living (ADL). The aim of this study was to investigate the incidence of hip fractures and the neurological symptoms contributing to hip fracture in patients with subacute myelo-optic-neuropathy (SMON), a drug-induced neurological disease manifesting various symptoms. METHODS: We investigated the incidence of hip fracture in 3,269 SMON patients with 24,187 medical check-ups from 1979 through 2007 by the SMON Research Committee in Japan. Neurological symptoms were evaluated in 80 patients who had undergone clinical examinations within 2 years before the fracture (hip-fracture group: age at examination = 75.7 ± 8.8 years (mean ± SD)), and the control group (160 SMON patients without a history of hip fracture; 76.5 ± 10.4) were matched for age, gender, and duration of illness. Incidence of hip fracture in SMON as well as severity of visual acuity, motor and sensory symptoms, and ADL were investigated. RESULTS: A total 230 hip fractures occurred in 208 patients (6.4%) with a men-to-women ratio of 21 : 187. In comparison with the Japanese general population, SMON patients showed a statistically high incidence of hip fracture in the 50s and 60s age groups in women (p < 0.002 in both), and in those under 40 (p < 0.02) and in their 50s (p < 0.002) in men. In those with neurological symptoms related to gait, the percentage of subjects who could walk with crutches was significantly higher in the hip-fracture group (43.8%) than in the control group (28.1%) (p < 0.05). Analysis of the vibratory sensation revealed that the hip-fracture group showed a significantly higher percentage of severe impairment (51.9%) than the control group (32.0%) (p < 0.025). There were no significant differences in variance between the two groups in other clinical symptoms or ADL. CONCLUSIONS: Impairment of vibration sense, a deep sensation, is more likely to be associated with falling and hip fracture than visual acuity or other neurological symptoms in SMON patients. Those persons with vibration sense disturbance, such as elderly or patients with neurological diseases, should be particularly cautious of falling.

Elevated beta1,4-galactosyltransferase-I induced by the intraspinal injection of lipopolysaccharide.

Beta1,4-galactosyltransferase-I (beta1,4-GalT-I) is one of the best studied glycosyltransferases. Previous studies demonstrated that beta1,4-GalT-I was a major galactosyltransferase responsible for selectin-ligand biosynthesis and that inflammatory responses of beta1,4-GalT-I deficient mice were impaired. In this study, we investigate the expression of beta1,4-GalT-I in lipopolysaccharide (LPS)-induced neuroinflammatory processes. The results of this study demonstrated that beta1,4-GalT-I was strongly induced by intraspinal administration of LPS. More than 90% galactose-containing glycans and beta1,4-GalT-I were expressed in immune cells. The ELISA assay shows focal injection LPS also induces TNF-alpha alteration. Double staining indicated beta1,4-GalT-I overlapped with TNF-alpha. Moreover, RT-PCR for beta1,4-GalT-I mRNA showed that beta1,4-GalT-I mRNA in microglia in vitro was affected in a dose- and time dependent manner in response to LPS or TNF-alpha stimulation. All these results indicated that the increase of beta1,4-GalT-I might attribute to the effect of TNF-alpha excreting during inflammation. E-selectin, which ligand was modified by beta1,4-GalT-I, was correlated with galactose-containing glycans following injecting LPS into spinal cord. We therefore suggest that beta1,4-GalT-I may play an important role in regulating immune cell migration into the inflammatory site.

Increased vulnerability of the spinal cord to radiation or intrathecal chemotherapy during adolescence: A report from the Children's Oncology Group.

PURPOSE: To assess the rate of spinal cord toxicity in adolescents resulting from chemoradiotherapy of parameningeal sarcoma. METHODS AND MATERIALS: Of 152 patients with parameningeal sarcoma treated per the Intergroup Rhabdomyosarcoma Study Group protocol from 1977 through 1989, eight developed paralyzing ascending myelitis after intrathecal chemotherapy with cytosine arabinoside, methotrexate, and hydrocortisone administered during and after radiation therapy to volumes that included part of the spinal cord. The eight cases include three not previously published. RESULTS: Of eight patients who developed CNS toxicity after intrathecal chemotherapy and radiotherapy for parameningeal rhabdomyosarcoma, all but one were between 13 and 18 years of age when treated. This severe toxicity occurred in one quarter of 28 adolescents treated with the regimen in comparison with one of 123 children 12 years of age or less (P < 0.0001), a rate that was as much as 30 times higher in the adolescents. Lengthening of the spinal cord during the pubertal growth spurt may account for the apparent increased vulnerability. CONCLUSIONS: Chemoradiotoxicity-associated spinal cord injury appears to be more likely to occur in adolescents than in younger or older ages. This observation appears to reverse a conventional wisdom in which the central nervous system is thought to become more resistant to the neurotoxic effects of chemoradiotherapy as it matures.