Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease, mediated by pathogenic T helper 17 (Th17) cells. However, the therapeutic effect is accompanied by the fluctuation of the proportion and function of Th17 cells, which prompted us to find the key regulator of Th17 differentiation in MS. Here, we demonstrated that the triggering receptor expressed on myeloid cells 2 (TREM-2), a modulator of pattern recognition receptors on innate immune cells, was highly expressed on pathogenic CD4-positive T lymphocyte (CD4⁺ T) cells in both patients with MS and experimental autoimmune encephalomyelitis (EAE) mouse models. Conditional knockout of Trem-2 in CD4⁺ T cells significantly alleviated the disease activity and reduced Th17 cell infiltration, activation, differentiation, and inflammatory cytokine production and secretion in EAE mice. Furthermore, with Trem-2 knockout in vivo experiments and in vitro inhibitor assays, the TREM-2/zeta-chain associated protein kinase 70 (ZAP70)/signal transducer and activator of transcription 3 (STAT3) signal axis was essential for Th17 activation and differentiation in EAE progression. In conclusion, TREM-2 is a key regulator of pathogenic Th17 in EAE mice, and this sheds new light on the potential of this therapeutic target for MS.
Animals ; Humans ; Mice ; CD4-Positive T-Lymphocytes/pathology* ; Cell Differentiation ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Mice, Inbred C57BL ; Multiple Sclerosis ; Th1 Cells/pathology*

Humans ; PPAR gamma/metabolism* ; Multiple Sclerosis ; Transcription Factors/metabolism* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

INTRODUCTION

Demyelinating central nervous system (CNS) disorders such as transverse myelitis (TM) and multiple sclerosis (MS) have been reported with mRNA Covid-19 vaccine. Some cases were relapses of a pre-existing condition but de novo and initial presentation of MS after BNT162b2 COVID-19 mRNA vaccine has very rarely been documented.

We report a 72-year-old female, right-handed, Filipina, with a one-month history of bilateral lower extremity weakness which occurred 7 days after she received her first booster dose of BNT162b2 mRNA vaccine. This was later accompanied by fecal and urinary incontinence. On examination, she had motor deficit below L1 myotome manifesting with loss of hip flexion, knee extension, dorsiflexion, and plantar flexion. There was also sensory deficit below T10 level with relative 80% sensation of vibratio, proprioception, light touch and complete loss of pain and temperature sensation. The initial impression was Transverse Myelitis which may be related to a post-vaccination state. Spinal magnetic resonance imaging (MRI) revealed long segment enhancing T2W hyperintense lesion at T2 to T7. Cranial MRI revealed ovoid areas of heterogeneous, predominantly T2/FLAIR hyperintense signals exhibiting restricted diffusion in the periventricular white matter of the fronto-parietal lobes. Cerebrospinal fluid (CSF) analysis was negative for infectious causes such as tuberculosis but with high levels of CSF immunoglobulin G. She was then diagnosed to have Multiple Sclerosis (MS) and was treated with high dose oral prednisone. However, there was no improvement in neurological deficits on follow-up.

This case adds to the reported rare cases of initial presentation of MS occurring after vaccination for COVID-19 and the first reported case in the Philippines. Early recognition and prompt treatment is important to improve outcomes.

Multiple sclerosis(MS) shows the pathological characteristics of "inflammatory injury of white matter" and "myelin repair disability" in the central nervous system(CNS). It is very essential for MS treatment and reduction of disease burden to strengthen repair, improve function, and reduce disability. Accordingly, different from the simple immunosuppression, we believe that key to strengthening remyelination and maintaining the "damage-repair" homeostasis of tissue is to change the current one-way immunosuppression strategy and achieve the "moderate pro-inflammation-effective inflammation removal" homeostasis. Traditional Chinese medicine shows huge potential in this strategy. Through literature research, this study summarized the research on remyelination, discussed the "mode-rate pro-inflammation-effective inflammation removal" homeostasis and the "damage-repair" homeostasis based on microglia, and summed up the key links in remyelination in MS. This review is expected to lay a theoretical basis for improving the function of MS patients and guide the application of traditional Chinese medicine.
Humans ; Multiple Sclerosis/pathology* ; Remyelination/physiology* ; Myelin Sheath/pathology* ; Inflammation/drug therapy* ; Homeostasis

The primary chemical components of Astragalus membranaceus include polysaccharides, saponins, flavonoids, and amino acids. Recent studies have shown that Astragalus membranaceus has multiple functions, including improving immune function and exerting antioxidative, anti-radiation, anti-tumor, antibacterial, antiviral, and hormone-like effects. Astragalus membranaceus and its extracts are widely used in clinical practice because they have obvious therapeutic effects against various autoimmune diseases and relatively less adverse reaction. Multiple sclerosis (MS) is an autoimmune disease of central nervous system (CNS), which mainly caused by immune disorder that leads to inflammatory demyelination, inflammatory cell infiltration, and axonal degeneration in the CNS. In this review, the authors analyzed the clinical manifestations of MS and experimental autoimmune encephalomyelitis (EAE) and focused on the efficacy of Astragalus membranaceus and its chemical components in the treatment of MS/EAE.
Animals ; Humans ; Astragalus propinquus/chemistry* ; Multiple Sclerosis/drug therapy* ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Drugs, Chinese Herbal/chemistry* ; Polysaccharides

Multiple sclerosis (MS) is regarded as a chronic inflammatory disease that leads to demyelination and eventually to neurodegeneration. Activation of innate immune cells and other inflammatory cells in the brain and spinal cord of people with MS has been well described. However, with the innovation of technology in glial cell research, we have a deep understanding of the mechanisms of glial cells connecting inflammation and neurodegeneration in MS. In this review, we focus on the role of glial cells, including microglia, astrocytes, and oligodendrocytes, in the pathogenesis of MS. We mainly focus on the connection between glial cells and immune cells in the process of axonal damage and demyelinating neuron loss.
Humans ; Multiple Sclerosis ; Neuroglia ; Inflammation/pathology* ; Brain/pathology* ; Spinal Cord/pathology*

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a pathologically similar disease used to model MS in rodents, are typical CD4+ T cell-dominated autoimmune diseases. CD4+ interleukin (IL)17+ T cells (Th17 cells) have been well studied and have shown that they play a critical role in the pathogenesis of MS/EAE. However, studies have suggested that CD8+IL17+ T cells (Tc17 cells) have a similar phenotype and cytokine and transcription factor profiles to those of Th17 cells and have been found to be crucial in the pathogenesis of autoimmune diseases, including MS/EAE, psoriasis, type I diabetes, rheumatoid arthritis, and systemic lupus erythematosus. However, the evidence for this is indirect and insufficient. Therefore, we searched for related publications and attempted to summarize the current knowledge on the role of Tc17 cells in the pathogenesis of MS/EAE, as well as in the pathogenesis of other autoimmune diseases, and to find out whether Tc17 cells or Th17 cells play a more critical role in autoimmune disease, especially in MS and EAE pathogenesis, or whether the interaction between these two cell types plays a critical role in the development of the disease.
Animals ; Mice ; Encephalomyelitis, Autoimmune, Experimental ; Th17 Cells ; CD8-Positive T-Lymphocytes/metabolism* ; CD4-Positive T-Lymphocytes/metabolism* ; Multiple Sclerosis/metabolism* ; Mice, Inbred C57BL

Xiaoxuming Decoction is an ancient classic herbal formula for the treatment of stroke. In ancient times, the connotation of stroke was very extensive, including facial neuritis, acute cerebral infarction, acute cerebral hemorrhage, sequelae of cerebral hemorrhage, unexplained weakness of limbs, cervical spondylosis, acute myelitis, acute radiculitis, Guillain Barre syndrome, multiple sclerosis, myasthenia gravis, motor neuron disease, dermatomyositis, hypokalemic paralysis peripheral neuritis. It has been identified that: ①Xiaoxuming Decoction is very common in the treatment of cerebrovascular diseases, such as cerebral infarction, cerebral hemorrhage and other cerebrovascular diseases, facial neuritis, acute myelitis, acute radiculitis, Guillain Barre syndrome, unexplained limb weakness, multiple sclerosis, motor neuron disease, myasthenia gravis, and rheumatic and immune system diseases, such as dermatomyositis, and can not only alleviate symptoms, but also improve prognosis and the long-term survival rate. ②Sudden limb failure, facial paralysis, and hypoalgesia without heat syndrome are the key indications of Xiaoxuming Decoction. ③This is a special prescription for the treatment of acute facial neuritis, and can cure in one week in the combination with moxibustion. ④In the treatment of facial neuritis complicated with hypertension or acute cerebrovascular disease, Xiaoxuming Decoction generally has a certain antihypertensive effect, without any hypertensive effect, which reflected its two-way regulatory effect for blood pressure. ⑤In the treatment of unknown limb weakness, acute myelitis, acute radiculitis, Guillain Barre syndrome, Xiaoxuming Decoction can rapidly alleviate the symptoms. ⑥This is the basic formula for multiple sclerosis and motor neuron disease. Long term use of Xiaoxuming Decoction can alleviate the symptom of limb weakness, reduce the occurrence of complications and delay the progress of the disease, but with a poor long-term prognosis. ⑦In the treatment of myasthenia gravis, Xiaoxuming Decoction can significantly improve muscle strength, and gradually help stop hormone reduction. After thymoma surgery, Xiaoxuming Decoction is also applicable to some patients with recurrent myasthenia gravis. ⑧Xiaoxuming Decoction also plays a role in the treatment of dermatomyositis and cervical spondylopathy. ⑨Raw ephedra is the monarch drug of Xiaoxuming Decoction, which is the key to the effect. The dosage starts with 6 g is titrated in a small dose and increases gradually. In addition, this formula is forbidden for those with red face, fast heart rate, high blood pressure, blocked stool, red tongue, yellow fur, wiry and rapid pulse or powerful pulse, and spout pulse.
Dermatomyositis ; Facial Nerve Diseases ; Guillain-Barre Syndrome ; Humans ; Motor Neuron Disease ; Multiple Sclerosis ; Myasthenia Gravis ; Myelitis ; Radiculopathy ; Spondylosis

PURPOSE: To quantify the relative importance of brain regions responsible for reduced functional connectivity (FC) in their Voiding Initiation Network in female multiple sclerosis (MS) patients with neurogenic lower urinary tract dysfunction (NLUTD) and voiding dysfunction (VD). A data-driven machine-learning approach is utilized for quantification. METHODS: Twenty-seven ambulatory female patients with MS and NLUTD (group 1: voiders, n=15 and group 2: VD, n=12) participated in a functional magnetic resonance imaging (fMRI) voiding study. Brain activity was recorded by fMRI with simultaneous urodynamic testing. The Voiding Initiation Network was identified from averaged fMRI activation maps. Four machine-learning algorithms were employed to optimize the area under curve (AUC) of the receiver-operating characteristic curve. The optimal model was used to identify the relative importance of relevant brain regions. RESULTS: The Voiding Initiation Network exhibited stronger FC for voiders in frontal regions and stronger disassociation in cerebellar regions. Highest AUC values were obtained with ‘random forests’ (0.86) and ‘partial least squares’ algorithms (0.89). While brain regions with highest relative importance (>75%) included superior, middle, inferior frontal and cingulate regions, relative importance was larger than 60% for 186 of the 227 brain regions of the Voiding Initiation Network, indicating a global effect. CONCLUSIONS: Voiders and VD patients showed distinctly different FC in their Voiding Initiation Network. Machine-learning is able to identify brain centers contributing to these observed differences. Knowledge of these centers and their connectivity may allow phenotyping patients to centrally focused treatments such as cortical modulation.
Area Under Curve ; Brain ; Female ; Gyrus Cinguli ; Humans ; Machine Learning ; Magnetic Resonance Imaging ; Multiple Sclerosis ; Urinary Tract ; Urodynamics

BACKGROUND AND PURPOSE: Alemtuzumab has shown high efficacy in clinical trials that primarily involved Western multiple sclerosis (MS) patients. To evaluate the therapeutic outcome of alemtuzumab in Korean patients with MS. METHODS: This study enrolled 23 consecutive patients who were treated with alemtuzumab from 2015 to 2018. Efficacy was evaluated using the annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS), and radiological activity. No evidence of disease activity (NEDA) was defined as no clinical relapse, no worsening of the EDSS score, and no radiological activity. The safety profiles were also assessed. RESULTS: The mean age was 36 years and 16 of the patients were female. Seventeen and 12 of 23 patients were followed up for 1 year and 2 years, respectively. The ARR was markedly reduced from 1.52 during the 1-year period preceding alemtuzumab administration to 0.21 after initiating alemtuzumab (p<0.001). During the first and second years after initiating alemtuzumab, EDSS worsening was observed in 3 (18%) and 0 (0%) patients, respectively, and radiological activity was exhibited in 9 (53%) and 4 (33%). NEDA was observed in 6 (35%) patients during the first year and in 8 (67%) patients during the second year. Intriguingly, one patient experienced 2 severe clinical exacerbations, which occurred at 10 months after the first and 10 months after the second infusion of alemtuzumab. Nineteen of the 23 patients exhibited infusion-associated reactions and 3 patients exhibited herpes zoster infection. Thyroid dysfunction occurred in two patients at 18 and 20 months after initiating alemtuzumab. CONCLUSIONS: Consistent with observations in Western populations, alemtuzumab therapy in Korean MS patients led to marked reductions of disease activity without unexpected safety issues.
Female ; Follow-Up Studies ; Herpes Zoster ; Humans ; Multiple Sclerosis ; Recurrence ; Thyroid Gland