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Multiple sclerosis (MS), an autoimmune disease of the central nervous system, generally starts as the relapsing remitting form (RRMS), but often shifts into secondary progressive MS (SPMS). SPMS represents a more advanced stage of MS, characterized by accumulating disabilities and refractoriness to medications. The aim of this study was to clarify the microbial and functional differences in gut microbiomes of the different stages of MS. Here, we compared gut microbiomes of patients with RRMS, SPMS, and two closely related disorders with healthy controls (HCs) by 16S rRNA gene and whole metagenomic sequencing data from fecal samples and by fecal metabolites. Each patient group had a number of species having significant changes in abundance in comparison with HCs, including short-chain fatty acid (SCFA)-producing bacteria reduced in MS. Changes in some species had close association with clinical severity of the patients. A marked reduction in butyrate and propionate biosynthesis and corresponding metabolic changes were confirmed in RRMS compared with HCs. Although bacterial composition analysis showed limited differences between the patient groups, metagenomic functional data disclosed an increase in microbial genes involved in DNA mismatch repair in SPMS as compared to RRMS. Together with an increased ratio of cysteine persulfide to cysteine in SPMS revealed by sulfur metabolomics, we postulate that excessive DNA oxidation could take place in the gut of SPMS. Thus, gut ecological and functional microenvironments were significantly altered in the different stages of MS. In particular, reduced SCFA biosynthesis in RRMS and elevated oxidative level in SPMS were characteristic.

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. Foxp3 + regulatory T (Treg) cells are reduced in frequency and dysfunctional in patients with MS, but the underlying mechanisms of this deficiency are unclear. Here, we show that induction of human IFN-γ − IL-17A − Foxp3 + CD4 + T cells is inhibited in the presence of circulating exosomes from patients with MS. The exosomal miRNA profile of patients with MS differs from that of healthy controls, and let-7i , which is markedly increased in patients with MS, suppresses induction of Treg cells by targeting insulin like growth factor 1 receptor ( IGF1R ) and transforming growth factor beta receptor 1 ( TGFBR1 ). Consistently, the expression of IGF1R and TGFBR1 on circulating naive CD4 + T cells is reduced in patients with MS. Thus, our study shows that exosomal let-7i regulates MS pathogenesis by blocking the IGF1R/TGFBR1 pathway. MiRNAs are small RNA molecules that can regulate gene expression. Here the authors show that expression of several exosomal miRNAs are altered in patients with multiple sclerosis, and that let-7i modulates regulatory T cell homeostasis to contribute to pathogenesis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, in which myelin and oligodendrocytes are the main targets recognized by inflammatory CD4+ T cells reactive to myelin peptides. Regulatory CD4+ T (Treg) cells normally keep homeostasis of the immune system by inhibiting detrimental effects of inflammatory T cells. However, Treg cells are reduced in patients with MS for unknown reason. This commentary highlights a novel function of circulating exosomes to inhibit the differentiation of Treg cells in MS. Our recent work has demonstrated that the circulating exosomes, a member of extracellular vesicles, of patients with MS exert this effect by transferring let-7i to naive CD4+ T cells. The transferred let-7i subsequently causes a decreased expression of insulin like growth factor 1 receptor (IGF1R) and transforming growth factor β receptor 1 (TGFBR1), leading to the inhibition of Treg cell differentiation. Thus, extrinsic microRNAs transferred by exosomes might have an active role in triggering autoimmune diseases. We hypothesize that extracellular vesicles including exosomes can be a communication tool between the gut microbiota and the host immune system. Further research in this area will expand the knowledge about the precise mechanism of autoimmune diseases and can lead to a new therapeutic approach.

[...]PE was not suspected at first after the seizure in 8 cases (73%). [...]there were 2 cases with a seizure as an early symptom among 285 cases of PE. Cases Case in this report Wang et al [3] Shah and Darwent [4] Meyer [5] Kupnik and Grmec [6] Marine and Goldhaber [7] (case no. 1) Marine and Goldhaber [7] (case no. 2) Fred and Yang [8] Fred et al [2] Hamilton and Thompson [9] (case no. 1) Hamilton and Thompson [9] (case no. 2) Age (y)/sex 87/F 51/F 20/F 50/M 69/M 33/M 34/F 37/M 61/M 67/M 60/F Initial symptom Chest discomfort Syncope Dyspnea Syncope Confusion Seizure Dyspnea Syncope Faint Confusion Seizure Type of the seizure (no. of seizures) Generalized tonic (4), with a focal sign Generalized tonic (2), with a focal sign Bilateral shaking (2) GTCS (1), with a focal sign GTCS (1) GTCS (1) Generalized tonic (5) Tonic-clonic in both upper extremities (1) Violent expiration with the head and the eyes moving to the left (1) Generalized convulsion (several times) Generalized convulsion (2), with a focal sign Symptoms leading to the suspicion of PE Sustained hypoxia Hypoxia, hypotension Exacerbation of dyspnea Seizure, syncope, tachycardia, hypoxia Seizure, confusion, tachypnea, tachycardia Exacerbation of confusion, hypoxia, hypotension Hypotension CPA Not suspected Not suspected Not suspected Seizures before the symptoms leading to the suspicion of PE + + + ? ? + + ? + + + d-Dimer (?g/mL) >10 1.0 NA Positive 3.5 NA NA NA NA NA NA DVT + ? NA NA NA + + ? + + + Risk factors for PE Prolonged immobility - Protein S deficiency - - Recent surgerya Oral contraception, family history - - - - Confirmation of PE CTA CTA UCG V-P scan NA Conventional angiogram Conventional angiogram Autopsy Autopsy Autopsy Autopsy Neurologic studies of the brain (abnormal findings) MRI, EEG (intermittent diffuse slow activity) CT, MRI, EEG NA CT, MRI NA CT, MRI, EEG CT, lumbar puncture NA Autopsy (hypoxic change) Lumbar puncture, autopsy (old cerebellar infarction) Lumbar puncture, autopsy Treatment of PE Heparin Urokinase, LMWH LMWH Heparin NA tPA, heparin Mechanical fragmentation, urokinase, heparin tPA None None None Outcome Full recovery Full recovery Death Death NA Full recovery Full recovery Death Death Death Death Table Summary of PE-related seizures: current one patient and those reported in the literature CPA, cardiopulmonary arrest; CTA, computed tomography angiogram; F, female; GTCS, generalized tonic-clonic seizure; LMWH, low-molecular-weight heparin; M, male; NA, not available; tPA, tissue plasminogen activator; UCG, ultrasonic cardiogram; V-P scan, ventilation-perfusion scan.

The balance between T helper type 1 (T H 1) cells and other T H cells is critical for antiviral and anti-tumour responses 1 – 3 , but how this balance is achieved remains poorly understood. Here we dissected the dynamic regulation of T H 1 cell differentiation during in vitro polarization, and during in vivo differentiation after acute viral infection. We identified regulators modulating T helper cell differentiation using a unique T H 1–T H 2 cell dichotomous culture system and systematically validated their regulatory functions through multiple in vitro and in vivo CRISPR screens. We found that RAMP3, a component of the receptor for the neuropeptide CGRP (calcitonin gene-related peptide), has a cell-intrinsic role in T H 1 cell fate determination. Extracellular CGRP signalling through the receptor RAMP3–CALCRL restricted the differentiation of T H 2 cells, but promoted T H 1 cell differentiation through the activation of downstream cAMP response element-binding protein (CREB) and activating transcription factor 3 (ATF3). ATF3 promoted T H 1 cell differentiation by inducing the expression of Stat1 , a key regulator of T H 1 cell differentiation. After viral infection, an interaction between CGRP produced by neurons and RAMP3 expressed on T cells enhanced the anti-viral IFNγ-producing T H 1 and CD8 + T cell response, and timely control of acute viral infection. Our research identifies a neuroimmune circuit in which neurons participate in T cell fate determination by producing the neuropeptide CGRP during acute viral infection, which acts on RAMP3-expressing T cells to induce an effective anti-viral T H 1 cell response. RAMP3, a component of the receptor for the neuropeptide CGRP, has a cell-intrinsic role in T helper type 1 cell fate determination.

Myasthenia gravis (MG) is occasionally associated with autoimmune diseases in the central nervous system (CNS), such as neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), Morvan syndrome, and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Here, we report five original cases associated with autoimmune disorders in the CNS among 42 patients with MG in a single tertiary hospital in Japan (11.9%). In four of these five cases, the second disease developed when the preceding disease was unstable. Accurate diagnosis of the newly developing disease may be difficult in such cases, because some neurological symptoms can be seen in both disorders. This implies the great importance of recognizing the possible co-occurrence of MG and disorders in the CNS. In addition, a comprehensive review of the literature revealed distinct clinical characteristics depending on the associated disease in the CNS, including thymic pathology and temporal relationship between MG and associated CNS disorders. Notably, NMOSD usually develops after the onset of MG and thymectomy, in clear contrast to MS. Thymoma is highly prevalent among patients with Morvan syndrome, in contract to cases with NMOSD and MS. The analysis of clinical characteristics, representing the first such investigation to the best of our knowledge, suggests different pathogeneses of these autoimmune diseases in the CNS, and provides significant implications for clinical practice.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Its early phase is characterized by a relapse-remitting disease course, followed by disability progression in the later stage. While chronic inflammation accompanied with degeneration is well-established as the key pathological feature, the pathogenesis of MS, particularly progressive MS, remains elusive. Sulfatide is a major glycolipid component of myelin, and previous studies in experimental autoimmune encephalomyelitis mouse models have demonstrated it to have immune-protective functions. Notably, sulfatide concentration is increased in the serum and cerebrospinal fluid of patients with MS, particularly those in a progressive disease course. Here, we show that the myelin-glycolipid sulfatide displays an ability to suppress the proliferation of polyclonally activated human T cells. Importantly, this suppressive effect was impaired in T cells obtained from MS patients having higher disability status. Therefore, it is plausible that progression of MS is associated with an escape from the immune-regulatory effect of sulfatide. Our study suggests that, although the precise mechanisms remain unrevealed, an escape of T cells from immunosuppression by sulfatide is associated with disease progression in the advanced stage. Further studies will provide novel insights into the pathogenesis of MS, particularly regarding disease progression, and help develop novel treatment strategies for this challenging disease.

Sleep disturbance is a common side effect of high-dose steroid pulse therapy (SPT). However, in clinical settings, the impact of this therapy on sleep architecture has not been objectively studied. This study aimed to investigate changes in sleep architecture associated with high-dose SPT administration in patients with neuroimmunological disorders. A prospective cohort study was conducted involving six hospitalized patients with neuroimmunological disorders who were administered intravenous methylprednisolone (1000 mg/day for 3 days). Objective sleep parameters were assessed on days 0, 1, and 3 using a SleepGraph, a validated portable electroencephalography (EEG) device. Subjective sleep was evaluated using the Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), sleep diary, and Likert scale. Rapid eye movement (REM) sleep significantly decreased from 71.2 ± 36.6 min on day 0 to 9.4 ± 8.3 min on day 1 and remained low on day 3 (16.5 ± 16.0 min). Total sleep time was also reduced, while non-REM (NREM) sleep remained relatively stable. Two patients who received lemborexant showed partial improvement in their sleep parameters. ISI and PSQI scores did not change significantly, possibly owing to the short observation period. These findings suggest that high-dose SPT can markedly reduce REM sleep. Moreover, portable EEG devices could be a practical approach for monitoring steroid-induced sleep alterations. Our findings provide clinical evidence that may help to deepen the objective understanding of sleep during SPT.

To evaluate the use of delay alternating with nutation for tailored excitation-prepared T1-weighted turbo spin echo (DANTE T1-SPACE) imaging for diagnosing optic neuritis and to analyze its correlation with clinical findings before and after treatment. Patients diagnosed with optic neuritis or non-arteritic anterior ischemic optic neuropathy (NA-AION) were evaluated at the Ophthalmology Department of Kyoto University Hospital. All patients underwent magnetic resonance (MR) studies before treatment initiation and ophthalmic examinations before and after treatment. Three ophthalmologists independently reviewed the MR scans for abnormalities. The magnetic resonance imaging (MRI) assessments included post-contrast DANTE T1-SPACE, post-contrast volumetric interpolated breath-hold examination (VIBE), and short T1 inversion recovery (STIR) scans. The presence of abnormalities in each sequence was determined. Of 36 eyes from 30 patients, 21 eyes from 17 patients were diagnosed with optic neuritis, and 15 eyes from 13 patients were diagnosed with NA-AION. DANTE T1-SPACE sequences showed better sensitivity for detecting optic neuritis than STIR sequences (100% vs 67%, p = 0.009). VIBE images did not confirm enhancement of lesions in some cases with optic neuritis. No differences were observed among the sequences for NA-AION. Lesion length evaluated by DANTE T1-SPACE sequences was associated with circumpapillary retinal nerve fiber layer thickness at the initial visit, eye pain, and the time interval from symptom onset to MRI scan. Contrast-enhanced DANTE T1-SPACE was better than other sequences of MRI for diagnosing optic neuritis.