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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.

The association between multiple sclerosis and anti-N-Methyl-D-Aspartate receptor encephalitis is limited to merely a few case reports, and the exploration of the pathogenic mechanisms underlying the overlap of these two disease entities is very limited. Therefore, case reports and literature review on N-Methyl-D-aspartate receptor antibody in patients with multiple sclerosis are unusual and noteworthy. A young female had the first episode of paresthesia and motor symptoms with positive anti-N-Methyl-D-Aspartate receptor antibody and recovered after immunotherapy, and at the first relapse, the patient developed disorders of consciousness with positive anti-N-Methyl-D-Aspartate receptor antibody, findings of magnetic resonance imaging showed features of autoimmune encephalitis, which was also controlled by immunotherapy. At the second relapse, anti-N-Methyl-D-Aspartate receptor antibody turned negative while oligoclonal bands presented positive, and findings of magnetic resonance imaging showed features of multiple sclerosis. Afterwards, we followed the patient after receiving disease modifying treatment to monitor the efficacy and safety of teriflunomide. Based on literature review, demyelinating diseases patients with anti-neuronal antibody have complex, diverse and atypical symptoms; therefore, high attention and increased alertness are necessary for neurologists. Conclusively, anti-neuronal antibody may present in many neuroinflammatory conditions, and diagnostic criteria should be used with caution if the clinical presentation is atypical, and neurologists should not rely excessively on laboratory tests to diagnose neurological diseases. Timely and comprehensive examination and consideration as well as early standardized treatment are the key factors to reduce patient recurrence and obtain a good prognosis.

Jian Zhang and colleagues identify the E3 ubiquitin ligase CBLB as a major inhibitor of host defense against Candida albicans infection and show that targeting CBLB can protect mice from lethal candidiasis. Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans , and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans , and deficiency of dectin-1, dectin-2, or both in Cblb −/− mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis.

Background Leucine rich repeat containing 4 (LRRC4), also known as netrin-G ligand-2 (NGL-2), belongs to the superfamily of LRR proteins and serves as a receptor for netrin-G2. LRRC4 regulates the formation of excitatory synapses and promotes axon differentiation. Mutations in LRRC4 occur in Autism Spectrum Disorder (ASD) and intellectual disability. Multiple sclerosis (MS) is a chronic neuroinflammatory disease with spinal cords demyelination and neurodegeneration. Here, we sought to investigate whether LRRC4 is involved in spinal cords neuron-associated diseases. Methods LRRC4 was detected in the CNS of experimental autoimmune encephalomyelitis (EAE) mice by the use of real-time PCR and western blotting. LRRC4 −/− mice were created and immunized with myelin oligodendrocyte glycoprotein peptide (MOG) 35–55 . Pathological changes in spinal cords of LRRC4 −/− and WT mice 15 days after immunization were examined by using hematoxylin and eosin (H&E), Luxol Fast Blue (LFB) staining and immunohistochemistry. The number of Th1/Th2/Th17/Treg cells in spleens and blood were measured with flow cytometry. Differential gene expression in the spinal cords from WT and LRRC4 −/− mice was analyzed by using RNA sequencing (RNA-seq). Adeno-associated virus (AAV) vectors were used to overexpress LRRC4 (AAV-LRRC4) and were injected into EAE mice to assess the therapeutic effect of AAV-LRRC4 ectopic expression on EAE. Results We report that LRRC4 is mainly expressed in neuron of spinal cords, and is decreased in the spinal cords of the EAE mice. Knockout of LRRC4 have a disease progression quickened and exacerbated with more severe myelin degeneration and infiltration of leukocytes into the spinal cords. We also first found that Rab7b is high expressed in EAE mice, and the deficiency of LRRC4 induces the elevated NF-κB p65 by up-regulating Rab7b, and up-regulation of IL-6, IFN-γ and down-regulation of TNF-α, results in more severe Th1 immune response in LRRC4 −/− mice. Ectopic expression of LRRC4 alleviates the clinical symptoms of EAE mice and protects the neurons from immune damages. Conclusions We identified a neuroprotective role of LRRC4 in the progression of EAE, which may be used as a potential target for auxiliary support therapeutic treatment of MS.

Background: Teriflunomide is a first-line oral immunomodulatory agent approved in China for the treatment of relapsing multiple sclerosis. Objective: To compare the treatment outcomes of teriflunomide and no disease-modifying therapy (DMT) treatment (in first year) in multi-center real-world Chinese multiple sclerosis patients. Design: Retrospective study. Methods: This study was conducted in five tertiary hospitals in different geographical regions of China. We collected clinical data of patients treated with teriflunomide and no DMT treatment (in first year) between 1 January 2017 and 31 August 2021. The effectiveness of teriflunomide was described. Potential factors influencing the effectiveness of teriflunomide were investigated. Results: A total of 372 patients treated with teriflunomide and 148 no DMT treatment patients were included. A total of 292 patients were treated with teriflunomide for at least 6 months, described as a stable teriflunomide cohort. The annualized relapse rate was significantly lower in the stable teriflunomide cohort than in the no DMT treatment cohort (0.23 ± 0.47 versus 0.87 ± 0.67, p < 0.001). The mean Expanded Disability Status Scale (EDSS) score of the stable teriflunomide cohort (1.77 ± 1.62) was slightly different from that of the no DMT treatment cohort (2.09 ± 2.00). A previous annualized relapse rate of ⩾1, a previous EDSS score of ⩾2, and a long disease duration of ⩾5 years were associated with better clinical effectiveness. Conclusion: Teriflunomide is associated with a lower relapse rate and less disability accumulation in Chinese patients with multiple sclerosis.

Background Percutaneous pedicle screw fixation (PPSF) is the primary approach for single-segment thoracolumbar burst fractures (TLBF). The healing angle at the thoracolumbar junction is one of the most significant criteria for evaluating the efficacy of PPSF. Therefore, the purpose of this study was to analyze the predictors associated with the poor postoperative alignment of the thoracolumbar region from routine variables using a support vector machine (SVM) model. Methods We retrospectively analyzed patients with TLBF operated at our academic institute between March 1, 2014 and December 31, 2019. Stepwise logistic regression analysis was performed to assess potential statistical differences between all clinical and radiological variables and the adverse events. Based on multivariate logistic results, a series of independent risk factors were fed into the SVM model. Meanwhile, the feature importance of radiologic outcome for each parameter was explored. The predictive performance of the SVM classifier was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy (ACC) and confusion matrices with 10-fold cross-validation, respectively. Results In the recruited 150 TLBFs, unfavorable radiological outcomes were observed in 53 patients (35.33%). The relationship between osteoporosis ( p  = 0.036), preoperative Cobb angle ( p  = 0.001), immediate postoperative Cobb angle ( p  = 0.029), surgically corrected Cobb angle ( p  = 0.001), intervertebral disc injury (Score 2 p  = 0.001, Score 3 p  = 0.001), interpedicular distance (IPD) ( p  = 0.001), vertebral body compression rate (VBCR) ( p  = 0.010) and adverse events was confirmed by univariate regression. Thereafter, independent risk factors including preoperative Cobb angle, the disc status and IPD and independent protective factors surgical correction angle were identified by multivariable logistic regression. The established SVM classifier demonstrated favorable predictive performance with the best AUC = 0.93, average AUC = 0.88, and average ACC = 0.87. The variables associated with radiological outcomes, in order of correlation strength, were intervertebral disc injury (42%), surgically corrected Cobb angle (25%), preoperative Cobb angle (18%), and IPD (15%). The confusion matrix reveals the classification results of the discriminant analysis. Conclusions Critical radiographic indicators and surgical purposes were confirmed to be associated with an unfavorable radiographic outcome of TLBF. This SVM model demonstrated good predictive ability for endpoints in terms of adverse events in patients after PPSF surgery.

Cerebrospinal fluid oligoclonal band (CSF-OCB) is an established biomarker in diagnosing multiple sclerosis (MS), however, there are no nationwide data on CSF-OCB prevalence and its diagnostic performance in Chinese MS patients, especially in the virtue of common standard operation procedure (SOP). With a consensus SOP and the same isoelectric focusing system, we conducted a nationwide multi-center study on OCB status in consecutively, and recruited 483 MS patients and 880 non-MS patients, including neuro-inflammatory diseases (NID, n = 595) and non-inflammatory neurological diseases (NIND, n=285). Using a standardized case report form (CRF) to collect the clinical, radiological, immunological, and CSF data, we explored the association of CSF-OCB positivity with patient characters and the diagnostic performance of CSF-OCB in Chinese MS patients. Prospective source data collection, and retrospective data acquisition and statistical data analysis were used. 369 (76.4%) MS patients were OCB-positive, while 109 NID patients (18.3%) and 6 NIND patients (2.1%) were OCB-positive, respectively. Time from symptom onset to diagnosis was significantly shorter in OCB-positive than that in OCB-negative MS patients (13.2 vs 23.7 months, P=0.020). The prevalence of CSF-OCB in Chinese MS patients was significantly higher in high-latitude regions (41°-50°N)(P=0.016), and at high altitudes (>1000m)(P=0.025). The diagnostic performance of CSF-OCB differentiating MS from non-MS patients yielded a sensitivity of 76%, a specificity of 87%. The nationwide prevalence of CSF-OCB was 76.4% in Chinese MS patients, and demonstrated a good diagnostic performance in differentiating MS from other CNS diseases. The CSF-OCB prevalence showed a correlation with high latitude and altitude in Chinese MS patients.

Background The HECT E3 ubiquitin ligase Nedd4 has been shown to positively regulate T cell responses, but its role in T helper (Th) cell differentiation and autoimmunity is unknown. Th17 cells are believed to play a pivotal role in the development and pathogenesis of autoimmune diseases. Nevertheless, the regulation of RORγt activation during Th17 cell differentiation by TCR signaling is yet to be elucidated. These uncharted aspects inspire us to explore the potential role of Nedd4 in Th17-mediated autoimmunity. Methods We evaluated the impact of Nedd4 deficiency on mouse T cell development and differentiation using flow cytometry and siRNA transfection, and subsequently validated these findings in T cells from patients with multiple sclerosis (MS). Furthermore, we investigated the influence of Nedd4 deficiency on Th17-mediated autoimmunity through experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Subsequently, we elucidated the molecular mechanism underlying the interaction between Nedd4 and RORgt through immunoprecipitation, mass spectrometry analysis, and lentiviral transduction. Additionally, we identified Nedd4 as an E3 ubiquitin ligase for RORγt. Moreover, we characterized the tyrosine residue sites and polyubiquitination patterns involved in RORγt ubiquitination. Results In this study, we report that loss of Nedd4 in T cells specifically impairs pathogenic and non-pathogenic Th17 responses, and Th17-mediated EAE development. At the molecular level, Nedd4 binds to the PPLY motif within the ligand binding domain of RORγt, and targets RORγt at K112 for K27-linked polyubiquitination, thus augmenting its activity. Conclusion Nedd4 is a crucial E3 ubiquitin ligase for RORγt in the regulating Th17 cell development and offers potential therapeutic benefits for treating Th17-mediated autoimmune diseases.

Lymphoplasma exchange (LPE), a technique combining plasma exchange with leukapheresis, is emerging as promising treatment for autoimmune diseases. Data on the efficacy and safety of LPE in myasthenia gravis (MG) therapy are scarce. In this study, we aimed to comprehensively review the clinical efficacy, safety, and immunological characteristics of LPE therapy in MG patients. A Chinese cohort of 276 generalized MG patients in state of exacerbation, including impeding crisis, myasthenia crisis, and preparation for thoracic exsection between January 2014 and December 2020, were evaluated in this study. A total of 276 patients with a median age of 45.5 ± 16.7 years underwent a total of 635 LPE sessions. Clinical scales of Quantitative Myasthenia Gravis (QMG) scores, Myasthenia Gravis Specific Manual Muscle Testing (MMT) scores, activities of daily living (ADL) scores, and quality of life (QOL) scores were improved during 4 weeks' follow-up. Adverse effects occurred in 20 out of 276 patients, with 14 patients having one adverse event each. Independent predictive factors for good response to LPE therapy were symptom onset before LPE therapy ≤3 days and age on LPE therapy <50 years of age. LPE decreased the serum levels of antibodies, immunoglobulins, and complements 4 weeks after the first replacement, with decreased levels of interleukin (IL)-17A and interferon (IFN)-γ and increased level of IL-10. LPE is an effective treatment for MG patients in state of exacerbation and preparation for thymectomy. Early use of LPE on early-onset MG may have good therapeutic effects. The potential mechanism for LPE is the polarization of cytokines from IL-17A, IFN-γ, into IL-10.