Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR-T cell therapy.

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.

Interleukin-6 trans-signaling regulates monocyte chemoattractant protein-1 production in immune-mediated necrotizing myopathy.

OBJECTIVE: Immune-mediated necrotizing myopathy (IMNM) is pathologically characterized by diffuse myofiber necrosis and regeneration, myophagocytosis, and a sparse inflammatory infiltrate. The monocyte chemoattractant protein-1 (MCP-1) is a key chemokine that regulates monocyte/macrophage infiltration into injured tissues. The interleukin-6 (IL-6) signalling in the induction of MCP-1 expression has not been investigated in IMNM. METHODS: MCP-1 expression in muscle specimens was assessed using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR). Levels of multiple serological cytokines were evaluated using the Meso Scale Discovery electrochemiluminescence system. Flow cytometry, RT-qPCR, enzyme-linked immunosorbent assay, western blot, dual-luciferase reporter assays, and chromatin immunoprecipitation-qPCR were performed to explore the effects of IL-6 signalling on MCP-1 production in human myoblasts. RESULTS: MCP-1 was scattered and was positively expressed within myofibers and a few inflammatory cells in the muscles of patients with IMNM. Sarcoplasmic MCP-1 expression significantly correlated with myonecrosis, myoregeneration, and inflammatory infiltration. Serum MCP-1, IL-6, and the soluble form of the IL-6 receptor (sIL-6R) were elevated in patients with IMNM compared with controls. Serological MCP-1 levels were significantly associated with serum IL-6 expression and clinical disease severity in IMNM patients. The IL-6/sIL-6R complex induced MCP-1 expression via the signal transducer and activator of transcription 3 (STAT3) pathway in human myoblasts. Mechanistically, phospho-STAT3 was enriched in the MCP-1 promoter region and promoted the transcription. CONCLUSION: IL-6 trans-signalling may contribute to the immunopathogenesis of IMNM by augmenting inflammation through regulation of MCP-1 expression in IMNM.

Astrocyte-Derived Exosomes Contribute to Pathologies of Neuromyelitis Optica Spectrum Disorder in Rodent Model.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that leads to severe disability. A large proportion of NMOSD patients are seropositive for aquaporin-4 autoantibodies (AQP4-IgG, named as NMO-IgG) targeting AQP4, which is selectively expressed on astrocytes in the central nervous system. This study tests the hypothesis that in response to NMO-IgG, the pathogenic astrocyte-derived exosomes are released and injure the neighboring cells. METHODS: IgG purified from serum of either NMOSD patients or healthy controls was used to generate astrocyte-derived exosomes (AST-ExosNMO vs AST-ExosCON ) in cultured rat astrocytes. The exosomes were respectively delivered to cultured rat oligodendrocytes in vitro, tissue culture of rat optic nerve ex vivo, and rat optic nerve in vivo to evaluate the pathogenic roles of AST-ExosNMO . The microRNA (miRNA) sequencing of AST-Exos and verification were performed to identify the key pathogenic miRNA. The custom-designed adeno-associated virus (AAV) antagonizing the key miRNA was evaluated for its therapeutic effects in vivo. Moreover, the serum levels of the key exosomal miRNA were measured between NMOSD patients and healthy controls. RESULTS: AST-ExosNMO led to notable demyelination in both cultured oligodendrocytes and optic nerve tissue. Exosomal miR-129-2-3p was identified as the key miRNA mediating the demyelinating pathogenesis via downstream target gene SMAD3. AAV antagonizing miR-129-2-3p protected against demyelination in an NMOSD rodent model. The serum exosomal miR-129-2-3p level was significantly elevated in NMOSD patients and correlated with disease severity. INTERPRETATION: Astrocytes targeted by NMO-IgG release pathogenic exosomes that could potentially be used as therapeutic targets or disease monitoring biomarkers in NMOSD. ANN NEUROL 2023;94:163-181.

The diagnostic value of serum YKL-40 for myocardial involvement in immune-mediated necrotising myopathy.

OBJECTIVES: This study aimed to determine the diagnostic value of YKL-40 for myocardial involvement in immune-mediated necrotising myopathy (IMNM). METHODS: We retrospectively analysed the data of patients with IMNM admitted to the Neurology Department at Tongji Hospital between April 2013 and August 2022. Clinical data including patients' demographics, clinical characteristics (disease duration, muscle strength, atrophy, rash, dysphagia, dyspnoea, and myalgia) and laboratory test results were collected from the electronic medical record system. Serum YKL-40 levels were measured using an enzyme-linked immunosorbent assay. A receiver operating characteristic (ROC) curve was drawn, and the area under the ROC curve was calculated to evaluate the diagnostic value of YKL-40 for cardiac involvement in IMNM. RESULTS: 29 patients with IMNM and15 sex and age-matched volunteers without history of heart diseases were recruited for the study. Compared with the healthy controls, serum YKL-40 levels were notably up-regulated [96.3 (55.5 120.6) pg/ml versus 19.6 (13.8 20.9) pg/ml; p=0.000] in patients with IMNM. We compared 14 patients with IMNM with cardiac abnormalities and 15 patients with IMNM without cardiac abnormalities. The most important finding was that serum YKL-40 levels were higher in the patients with IMNM with cardiac involvement based on cardiac magnetic resonance (CMR) examination [119.2 (88.4 185.69) pm/ml versus 72.5 (35.7 98) pm/ml; p=0.002]. YKL-40 had a specificity and sensitivity of 86.7% and 71.4% respectively, at a cut-off value of 105.46 pg/ml for predicting myocardial injury in patients with IMNM. CONCLUSIONS: YKL-40 could be a promising non-invasive biomarker for diagnosing myocardial involvement in IMNM. However, larger prospective study is warranted.

TWEAK and Fn14 are overexpressed in immune-mediated necrotizing myopathy: implications for muscle damage and repair.

OBJECTIVES: TNF-like weak inducer of apoptosis (TWEAK) and its sole receptor fibroblast growth factor-inducible 14 (Fn14) are involved in various inflammatory conditions. This study was performed to investigate the potential role of TWEAK/Fn14 in immune-mediated necrotizing myopathy (IMNM). METHODS: Muscle biopsies from patients with IMNM (n = 37) and controls (n = 11) were collected. Human muscle cells were treated with TWEAK in vitro. Muscle biopsies and cultured muscle cells were analysed by immunostaining and quantitative PCR. Serum levels of TWEAK and Fn14 were detected by ELISA. RESULTS: TWEAK and Fn14 were overexpressed in IMNM muscle biopsies. The percentage of Fn14-positive myofibers correlated with disease severity, myonecrosis, regeneration and inflammation infiltrates. Fn14-positive myofibers tended to be surrounded or invaded by CD68+ macrophages. TWEAK treatment had a harmful effect on cultured muscle cells by inducing the production of multiple chemokines and pro-inflammatory cytokines. Serum Fn14 levels were increased in patients with IMNM and correlated with muscle weakness. CONCLUSIONS: TWEAK/Fn14 signalling was activated in IMNM, most likely aggravating muscle damage via amplifying inflammatory response and macrophages chemotaxis. Fn14 seems to be a biomarker for assessing disease severity in IMNM. In addition, Fn14 may also contribute to muscle injury repair.

Dynamic nomogram for predicting generalized conversion in adult-onset ocular myasthenia gravis.

PURPOSE: To explore the factors and risk mapping model of progression from ocular myasthenia gravis (OMG) to generalized myasthenia gravis (GMG) in adult-onset patients. METHODS: A retrospective, observational cohort study was performed for 435 OMG patients with onset age older than 14 years old. Multivariate Cox regression was used to identify the independent factors affecting generalized conversions that then were incorporated into the construction of the nomogram. RESULTS: Two hundred thirty-seven patients (54.5%) had transformed into GMG after a median of 1.1 years (range 0.1--9.1 years). The 6-, 12-, and 24-month generalized conversion rates were 31.7%, 49.8%, and 65.4%, respectively. Multivariable analysis showed that the early-onset age, male sex, concomitant autoimmune diseases (AID), positive results of anti-acetylcholine receptor antibodies, repetitive nerve stimulation abnormalities, the presence of thymoma, and prednisone treatment were significantly associated with the generalized conversions (hazard ratio [HR] = 0.598, 0.686, 1.554, 1.541, 2.020, 2.510, and 0.556, respectively). A nomogram was established to predict the possibility of generalization-free survival (GFS) in adult-onset OMG patients, and the model demonstrated good predictive performance with a C-index of 0.736 (95% confidence interval 0.703 ~ 0.769). Moreover, subgroup analyses were performed based on the presence or absence of prednisone therapy, and the results indicated that prednisone therapy has better prevention of generalized conversions in male, non-thymoma patients, and patients without other AID. CONCLUSION: A new predictive nomograph and web-based survival calculator we developed show favorable applicability and accuracy in predicting long-term GFS in adult-onset OMG patients.

Effect of thymectomy on the frequencies of peripheral regulatory B and T lymphocytes in patients with Myasthenia gravis-a pilot study.

AIM: We aimed to investigate the relationship between the peripheral lymphocyte subset frequency and thymectomy in patients with myasthenia gravis (MG). MATERIALS AND METHODS: The frequencies of regulatory B (Breg) and regulatory T (Treg) cells in peripheral blood samples obtained from 69 patients with MG and 10 healthy controls were analyzed using flow cytometry. Serum acetylcholine receptor antibodies (AchR-Ab) were measured. Patients with MG were subdivided into pre-thymectomy, post-thymectomy, and normal thymus control group. RESULTS: The percentage of Breg cells was significantly decreased in both the pre-thymectomy (7.92 ± 1.30%) and post-thymectomy (8.14 ± 1.34%) groups compared to healthy controls (16.02 ± 2.78%) and reduced in the exacerbation and relapse phase compared to the stable maintenance stage. The proportion of cluster of differentiation (CD) 4 + CD25 + T cells and CD4 + CD25 + CD127low/- Treg cells in MG patients were not significantly different than healthy controls. AchR-Ab titers in aggravating or recurrence patients after thymectomy were significantly higher than that of the stable remission patients (11.13 ± 0.70 and 6.03 ± 0.85 nmol/L, respectively; p < 0.001). CONCLUSION: The frequency of Breg cells may serve as a potential indicator of MG prognosis, while Treg cell frequency did not demonstrate the same prognostic ability. The concentration of AchR-Ab can be used as a dynamic monitoring index of disease severity in patients with MG.

Differences in immunophenotypes between myasthenia gravis patients with and without thyroid antibodies.

INTRODUCTION/AIMS: Immunophenotypes are related to the therapeutic efficacy of specific immunomodulating agents in patients with myasthenia gravis (MG), but the relationship of immunophenotype to the presence or absence of thyroid antibodies is unknown. This study aims to evaluate differences in the immunophenotypes between MG patients with and without thyroid antibody (TAb) positivity to provide insight for future targeted immunotherapies. METHODS: This retrospective observational study included 48 MG patients with acetylcholine receptor antibody (AchR-Ab), of which 15 (31.25%) were TAb positive. Ocular MG (OMG) was defined as ocular-only manifestations for the duration for which records were available. Peripheral lymphocyte subpopulations were measured by flow cytometry. RESULTS: TAb positive patients appeared to have a higher prevalence of OMG than TAb negative patients (53.33% vs. 24.24%, p  = .048). Percentages of B cells (mean difference (MD) = 6.16, 95% confidence interval (CI): 1.91-10.40, p = .007) and CD8 + CD28+ cells (MD = 15.14, 95%CI: 5.17-25.11, p  = .013) were higher in TAb positive patients than those in TAb negative patients, while AChR-Ab titers (MD = -6.49 nmol/L, 95%CI: -9.29 to -3.70, p  < .001), percentages of T cells (MD = -6.43, 95%CI: -11.92 to -0.94, p = .023), CD3 + HLA-DR+ cells (MD = -6.47, 95%CI: -12.31 to -0.63, p  = .031) and CD8+ T cells (MD = -6.60, 95%CI: -9.86 to -3.34, p < .001) were lower. DISCUSSION: The immunophenotypes of MG patients with and without TAb positivity were significantly different, suggesting that their sensitivity to immunotherapy may be different. Further studies focused on differences between TAb positive and TAb negative MG patients in their responses to specific immunotherapies are needed to support our exploratory findings.

Distinct Immunological Features of Inflammatory Demyelinating Diseases of the Central Nervous System.

OBJECTIVE: The immunological features between neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), lacked systemic comparisons. Accordingly, we aimed to investigate immunological differences between NMOSD, MS, and MOGAD. METHODS: Patients with MOGAD, MS, and NMOSD who received immunological tests including cytokine profiles and cytometry analysis of the lymphocyte subgroups were retrospectively reviewed and divided into training and validation sets. Discriminatory models based on immunological data were established to identify optimal classifiers using orthogonal partial least square discriminant analysis (OPLS-DA). Constructed models were tested in another independent cohort. RESULTS: OPLS-DA of the immunological data from 50 patients (26 NMOSD, 14 MS, and 10 MOGAD) demonstrated the discriminatory values of a relatively low level of T-lymphocyte subsets, especially the CD4+ T cells, in MOGAD; a decreased NK cell, eosinophil, and lymphocyte level; an elevated neutrophil-to-lymphocyte ratio in NMOSD; and a declined IFN-γ-producing CD4+ T cells/Th with an increased IL-8 concentration in MS. All the models (NMOSD vs. MS, NMOSD vs. MOGAD, and MS vs. MOGAD) exhibited a significant predictive value and accuracy (>85%). CONCLUSIONS: NMOSD, MS, and MOGAD may be different in pathogenesis, and several immunological biomarkers can serve as potential classifiers clinically.

Regulatory T cells protect against brain damage by alleviating inflammatory response in neuromyelitis optica spectrum disorder.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) is mainly an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. Systemic and local inflammatory responses play a key role in the pathophysiology of NMOSD. However, the role of the crucial immunomodulators CD4+CD25+ forkhead box P3+ (Foxp3) regulatory T cells (Tregs) has not been investigated in NMOSD. METHODS: Twenty-five patients with anti-AQP4-postive NMOSD undergoing an attack and 21 healthy controls (HCs) were enrolled. Frequencies of T cell subsets and Tregs in the peripheral blood were assessed by flow cytometry. Additionally, a model of NMOSD using purified immunoglobulin G from anti-AQP4-antibodies-positive patients with NMOSD and human complement injected into brain of female adult C57BL/6J mice was established. Infiltrated Tregs into NMOSD mouse brain lesions were analyzed by flow cytometry, histological sections, and real-time quantitative Polymerase Chain Reaction. Astrocyte loss, demyelination, and inflammatory response were also evaluated in our NMOSD mouse model. Finally, we examined the effects of both depletion and adoptive transfer of Tregs. RESULTS: The percentage of Tregs, especially naïve Tregs, among total T cells in peripheral blood was significantly decreased in NMOSD patients at acute stage when compared to HCs. Within our animal model, the number and proportion of Tregs among CD4+ T cells were increased in the lesion of mice with NMOSD. Depletion of Tregs profoundly enhanced astrocyte loss and demyelination in these mice, while adoptive transfer of Tregs attenuated brain damage. Mechanistically, the absence of Tregs induced more macrophage infiltration, microglial activation, and T cells invasion, and modulated macrophages/microglia toward a classical activation phenotype, releasing more chemokines and pro-inflammatory cytokines. In contrast, Tregs transfer ameliorated immune cell infiltration in NMOSD mice, including macrophages, neutrophils, and T cells, and skewed macrophages and microglia towards an alternative activation phenotype, thereby decreasing the level of chemokines and pro-inflammatory cytokines. CONCLUSION: Tregs may be key immunomodulators ameliorating brain damage via dampening inflammatory response after NMOSD.

Upregulation of circ-FBL promotes myogenic proliferation in myasthenia gravis by regulation of miR-133/PAX7.

Myasthenia gravis (MG) is a disease involving neuromuscular transmission that causes fatigue of skeletal muscles and fluctuating weakness. It has been shown that impairment of myogenic differentiation and myofiber maturation may be the underlying cause of MG. In this study, we detected the abnormal expression of circular RNA (circRNA) using next-generation sequencing in patients with MG. We then investigated the regulatory mechanism and the relationship among circRNA, microRNA, and messenger RNA using quantitative reverse-transcription polymerase chain reaction, bioinformatics analysis, and luciferase report analysis. The expression of inflammatory cytokines and regulatory T lymphocytes was shown to be increased. Circ-FBL was significantly increased in MG patients. Bioinformatics and luciferase report analyses confirmed that miR-133 and PAX7 were the downstream targets of circ-FBL. Overexpression of circ-FBL promoted myoblast proliferation by regulation of miR-133/PAX7. Taken together, our study showed that upregulation of circ-FBL promoted myogenic proliferation in patients with MG by regulating miR-133/PAX7.

Overlapping syndrome mimicking infectious meningoencephalitis in a patient with MOG and GFAP IgG.

BACKGROUND: Central nervous system overlapping autoimmune syndromes are uncommon, especially with the coexistence of MOG-IgG and GFAP-IgG. CASE PRESENTATION: A 23-year-old woman presented with transient convulsions, a loss of consciousness, persistent fever, headache, and vomiting. Cerebrospinal fluid (CSF) analysis revealed elevated cellularity, and magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement. She had fever and headache with antiviral and antibiotic treatment for 2 weeks, and she had empirical anti-tuberculosis treatment and oral prednisolone therapy. She was followed for 3 months after presentation with improved symptoms and normal CSF analysis. A 3-month follow-up MRI showed asymmetric lesions in the cerebellum, corona radiata, and white matter with enhancement. The anti-tuberculosis treatment was continued, and steroid therapy was discontinued. After she stopped taking prednisolone, an interrupted headache gradually appeared. MRI at 4 months after presentation revealed a partial reduction in lesions but enlarged areas in the left cerebellum and right parietal white matter and a new lesion in the region of the right ependyma with linear enhancement. Her CSF was positive for anti-myelin oligodendrocyte glycoprotein (MOG) and anti-glial fibrillary acidic protein (GFAP) antibodies using a transfected cell-based assay. She was diagnosed with overlapping syndrome of MOG­IgG­associated disease and GFAP astrocytopathy. She received steroid pulse therapy (methylprednisolone, 1 g for 5 days), followed by a gradual tapering of oral prednisolone and the addition of an immunosuppressant (tacrolimus, 3 mg per day). Six months after the initial presentation, she had no symptoms. An MRI showed that the lesions had diminished, and no enhancement was found. CONCLUSIONS: We report a case that was positive for double antibodies, which was initially misdiagnosed as infectious meningoencephalitis. This case broadens the clinical and phenotypic presentation of the overlapping syndrome spectrum.

Immunotherapy reversed myopathy but not cardiomyopathy in a necrotizing autoimmune myopathy patient with positive anti-SRP and MDA-5 autoantibodies.

BACKGROUND: Necrotizing autoimmune myopathy (NAM) is pathologically characterized by myofiber necrosis and regeneration with paucity or absence of inflammatory cells in muscle biopsy. Two autoantibodies, namely anti-signal recognition particle (SRP)-antibodies and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)-antibodies, are typically specific with NAM. Anti-SRP-positive NAM can be associated with cardiomyopathy which responds well to immunotherapy. Here we reported an anti-SRP-antibody and anti-MDA5-antibody NAM patient who developed severe cardiomyopathy after gaining significant improvement of myopathy and subsequently accepted heart transplantation. CASE PRESENTATION: A NAM case with both positive anti-SRP and MDA-5 antibodies who gained significant improvement of the skeletal muscle weakness with immunotherapy, but 3 years later he developed severe dilated cardiomyopathy and at last received heart transplantation. Myocardial biopsy showed disarranged and atrophic myofibers, remarkable interstitial fibrosis without inflammatory infiltrates. Immunohistochemistry analysis revealed increased polyubiquitin-binding protein p62/SQSTM1 protein expression and the positive staining of cleaved-caspase 3 in a few cardiomyocytes. After the transplantation, the patient was symptom-free on oral prednisone (10 mg/day) and tacrolimus (2 mg/day). CONCLUSIONS: We described the first case of anti-SRP and anti-MAD5 positive NAM who had received heart transplantation because of cardiopathy. Though the myopathy had been clinically improved after immunotherapy, the cardiomyopathy remained progressive and lethal. The processes of dysfunctional autophagy and augmented apoptosis were putatively pathophysiological mechanisms underlying cardiac damage in anti-SRP and anti-MAD5 positive NAM.

Isolated cortical vein thrombosis after nitrous oxide use in a young woman: a case report.

BACKGROUND: Nitrous oxide has become a popular inhalant as abused substance by young Chinese people in recent years. It has been mainly associated with medical conditions including megaloblastic anemia and myeloneuropathy. CASE PRESENTATION: We report a case of a 25-year-old high school graduate who had been abusing nitrous oxide for twenty months. She had a history of peripheral neuropathy and subacute combined degeneration in between. The young woman presented with headache, motor aphasia and right arm paralysis of eight hours after intermittently consuming nitrous oxide for one week. D-dimer was increased (1.1 mg/ml). Blood vitamin B12, folate, homocysteine and beta-HCG levels were normal. Head CT showed hemorrhagic infarction and subarachnoid hemorrhage. MR angiography and venography were normal. Head MRI identified left frontal isolated cortical vein thrombosis. Her muscle strength and verbal fluency significantly improved after initiation of Low Molecular Weight Heparin and serial head MRI showed continuous reduction in the size of thrombus. CONCLUSIONS: For the first time nitrous oxide use is found to be related to isolated cortical vein thrombosis. Public education regarding the potential consequences of abusing nitrous oxide especially in high-risk individuals is urgently needed.

Unilateral cerebral cortical encephalitis with epilepsy: a possible special phenotype of MOG antibody-associated disorders.

Myelin oligodendrocyte glycoprotein (MOG) antibody-related encephalomyelitis is an increasingly recognized entity with heterogeneity in phenotype. Among all clinical phenotypes, encephalitis restricted to cerebral cortex might be most easily ignored and under-estimated type. Here, we described two cases of cerebral cortical encephalitis with MOG seropositivity to facilitate the awareness of the manifestations of the disease. In case 1, the patient presented with headaches and fevers turned out to have elevated CSF cells and cerebral cortical FLAIR hyperintense lesions in brain MRI. He was treated as intracranial infection during his first and second admission and fully resolved when discharged. During the patient's third admission, the patient experienced a seizure, and we found cerebral cortical FLAIR hyperintensity again and MOG antibody was positive in the serum. Therefore, we considered the patient suffered from MOG antibody encephalitis. In case 2, the patient also had headache, fever, and experienced a seizure. MOG antibody was positive in the serum and brain MRI showed cortical hyperintense lesions. Both the patients were young man, response well to corticosteroids and recovered completely. The two cases suggested that encephalitis, especially benign recurrent unilateral cerebral cortical encephalitis with epilepsy, might be a special phenotype of MOG antibody-associated disorders.

Molecular and clinical relationship between live-attenuated Japanese encephalitis vaccination and childhood onset myasthenia gravis.

OBJECTIVE: The incidence of childhood onset myasthenia gravis (CMG) in China is higher than that in other countries; however, the reasons for this are unclear. METHODS: We investigated the clinical and immunological profiles of CMG, and assessed the potential precipitating factors. For the mouse studies, the possible implication of vaccination in the pathogenesis was explored. RESULTS: In our retrospective study, 51.22% of the 4,219 cases of myasthenia gravis (MG) were of the childhood onset type. The cohort study uncovered that the pathophysiology of CMG was mediated by immune deviation, rather than through gene mutations or virus infections. The administration of the live-attenuated Japanese encephalitis vaccine (LA-JEV), but not the inactivated vaccine or other vaccines, in mice induced serum acetylcholine receptor (AChR) antibody production, reduced the AChR density at the endplates, and decreased both muscle strength and response to repetitive nerve stimulation. We found a peptide (containing 7 amino acids) of LA-JEV similar to the AChR-α subunit, and immunization with a synthesized protein containing this peptide reproduced the MG-like phenotype in mice. INTERPRETATION: Our results describe the immunological profile of CMG. Immunization with LA-JEV induced an autoimmune reaction against the AChR through molecular mimicry. These findings might explain the higher occurrence rate of CMG in China, where children are routinely vaccinated with LA-JEV, compared with that in countries, where this vaccination is not as common. Efforts should be made to optimize immunization strategies and reduce the risk for developing autoimmune disorders among children. Ann Neurol 2018;84:386-400.

Tacrolimus combined with corticosteroids effectively improved the outcome of a cohort of patients with immune-mediated necrotising myopathy.

OBJECTIVES: To assess the efficacy and safety of tacrolimus in combination with corticosteroids in patients with immune-mediated necrotising myopathy. METHODS: The medical records of 20 hospitalised patients with immune-mediated necrotising myopathy (IMNM) who had received tacrolimus combined with oral prednisone from January 2014 to August 2017 were retrospectively reviewed. The recruited patients were shifted to the combined therapy because they failed to respond well to monotherapy with oral prednisone. The clinical efficacy during an average follow-up of 21 months (range, 14-24 months) was assessed by evaluating the changes of serum creatine kinase (CK) levels, the Medical Research Council (MRC) grading of the weakest muscle groups and dosage of oral prednisone. Adverse effects were monitored to assess the safety of tacrolimus. RESULTS: After starting tacrolimus, most of the 20 patients showed significant improvement in muscle strength and remarkable decline in serum CK levels at the follow-up points (p<0.0001). In addition, the daily dosage of prednisone was statistically significantly reduced (p<0.0001) after the combination therapy. No serious adverse events attributable to tacrolimus occurred in the patients. CONCLUSIONS: Early co-administration of tacrolimus with corticosteroid promoted the remission and recovery of patients with IMNM and seemed to be a relatively safe treatment programme for physician managing immune-mediated necrotising myopathy.

Aquaporin-4 antibody positive neuromyelitis optica spectrum disorder subsequent to rhabdomyolysis: a case report and literature review.

Rhabdomyolysis could be caused by various mechanisms including autoimmune reaction. Here, we reported a case of 76-year-old-woman diagnosed with aquaporin-4 (AQP4) IgG positive neuromyelitis optica spectrum disorder (NMOSD) following rhabdomyolysis. After a review of literature, we propose that physical injury of skeletal muscle cells may lead to the production of AQP4 IgG and this AQP4 IgG might further decrease in the stability of skeletal muscle cells creating a positive feedback loop. HyperCKemia might be an inducement of NMOSD.

Immunopathological Characterization of Muscle Biopsy Samples from Immune-Mediated Necrotizing Myopathy Patients.

BACKGROUND Immune-mediated necrotizing myopathy (IMNM) is a relatively new proposed category of idiopathic inflammatory myopathies (IIMs), characterized by the presence of abundant necrotic muscle fibers, myophagocytosis, and sparse inflammatory infiltrates. The aim of our study was to analyze the immunopathological characteristics of IMNM by detecting biopsy samples from a cohort of patients, and to delineate the pathways involved in the pathogenesis. MATERIAL AND METHODS A retrospective evaluation of muscle biopsy samples, clinical and laboratory data, and immunohistochemical analysis of macrophages MHC-I and MAC, was performed for all patients diagnosed as having IMNM but without a prior exposure to statins. RESULTS Immunohistochemical analysis revealed the presence of CD68+ macrophages mainly in the necrotic muscle fibers and the endomysial connective tissue. MHC-I and MAC positively stained not only the necrotic fibers or vessels but also the non-necrotic ones. CONCLUSIONS Our data describe general immunological features in IMNM patients, which may be helpful in serving as biomarkers, aid in diagnostic decisions, and provide clues into the underlying mechanisms involved in this disease.

Analysis of mortality and related factors in 2195 adult myasthenia gravis patients in a 10-year follow-up study.

OBJECTIVE: To analyze the mortality and potential risk factors for death in myasthenia gravis (MG) patients. MATERIALS AND METHODS: A total of 2195 adult patients with MG (aged older than 18 years) diagnosed during the period between 2003 and 2013 were followed-up and retrospectively reviewed. RESULTS: During the 10-year follow-up, 129 patients died and the total mortality rate was 5.88%. The risk factors associated with MG-related deaths were duration of the disease, occurrence of myasthenic crisis, severity of disease that included the Myasthenia Gravis Foundation of America (MGFA) grade III and IV at onset, elevation of acetylcholine receptor antibody (AchR-abs) titers, presence of thymic pathology, and failure of administrating immunosuppressants (P < 0.05). In addition, the non-MG related factors, including the history of preceding strokes, and the presence of chronic obstructive pulmonary disease (COPD), diabetes mellitus, atrial fibrillation, hyperlipidemia, myocardial infarction, and malignant tumors, were closely linked with death in the MG population (the hazard ratios [HRs] were 3.251, 4.173, 3.738, 3.886, 1.945, 2.177, and 14.7, respectively; P< 0.05). CONCLUSIONS: The severity of disease at entry, presence of AchRabs, thymic pathology, and duration of the disease predict a higher risk for death. Systemic illnesses including stroke, COPD, diabetes mellitus, atrial fibrillation, hyperlipidemia, myocardial infarction, and malignant tumor, which may also increase the risk of death, should be carefully monitored and managed.