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The perioperative period represents a critical window in cancer management, during which anesthetic choice may influence tumor biology. Sevoflurane, a volatile anesthetic widely used in neurosurgery, has been shown to modulate gene expression in glioblastoma (GBM). This study aimed to identify novel biomarkers in GBM and to investigate their functional roles and prognostic significance, thereby exploring the potential impact of this common perioperative agent on tumor behavior and patient outcomes. Comprehensive bioinformatics analysis were used to screen novel prognostic biomarker, including differential expression, enrichment analysis, Protein-protein interaction, survival analysis, risk assessment, immune infiltration, TIDE scores. Then, the functional role of the key gene THBS1 was validated experimentally in glioblastoma cell lines (A172 and U251). The effects of sevoflurane exposure and THBS1 overexpression on apoptosis, invasion, and oxidative stress were assessed through Western blotting, measurement of intracellular reactive oxygen species (ROS), quantification of mitochondrial cytochrome c (Cyt-C) release by ELISA, and Transwell invasion assays. Mechanistic involvement of the PI3K/AKT pathway was confirmed using a specific inhibitor (LY294002). We collected DEGs yielding 551 up-regulated and 890 down-regulated genes. Venn analysis identified 43 up-regulated and 35 down-regulated intersection genes linked to oxidative stress and cancer, which were enriched in immune, metabolic, oxidative stress, and GBM-associated pathways. PPI networks and survival analysis identified 35 hub genes, with six (MAP2K3, FOSL1, HBEGF, S100B, THBS1, IRS1) significant correlation with overall survival. The high-risk group presented decreased immune cell infiltration and higher TIDE scores, suggesting a more conspicuous likelihood of immune evasion. Survival analysis confirmed a more unfavorable prognosis in high-risk patients. Our results demonstrated that sevoflurane exposure induced glioma cell apoptosis and suppressed cellular migration. Overexpression of THBS1 effectively alleviated these sevoflurane-induced effects, mitigating both the pro-apoptotic and anti-migratory outcomes. Further investigation revealed that THBS1 overexpression counteracted the sevoflurane-induced accumulation of reactive oxygen species (ROS), mitochondrial cytochrome c (Cyt-C), and cleaved caspase-3 protein levels. Notably, the addition of a PI3K inhibitor reversed all the protective effects conferred by THBS1 overexpression, suggesting that the PI3K/AKT signaling pathway mediates the regulatory role of THBS1 in sevoflurane-associated cellular responses. This study identified oxidative stress-correlated DEGs and prognostic risk model in sevoflurane-treated GBM for computationally predicting potential immunotherapy response and drug sensitivity. Therefore, THBS1 mediated a protective response against sevoflurane-induced cytotoxicity and migration inhibition in GBM via PI3K/AKT activation, highlighting a potential molecular interaction between anesthetic exposure and tumor cell behavior.
Immune-checkpoint inhibitor (ICI) related encephalitis (ICI-IE) is a severe adverse event, associated with high morbidity and mortality and requiring prompt ICI discontinuation. The safety of rechallenge with ICI after initial adverse event is largely unknown and must be considered only after cautiously weighing risks and benefits of resuming treatment. A 66-year-old otherwise healthy female was diagnosed with localized renal cell carcinoma, which was treated with immunotherapy, ipilimumab/ nivolumab. After the second cycle of treatment, she developed subacute progressive personality changes, memory loss and encephalopathy, and was diagnosed with CTCAE grade III immune-related limbic encephalitis. Her chemotherapy regimen with ipilimumab and nivolumab were promptly discontinued and she was treated with seven days of intravenous solumedrol with prolonged oral steroid taper. Four years later, she had recurrent metastatic disease, prompting the decision to pursue palliative immunotherapy with cabozantinib and immune checkpoint rechallenge with Nivolumab. Given her history of ICI-IE, neuroimmunology was consulted to discuss risks of rechallenge with ICI. Over 9 months after initiation of therapy, she remained without recurrence of immune-related adverse events (irAE) related to treatment. We present one of the first reports of successful rechallenge of immune checkpoint inhibition after ICI-IE in the setting of recurrent metastatic renal cell carcinoma. This treatment success may bolster the management options for refractory oncologic disease. Given potential risks associated with ICI rechallenge, it is imperative to employ a multidisciplinary approach with consideration of potential risks and benefits of treatment.
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis. Currently, the development of its animal models lacks maturity and efficiency. This study aimed to establish a reliable and efficient mouse model of anti-NMDAR encephalitis and to investigate the pathological mechanisms. Immunoadsorption eluates were collected from three patients with anti-NMDAR encephalitis and three control patients. Immunoglobulin G (IgG) was purified from these eluates. A passive transfer mouse model was established by injecting the IgG into the hippocampal region of mice. RNA sequencing was performed on IgG treated neurons in vitro. And the role of the PI3K-AKT-HIF-1α signaling axis in NMDAR-IgG-induced neuronal injury was validated. Compared with control-IgG, injection of NMDAR-IgG resulted in detectable antibody binding to hippocampal neurons in brain at 7 days post-injection, accompanied by loss of the postsynaptic scaffolding protein. Behavioral assessments revealed that NMDAR-IgG-treated mice exhibited cognitive impairment, depressive-like and despair-like behaviors on day 7, which had resolved by day 14. RNA sequencing of NMDAR-IgG-treated neurons in vitro identified dysregulation of the PI3K-AKT-HIF-1α signaling axis. Western blot demonstrated activation of this signaling axis in neurons following NMDAR-IgG treatment in both in vivo and in vitro. Additional experiments demonstrated that this signaling axis constitutes a critical pathway mediating NMDAR-IgG-induced neuronal injury. Finally, RNA sequencing and immunofluorescence confirmed microglial activation and increased HIF-1α secretion in the brains of NMDAR-IgG-treated mice. We established a mouse model of anti-NMDAR encephalitis using antibodies purified from human immunoadsorption eluates. Furthermore, our findings demonstrate that the PI3K-AKT-HIF-1α signaling axis serves as a molecular pathway mediating NMDAR-IgG-induced neuronal injury.
Parkinson's disease (PD) is characterized by progressive motor deficits and dopaminergic neuronal loss. Aberrant neuroinflammation contributes to neurodegeneration. Prompted by published case reports describing motor improvement following levofloxacin (LVFX) administration in patients with parkinsonian syndromes, as well as an additional clinical observation from our center, we investigated its effects in cellular and mouse models. In LPS-stimulated BV2 microglial cells, levofloxacin was associated with reduced activity of the TLR4/NF-κB/NLRP3 axis, reducing pro-inflammatory cytokine release and oxidative stress. TLR4 knockdown experiments suggested that TLR4 is involved in mediating this anti-inflammatory action. Conditioned medium from levofloxacin-treated microglia attenuated LPS-induced neuronal viability loss and apoptosis in SH-SY5Y cells. Furthermore, levofloxacin attenuated activation of the TLR4/NF-κB/NLRP3 pathway and glial activation in an LPS-induced mouse model of neuroinflammation. In an MPTP-induced mouse model of PD, levofloxacin alleviated dopaminergic neuronal degeneration and motor deficits. These findings are consistent with clinical observations and preclinical evidence and suggest that levofloxacin may have beneficial effects in models of PD-like pathology, at least in part, by modulating the neuroinflammatory TLR4/NF-κB/NLRP3 axis.
Narcolepsy type 1 is a sleep-wake disorder characterized by hypocretin deficiency. It has been considered an autoimmune disorder for decades due to the strong associating with the HLA-DQB1*06:02 allele and possible relations to the H1N1 pandemic in 2009. However, the pathophysiological mechanisms underlying the loss of hypocretin neurons is not understood. We hypothesize that a hypocretin neuron-specific antigen, other than hypocretin itself but sharing an expression pattern, may be the target of the autoimmune response leading to the development in individuals with narcolepsy type 1. In this study, we employed an in silico method to identify novel candidate antigens for an autoimmune response leading to the destruction of hypocretin cells. A combination of multiple publicly available datasets, based on human brain tissue from healthy individuals, was used to map the expression profile of hypocretin. Genes were categorized based on their expression pattern and its association with hypocretin expression. 15 candidate genes were identified as potentially relevant targets in the development of NT1, with varying degrees of confidence regarding the likelihood of their involvement. Six candidate genes also showed higher expression within hypocretin cells compared to other cells in the hypothalamus of which NPVF seems most promising. This study provides important new directions and potential targets for investigating and understanding the pathophysiology of narcolepsy type 1.
Objective study was the quantification of controlled/inadequately controlled generalized myasthenia gravis (gMG) disease burden, health care resource utilization and costs in MG patients, followed-up at a reference center for MG in Italy. The study is a 2010 to 2020 retrospective analysis of gMG patients. Clinical and health economics variables were those observed during routine clinical care. Data were anonymized and treated in aggregated forms in compliance with GDPR. Only patients with gMG were included in the study. Out of 237 patients, 55.3% were males and 44.7% females with a median follow up duration of 4.7 years. Males were older, with a median age at onset of 58.3 years versus 45.7 years for females; an increased representation of late and very late onset patients was recorded. A shorter time from onset to diagnosis was observed in males. The incidence rate per year of exacerbations changed from 0.76 in the first year to 0.23 at the sixth year, with a similar trend for MG crisis; both exacerbations and crisis incidence were higher in inadequately controlled patients. Disease burden and health care resources utilizations were particularly evident in inadequately controlled patients, which showed a 138% increase of costs. Our data confirmed the observed epidemiological changes occurring in MG population and the high use of health care system resources in uncontrolled patients. The estimates obtained will provide a useful basis for assessing the impact of recently introduced targeted therapies on healthcare expenditure for MG.
Multiple Sclerosis (MS) is a chronic neurological disorder, prevalent in young adults. MS leads in disability accrual, thus affecting overall patients' quality of life. Moreover, the management of MS poses significant burden on health systems worldwide. The present study delves into the impact of different health providing settings (e.g. private office/Clinic vs. specialized MS Center) on the effectiveness of MS management, as well as on patient-reported outcomes related to the quality of life (Axis A). Moreover, the study addresses their relative effectiveness in a health crisis, such as the COVID-19 pandemic (Axis B). Data were collected based on questionnaires administered to people with MS (pwMS). Upon the pandemic and prior to the COVID-19 vaccines being available, all data were collected via online questionnaires. Since March 2021, data were collected both online and in person. Overall, 776 pwMS participated in the study and answered Axis B questionnaire. Of those, 215 additionally answered Axis A questionnaire. Regarding Axis A, disease management by a specialized MS Center was associated with increased access to healthcare professionals (p < 0.001) and/or MRI examinations (p < 0.001) and was also linked to improved time-to-diagnosis following symptom onset, compared to the disease management in a private office/Clinic (p < 0.001). Regarding Axis B, specialized MS centers demonstrated remarkable adaptability during the pandemic, swiftly implementing remote care solutions to ensure continuity of care. These findings suggest that care delivered in specialized MS centers is associated with improved access to healthcare services and better patient-reported outcomes, both under routine care conditions and during healthcare crises.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy that typically responds to conventional therapy. However, a subset of patients such as anti-neurofascin-155 (NF155) Ab-positive exhibit unique clinical features and a poor response to conventional therapy. To characterize the clinical, electrophysiological, pathological, and therapeutic features of Thai patients with anti-NF155 Ab-positive paranodopathy and to compare them with antibody-negative CIDP patients. A retrospective cohort study, anti-NF155 Ab-positive paranodopathy patients were compared to CIDP patients who were negative for all nodal/paranodal antibodies. Clinical data, nerve conduction studies, cerebrospinal fluid (CSF) profiles, sural nerve biopsies, and treatment outcomes were analyzed. Of 41 CIDP patients tested, 11 (26.8%) were anti-NF155 Ab-positive. These patients had a younger age of onset (median 32.8 years), a higher prevalence of tremor (54.5%) and sensory ataxia (36.4%), and more frequently exhibited a distal-predominant sensorimotor phenotype. All met the EAN/PNS 2021 diagnostic criteria. Nerve biopsies showed mild generalized fiber loss without clear demyelination. Onion bulb formations were not present in anti-NF155 Ab-positive patients. Only 20% responded to IVIg, compared to 92.9% of antibody-negative patients (p = 0.006). Rituximab led to clinical improvement in 83.3% of anti-NF155 Ab-positive patients, with the median onset of response at 102 days. Anti-NF155 Ab-positive paranodopathy represents a distinct clinical subtype associated with a poor IVIg response and good rituximab efficacy. Antibody testing should be considered in patients with distal weakness, tremor, high CSF protein, or IVIg refractoriness. Early identification may allow for tailored treatment and improved outcomes.
Little is known about the long-term health-related quality of life (HRQOL) of adults with pediatric-onset MS (POMS) nor the factors that may modify HRQOL in this population. We sought to define symptom burden and HRQOL among adults with POMS and to interrogate the potential relationship of adverse childhood experiences (ACEs) with HRQOL. In this cross-sectional study, 98 adults with POMS were recruited through the North American Research Committee on Multiple Sclerosis Registry, Nationwide Children's Hospital, and Ohio State University. Participants completed demographics, Multiple Sclerosis Quality of Life-54 (MSQoL-54), SymptoMScreen, Patient-Determined Disease Steps (PDDS), MS Resiliency Scale (MSRS), and ACEs questionnaires. The Pearson correlations were computed between ACE, MSQoL-54, PDDS, and SymptoMScreen scores. Multivariable linear regression was performed for MSQoL-54 outcomes using ACE and MSRS scores. Participants were 90% female with a mean age of 53 years. A higher number of ACEs was associated with poorer physical and mental HRQOL (p = 0.003 and p = 0.01, respectively) and SymptoMScreen (p = 0.002). Higher resiliency scores (MSRS) were associated with greater physical and mental HRQOL (both p < 0.001). ACEs may have a long-standing impact on the lived experience of POMS patients into adulthood. Future work should explore the role of resiliency in mitigating these effects.
BCL6, a transcription factor central to T follicular helper (TFH) cell differentiation, has recently been identified as a key regulator of T cell-mediated neuroinflammation. While previous research has established a connection between Th17 cells and B cell responses in autoimmune diseases, most notably in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis-the role of BCL6 in T cell subsets beyond TFH cells remains unclear. In this study, we explored the impact of T cell-specific BCL6 deficiency on EAE progression. Our findings reveal that mice with BCL6-deficient T cells display significantly reduced disease severity in a B cell-independent model, characterized by decreased infiltration of pathogenic T cells, B cells, and myeloid cells into the central nervous system (CNS). Interestingly, BCL6 deficiency resulted in an increased number of inflammatory Th17 cells in peripheral organs including the spleen and lymph nodes, but a notable reduction of these cells in the CNS. We also discovered that BCL6-deficient Th17 cells exhibited impaired migration in response to the Th17-attracting chemokine CCL2. Moreover, the adoptive transfer of BCL6-deficient, MOG-specific Th17 cells failed to induce EAE, likely due to their diminished responsiveness to the CCR2-CCL2 chemotactic axis, which is crucial for CNS infiltration. These results suggest that BCL6 expression in T cells is critical for the migration of inflammatory Th17 cells into the CNS, contributing to neuro-autoimmunity. Our study identifies a novel role for BCL6 in regulating T cell migration during neuroinflammation and underscores its potential as a therapeutic target in multiple sclerosis.
Neuromyelitis optica spectrum disorder (NMOSD) predominantly affects women of reproductive age, posing significant risks for pregnancy-associated relapses and adverse perinatal outcomes. While biologic agents such as satralizumab are established therapies for NMOSD, data regarding their safety and efficacy when initiated during pregnancy remain scarce. Here we report the case of a 32-year-old woman with a history of NMOSD (diagnosed at age 24), taking oral low-dose prednisolone before conception. To mitigate the risk of relapse, satralizumab was first injected at 28 + 3 weeks of gestation. She delivered vaginally at 40 + 1 weeks of gestation without peripartum complications or disease relapse. Notably, while transplacental transfer of satralizumab was demonstrated, the drug was undetectable in breast milk and the neonate developed normally. To our knowledge, this is the first reported case of satralizumab initiation during pregnancy for relapse prevention in a patient with NMOSD. Our findings suggest that satralizumab may represent a viable therapeutic option for NMOSD management even when pregnancy is already established.
Conventional therapies for acetylcholine receptor antibody-positive (AChR-Ab+) generalized Myasthenia Gravis (gMG) often provide inadequate disease control. Although neonatal Fc receptor (FcRn) inhibitors have proven effective in clinical trials, real-world evidence on their use and effectiveness in heterogeneous patient populations is still limited. This study evaluates clinical outcomes, steroid-sparing effects, and treatment utilization of efgartigimod in patients with refractory AChR-Ab+ gMG. We conducted a retrospective analysis of 27 adult patients with AChR-Ab+ gMG treated with efgartigimod. Effectiveness, treatment utilization and long-term outcomes were evaluated over seven treatment cycles using longitudinal Myasthenia Gravis Activities of Daily Living (MG-ADL) scores, inter-cycle interval duration, daily corticosteroid dosing, need for rescue therapies, and transition to other advanced therapies. In total, 130 treatment cycles were analyzed. Overall, the patients showed rapid and sustained clinical improvement. Baseline MG-ADL scores (EMM = 8.48) significantly decreased by 2.96 points by cycle-2 (p < 0.001), reaching maximum reduction of 3.95 points by cycle-6. Severe impairment (MG-ADL ≥ 10) decreased from 41% at baseline to 0% by cycle-5, while 66% of patients achieved mild symptoms (MG-ADL 2-4) or Minimal Symptom Expression by cycle-7. Significant corticosteroid-sparing effect occurred by cycle-3 (p = 0.023), with mean daily methylprednisolone doses decreasing from 5.8 mg at baseline to 2.3 mg by cycle-5. Four patients (15%) were non-responders and transitioned to complement inhibition therapy. Real-world efgartigimod use provides rapid symptomatic relief and significant corticosteroid reduction in patients with refractory AChR-Ab+ gMG. While most achieve sustained improvement, non-responders and patients with history of myasthenic crises require close monitoring and potential transition to alternative advanced therapies.
The AC-18 cytoplasmic discrete dots pattern, associated with anti-GW body autoantibodies, is traditionally linked to systemic autoimmunity, but its relationship with CNS involvement remains under-explored. We aimed to characterize the AC-18 pattern as a non-specific serological correlate of central nervous system (CNS) involvement in a case-control cohort. Out of 52,196 ANA tests screened, the AC-18 pattern was identified in 397 tests, corresponding to a test-level frequency of 0.76%. After applying exclusion criteria and removing duplicate records, 300 unique patients with isolated AC-18 positivity were included in the final cohort. This group was compared with 300 seronegative controls. Multivariate models evaluated whether AC-18 was independently associated with CNS disorders (including primary headaches, cerebrovascular events, demyelinating and neurodegenerative conditions), adjusting for age, sex, and autoimmunity. Overall neurological disorders were significantly more frequent in AC-18-positive patients than controls (17.7% vs. 6.7%, p < 0.001). CNS disorders were also more frequent in AC-18-positive patients (12.7% vs. 4.0%, p < 0.001). Following adjustment for age, sex, and autoimmunity, AC-18 positivity remained associated with CNS disorders (adjusted OR 3.50, 95% CI 1.78-6.87, p < 0.001). ROC analysis of the multivariable models showed moderate discriminatory performance for overall neurological disorders (AUC 0.72) and CNS-related outcomes (AUC 0.71). AC-18 positivity was associated with CNS involvement in this retrospective case-control cohort. Given the heterogeneous nature of CNS diagnoses and the moderate discriminatory performance of the multivariable models, AC-18 should be interpreted as an exploratory, non-specific serological correlate rather than a diagnostic or pathogenic biomarker.
Generalized myasthenia gravis (gMG), an antibody-induced autoimmune disorder of the neuromuscular junction, is characterized by fluctuating skeletal muscle weakness and fatigability. Approximately 85% of patients with MG have antibodies against the acetylcholine receptor (AChR), 5-10% against muscle-specific kinase receptor, and 1-5% against lipoprotein-related protein 4 (LRP4). In addition to the detection of antibodies providing insight into the diagnosis and prognosis of gMG, it also affects the choice of treatment. In the majority of cases, gMG can be managed effectively using a tailored regimen of acetylcholinesterase inhibitors, immunosuppressive medication, and thymectomy. However, existing treatments fail to adequately manage the manifestations in 10-15% of individuals with gMG (refractory gMG). Eculizumab, a recombinant humanized monoclonal antibody that specifically targets the complement protein C5, is approved for anti-AChR-positive gMG patients. Anti-AChR antibodies, anti-LRP4 antibodies, and anti-Titin antibodies all have the capacity to activate the complement protein signaling pathway. We report two cases of refractory gMG with multiple antibody positivity. The first case, an 82-year-old male patient, was positive for anti-AChR, anti-LRP4, and anti-Titin antibodies; the second case, a 67-year-old female, was positive for anti-AChR and anti-LRP4 antibodies. Both cases of refractory gMG responded well to eculizumab treatment. This report of highlights two cases of refractory gMG with multiple antibody positivity (both patients had anti-AChR and anti-LRP4 antibodies) that responded to eculizumab. These findings warrent further experience with eculizumab treatment in gMG patients with multiple antibody positivity.
Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.
Neurosarcoidosis (NS) is a rare inflammatory disorder of the nervous system with significant morbidity. Diagnostic challenges stem from non-specific clinical features and the lack of sensitive and specific biomarkers. While complement dysregulation has been implicated in systemic sarcoidosis, its role in NS remains unclear. This study explores the diagnostic and prognostic value of complement and neuronal injury biomarkers in serum and cerebrospinal fluid (CSF) of individuals with NS. We conducted a case-control study using paired serum and CSF samples from NS patients and non-sarcoidosis controls. Concentrations of complement activation products: iC3b, Ba, Terminal Complement Complex [TCC]), regulators: C1 inhibitor [C1inh], factor H [FH], and components: C3, C5, C9, Factor B [FB], and other markers such as CXCL12 and neurofilament light chain (NfL) were quantified using ultrasensitive assays. Multivariable logistic regression and receiver operating characteristic (ROC) curve analysis were employed to assess the diagnostic and prognostic performance of individual and combined biomarkers. Significant differences in biomarker profiles were observed between neurosarcoidosis patients (n = 28) and controls (n = 30). In serum, patients with neurosarcoidosis exhibited lower C3 levels (915.24 vs 1380.07 ng/ml; p < 0.001) and higher Factor B (205.21 vs 168.51 ng/ml; p = 0.010) and neurofilament light chain (2.07 × 10-5 vs 8.96 × 10-6 pg/ml; p = 0.023), indicating complement dysregulation and neuronal injury. In cerebrospinal fluid, complement components including C3 (12.98 vs 4.45 μg/ml), Factor B (0.55 vs 0.18 μg/ml), and C5 (0.63 vs 0.13 μg/ml) were significantly elevated (all p < 0.001). C3 demonstrated strong diagnostic performance (AUC = 0.937), while multi-biomarker panels, including C3 + Factor B (AUC = 0.996) and C3 + Factor B + C9 (AUC = 1.0), provided near-perfect discrimination. These findings remained robust following adjustment for age and sex. In differentiating relapsing (n = 18) from stable (n = 8) neurosarcoidosis, individual serum biomarkers showed modest performance (AUC 0.65-0.67), but combinations such as Factor B + C5 + Ba + NfL improved classification (AUC = 0.944). In CSF, multi-biomarker panels including TCC + FH + C5 and iC3b + C3 + C5 achieved excellent discrimination (AUC = 1.0). Our findings highlight the central role of complement system dysregulation as a driver of neuroinflammation in NS. Multi-biomarker panels, particularly those involving complement components, enhance diagnostic and prognostic accuracy. These results support the development of biomarker-driven, minimally invasive approaches for diagnosing and monitoring NS.
Neurological involvement in leptospirosis but increasingly recognized, with myelitis representing a disabling complication. Conus medullaris involvement has not been systematically described and may reflect region-specific vulnerability to immune-mediated injury, post leptospirosis infection. We report a case series of three patients with serologically confirmed leptospirosis who developed acute myelitis during the immune phase, with radiological involvement of the conus medullaris. Clinical, cerebrospinal fluid, and imaging features were analyzed. A proteome-wide in silico comparison was performed between human myelin oligodendrocyte glycoprotein and the Leptospira interrogans proteome to identify shared antigenic motifs. All patients presented with acute bladder dysfunction, lower limb weakness, or sensory symptoms following a febrile illness. Magnetic resonance imaging showed conus medullaris involvement, either isolated or as part of longitudinal cord lesions. Cerebrospinal fluid revealed inflammatory changes. Treatment with steroids, with adjunctive immunotherapy in severe cases, resulted in clinical improvement. In silico analysis did not demonstrate full-length homology but identified 19 shared peptide motifs with moderate sequence identity, several overlapping predicted B-cell and T-cell epitope regions. This series suggests a possible para-infectious conus-predominant myelitis pattern in leptospirosis. The identification of shared antigenic motifs provides biological plausibility for immune-mediated demyelination through molecular mimicry. Recognition of this pattern in endemic regions may facilitate early diagnosis and timely immunotherapy.
Myasthenia gravis (MG) is one of the most prevalent disorder of the neuromuscular junction (NMJ). Non-coding RNAs regulate myoblast proliferation and differentiation. The differential expression of miRNAs was analysed by using RNA microarrays. Protein levels and gene expression were analysed by using Western blotting and quantitative real-time polymerase chain reaction. The interactions of miR-4310 with circ_0018483 or ERBB receptor feedback inhibitor 1 (ERRFI1) were assessed using dual-luciferase reporter assays. The expression and aggregation of acetylcholine receptors (AChRs) were observed and analysed by using immunofluorescence. The expression of miR-4310 was downregulated in the whole blood of patients. circ_0018483 exhibited a sponge effect on miR-4310, and the inhibition of miR-4310 weakened AChR function. Additionally, miR-4310 targeted ERRFI1 and circ_0018483, and circ_0018483 affected the expression and aggregation of AChR by regulating miR-4310 and ERRFI1. circ_0018483 regulates the expression of ERRFI1 by targeting miR-4310, which in turn affects AChR expression and aggregation at the NMJ. We confirmed a novel circ_0018483/miR-4310/ERRFI1 ceRNA axis in MG. Our findings suggest novel AChR regulation and MG molecular mechanisms research avenues.
Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition increasingly linked to disturbances in immune signaling and neuroimmune cross-talk. This PRISMA-ScR-guided scoping review synthesizes contemporary evidence to propose a structured immunological classification of ASD comprising six immune-related subtypes: immune overactivation, immune deficiency, autoimmunity-linked ASD, gut-immune axis dysregulation, post-infectious or immune-triggered onset patterns, and maternal immune activation. Each subtype is defined by characteristic neuroimmune features - including cytokine imbalances, aberrant microglial activation, altered microbiome-immune communication, and prenatal immune priming - reflecting distinct biological pathways through which immune dysfunction may influence neurodevelopment. Based on 42 mapped sources identified through a search strategy that primarily emphasized literature published between 2020 and 2025, while incorporating selected foundational earlier studies through citation chaining when necessary for conceptual and mechanistic context, and spanning human clinical and epidemiological studies, animal models, and integrative neuroimmune reviews, this synthesis identifies candidate biomarkers and immune signatures relevant to each subtype, including systemic and CNS-localized inflammation, autoantibodies, disrupted gut-immune-brain pathways, and maternal cytokine profiles. The framework also clarifies ongoing debates by distinguishing immune-mediated vulnerability and timing-dependent unmasking of susceptibility from assumptions of direct causation regarding environmental or infectious exposures. Conceptualizing ASD along immune-related subtypes provides a foundation for precision-based diagnostic and therapeutic approaches, highlighting opportunities for targeted immunomodulation, microbiome-informed interventions, and biomarker-driven stratification, thereby advancing translational efforts at the interface of immunology, neuroscience, and developmental psychopathology.