Neurology® Neuroimmunology & Neuroinflammation最新文献

Background and objectives: Neuromyelitis optica spectrum disorder (NMOSD) is characterized by inflammatory relapses that result in severe disability, including blindness and paralysis. Relapse prevention with safe and effective treatments is key to reducing long-term disability. We aim to compare the efficacy and safety of rituximab-the most commonly used treatment-with recently approved NMOSD-specific treatments-eculizumab, inebilizumab, satralizumab-and other common off-label NMOSD treatments-mycophenolate mofetil (MMF) and azathioprine. The primary outcomes are relapse-free survival and annualized relapse rate. Secondary outcomes are serious infectious adverse event (SIAE) and treatment-limiting adverse event (TLAE)-free survival.

Methods: A retrospective cohort study of NMOSD was conducted on patients at the Mass General Brigham hospital network. Patients meeting 2015 NMOSD diagnostic criteria, who were seen between 2000 and 2024 were included. Poisson regression, frequentist negative binomial analysis with inverse probability of treatment weighting, and Cox proportional hazard models were used to assess relapse rates, relapse-free survival, and SIAEs.

Results: A total of 176 patients with NMOSD were followed for a median of 9 years (interquartile range: 5-14), contributing 691 relapse assessments. The median age at first attack was 42 years, and 83% were female. Compared with rituximab, relapse risk was significantly lower with C5 inhibitors (HR 0.12, 95% CI 0.07-0.24), inebilizumab (HR 0.22, 95% CI 0.12-0.65), and satralizumab (HR 0.19, 95% CI 0.11-0.42). Annualized relapse rates were the lowest for C5 inhibitors (0, 95% CI 0-0.063) and the highest for azathioprine (0.34, 95% CI 0.18-0.56). A composite outcome of relapse, SIAE, and TLAE favored C5 inhibitors (HR 0.22, 95% CI 0.05-0.67), while azathioprine (HR 2.33, 95% CI 1.08-4.86) and MMF (HR 1.75, 95% CI 1.02-2.95) showed increased risk compared with rituximab. C5 inhibitors had the lowest incidence of serious infections (incidence rate ratio 0.16, 95% CI 0.05-0.42 vs rituximab).

Discussion: Clinicians should consider using NMOSD-approved treatments given their favorable efficacy and safety profiles in the real-world setting. MMF and azathioprine should be avoided. We caution against rituximab as a default first-line given the cumulative risk of relapse, SIAEs, and TLAEs over time.

Classification of evidence: This study provides Class III evidence that, in patients with NMOSD, FDA-approved disease-modifying therapies are associated with lower relapse rates and fewer serious adverse events compared with rituximab.

Background and objectives: Glioblastoma, a highly aggressive and uniformly lethal brain tumor, resists current treatments and immunotherapies by creating a potently immunosuppressive microenvironment. The objective of this study was to determine whether niacin modulates systemic immunity in patients with newly diagnosed glioblastoma.

Methods: In a first-in-human phase I clinical trial (NCT04677049), we investigated the immunologic effects of niacin administration alongside standard-of-care surgery and chemoradiation in patients with newly diagnosed glioblastoma.

Results: Niacin treatment increases the frequencies of circulating memory T cells and natural killer cells while decreasing nonclassical monocytes. Furthermore, niacin elevated serum levels of the proinflammatory cytokine interleukin (IL)-12p70 and granulocyte colony-stimulating factor and reduced growth-regulated α protein.

Discussion: These data demonstrate that niacin induces systemic immunomodulatory effects in patients with glioblastoma, shifting the immune landscape toward an antitumor profile and supporting further evaluation of niacin as a potential therapeutic adjunct.

Trial registration information: This ongoing study was registered as NCT04677049 on March 1, 2021, with the first patient enrolled on March 18, 2021.

Classification of evidence: This study provides Class IV evidence that niacin dose escalation modulates immune response in patients with glioblastoma treated with standard of care, including maximal safe resection, concurrent radiation and temozolomide, and adjuvant temozolomide administration. This is a Class IV study because it is an open-label trial with no blinding or comparison group.

Objectives: Dysferlinopathy is an autosomal recessive muscular dystrophy caused by pathogenic variants of the DYSF gene. Currently, no clinical effective treatment is available. Given the myopathologic and animal model evidence on complement activation in dysferlinopathy, we explored the potential therapeutic effect of complement inhibition.

Methods: We reported a case of teenager-onset dysferlinopathy with progressive proximal weakness, markedly elevated serum creatine kinase levels, and assistance requirement for ambulation when admission. Muscle biopsy showed dysferlin deficiency and marked deposition of complement C5b-9 on nonnecrotic sarcolemma. Based on these findings and previous preclinical studies, the patient received eculizumab (900 mg weekly for 4 weeks) with informed consent.

Results: Clinical improvement was observed following complement inhibition therapy. By week 5, all tested muscle groups reached Medical Research Council grade 5/5, and the North Star Assessment for Dysferlinopathy score increased from 28 to 39. The 6-minute walk test (6MWT) improved from 220 m to 363 m. The muscle MRI revealed reduced muscle edema after eculizumab treatment. These benefits were sustained at 13-month follow-up.

Discussion: Complement inhibition showed promising clinical improvement in this single case of dysferlinopathy. Further studies with larger sample sizes are needed to investigate the efficacy and safety of complement inhibitors in dysferlinopathy.

Background and objectives: Epstein-Barr virus (EBV) infection is a prerequisite for the development of multiple sclerosis (MS), yet whether EBV acts merely as a trigger at disease onset or also contributes to immune dysregulation and disease progression remains unclear. To explore potential mechanisms linking EBV to immune alterations, we performed a comprehensive analysis of EBV markers and immune-related gene expression in peripheral blood samples from therapy-naïve persons with MS (PwMS) and healthy donors (HD) and assessed EBV transcripts in CSF cells to explore compartment-specific viral activity.

Methods: Peripheral blood mononuclear cells (PBMCs) and serum from PwMS (n = 77) and HD (n = 40) were analyzed. EBV serology, DNA load, and RNA expression were assessed by ELISA, droplet digital PCR, and preamplified real-time RT-PCR, respectively. EBV RNA was also evaluated in PwMS CSF cells. Gene expression profiling of 47 immune-related genes selected for their relevance to MS was also performed in PBMCs. Data were analyzed using univariate and multivariate statistical approaches also considering demographic, clinical, and radiologic information. Exploratory factor analysis (EFA) was used to identify transcriptional signatures associated with MS.

Results: Anti-EBNA1 IgG titers were higher in PwMS. In addition, EBV RNA and DNA were more frequently detected, and viral load was increased compared with HD. Notably, EBV transcripts associated with latency II/III (LMP1, LMP2A, EBNA1, EBNA3A) and lytic reactivation (BZLF1, gp350/220) were more prevalent in PwMS. Although viral RNA was detected in only 7% of CSF samples, all positive cases showed profiles consistent with viral reactivation. Immune gene expression analysis revealed broad upregulation of cytotoxic effectors, type I interferon pathways, and chemokine signaling in PwMS. EFA identified a significantly different gene signature linking BZLF1 expression with inflammatory genes, type I interferon responses, and chemokines involved in immune cell migration, in PwMS.

Discussion: Our findings support the hypothesis that EBV latency disruption and lytic reactivation contribute to immune dysregulation in MS. The association between EBV transcriptional activity and immune gene alterations may uncover potential peripheral biomarkers of EBV-driven pathology. These molecular signatures may provide insights into novel therapeutic avenues and peripheral biomarkers for MS monitoring.

Objectives: A score evaluating age at onset, sex, clinical phenotype, and treatment received (MOG-AR) has been proposed to identify MOGAD patients at high relapse risk. The aim of this study was to validate the MOG-AR score in a multicenter cohort and to assess other variables potentially associated with relapses.

Methods: MOGAD patients were retrospectively enrolled from 24 centers. The MOG-AR score was applied and 4 categories of relapse risk were identified (grade I: lowest risk; grade IV: highest risk), accordingly. The association of MOG-AR score and additional variables with a relapsing course were then explored.

Results: Of 190 included patients, the median age at onset was 37 [IQR 23-51] years and 107 (56%) were female. A total of 78 patients (41%) experienced a relapse during a median of 43.6 months [24.8-75.4]. Using the proposed cutoff of 9, the MOG-AR score had a sensitivity of 53.9% [95% CI 55.6-73.9] and a specificity of 65.18% [95% CI 55.60-73.93]; area under the curve: 0.64 (95% CI 0.57-0.72). Among additional investigated factors, only immunosuppressive treatment after the presenting MOGAD attack was associated with a lower relapse risk.

Discussion: MOG-AR score failed to accurately predict a relapsing disease course. Only immunosuppressive treatment after the first event was significantly associated with a lower relapse risk.

Objectives: To comprehensively characterize complement pathway activation in chronic inflammatory demyelinating polyneuropathy (CIDP) and its association with clinical disease features using advanced complement profiling.

Methods: Complement protein levels indicative of classical, lectin, and alternative pathway activation were quantified by multiplex ELISA and compared between 28 patients with typical CIDP, 24 patients with Charcot-Marie Tooth neuropathy (CMT), and 24 demographically matched healthy controls (HD).

Results: Serum levels of activated complement proteins-C3a, C4a, Ba, Bb, C5a, and the soluble terminal complement complex sC5b-9 (sTCC)-were significantly elevated in CIDP patients compared to healthy donors (HD) (p < 0.001). Except for C3a, these protein levels were also significantly higher in CIDP patients than in those with Charcot-Marie-Tooth disease (CMT). Among CIDP patients, those with active, unstable disease exhibited significantly higher levels of terminal complement components (C5a and sTCC) compared to patients with stable disease or in remission (p < 0.001).

Discussion: These findings highlight the critical involvement of aberrant complement activation in the pathophysiology of CIDP and provide a rationale for further investigation into targeted complement inhibition as a therapeutic approach.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a key immunomodulatory receptor broadly expressed on myeloid cells such as macrophages and microglia. It plays versatile roles in neurodegenerative diseases, tissue repair, and tumor immunity by orchestrating glucose metabolism and inflammatory responses. This review systematically summarizes the structural characteristics of TREM2, its ligand-binding mechanisms, and downstream signaling pathways-including the phosphoinositide 3-kinase/protein kinase B(PI3K/Akt), mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and signal transducer and activator of transcription 3 (STAT3) cascades-with a particular focus on its central role in macrophage metabolic reprogramming.In neurodegenerative diseases such as Alzheimer disease, TREM2 contributes to the attenuation of neuroinflammation and slows disease progression by promoting β-amyloid (Aβ) clearance, inhibiting tau hyperphosphorylation, and modulating microglial polarization. Loss-of-function sequence variants, such as R47H, disrupt lipid metabolism, impair phagocytic activity, and destabilize immune homeostasis, thereby significantly increasing disease susceptibility. Furthermore, by enhancing glycolysis and suppressing fatty acid oxidation, TREM2 facilitates macrophage polarization toward a reparative M2 phenotype, promoting neuroregeneration and remyelination in conditions such as spinal cord injury and multiple sclerosis.Within the tumor microenvironment, TREM2 influences tumor progression and therapeutic resistance by modulating the metabolic reprogramming of tumor-associated macrophages (TAMs)-notably through activation of pyruvate kinase muscle isozyme M2 (PKM2)-dependent glycolysis-and promoting an immunosuppressive phenotype. In metabolic disorders such as diabetes and obesity, TREM2 exerts protective effects by inhibiting NLRP3 inflammasome activation and maintaining lipid homeostasis, highlighting its therapeutic potential.This review also outlines the translational prospects of TREM2 as a therapeutic target, including the development of agonists, gene regulatory strategies, and its potential use as a biomarker. Future studies should aim to elucidate the ligand-specific biased signaling and dynamic regulatory networks of TREM2 within tissue microenvironments to advance precision interventions in neuroimmunometabolic diseases.

Background and objectives: Mucosal-associated invariant T (MAIT) cells are unconventional T cells with emerging roles in antitumor immunity. Their phenotype in the brain and potential role in immunity to gliomas-including lower-grade (WHO grades I and II) and higher-grade gliomas such as grades III and IV (glioblastoma)-remain poorly defined.

Methods: We assessed the role of MAIT cells in glioma using publicly available transcriptomic data from patient cohorts. We then characterized MAIT cells in the mouse brain using flow cytometry and assessed their impact on survival and on other immune cells in the murine GL261 model of high-grade glioma. We tested previously developed methods to activate and expand MAIT cells in mice for their effect on brain MAIT cells.

Results: Analysis of The Cancer Genome Atlas revealed an association between a gene signature of activated, but not naïve, MAIT cells and improved survival in patients with grade III glioma. In mice, MAIT cells were predominantly brain-resident and infiltrated GL261 tumors where they produced IL-17 and IFN-γ. Notably, MAIT cell-deficient Mr1^-/- mice displayed reduced survival after GL261 tumor induction, suggesting a protective role for MAIT cells in higher grade gliomas. Injection of MAIT antigen and adjuvants expanded brain-resident MAIT cells, but expansion of MAIT cells alone prior to GL261 tumor induction did not significantly alter survival.

Discussion: Overall, this study supports a protective role for a population of brain-resident MAIT cells in glioma and highlights their potential involvement in immune surveillance of the CNS. Our findings also lay a foundation to explore the therapeutic modulation of MAIT cells in the brain.

Background and objectives: Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease mainly driven by aquaporin-4 antibodies (AQP4-IgG). During an attack, AQP4-IgG activates the complement system, leading to astrocyte destruction, inflammation, neuronal damage, and thus devastating and often irreversible neurologic deficits. Terminal complement inhibitors such as eculizumab and ravulizumab effectively prevent relapses, yet their therapeutic potential in stopping ongoing complement-mediated injury during acute attacks remains insufficiently explored.

Methods: We conducted a multinational retrospective case series across NMOSD-specialized centers in 6 countries, analyzing 33 AQP4-IgG-positive patients (mean age: 48.1 years; 28 women) treated with component 5 (C5) inhibition during or shortly after acute relapse (mean 20.1 days from symptom onset; range 2-62). Eculizumab was used in 25 patients and ravulizumab in 8. Two additional patients were excluded because of delayed treatment initiation beyond 62 days.

Results: Lesion locations included myelitis (57.6%) and optic neuritis (30.3%). Expanded Disability Status Scale scores worsened from a pre-relapse median of 0 (interquartile range [IQR] 0-2) to a nadir of 6.5 (IQR 3.5-8), improving to 3.5 (IQR 3-6.5) at 1-3 months and 2.5 (IQR 2-6) at 6 months. All patients stabilized clinically; 20 continued C5 inhibition as attack-preventing therapy. Good, moderate, and poor/absent recovery were observed in 15, 11, and 7 patients, respectively. Earlier treatment was associated with better outcomes: treatment within 21 days yielded an odds ratio of 1.58 (95% CI 0.32-8.52) for good response. Plasma exchange was administered in 57.6% and was associated with higher overall response rates, but not with good response alone.

Discussion: These findings highlight the potential of complement inhibition as a treatment option for acute NMOSD attacks, particularly in patients with insufficient response to standard therapies. Given the absence of clinical worsening and the encouraging course observed in most of the patients, further investigation into the role of C5 inhibition in acute attack management is warranted.

Classification of evidence: This retrospective case series provides Class IV evidence that the C5 complement inhibitors eculizumab or ravulizumab may improve disability in patients with NMOSD when given during or shortly after acute relapse.