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.

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.

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.

Background and objectives: Complement-targeting therapies are pivotal in managing neuromyelitis optica spectrum disorder (NMOSD), calling for a deeper understanding of complement activation across idiopathic inflammatory demyelinating diseases (IIDDs) of the CNS. C4d, a covalently bound complement split product, offers prolonged detectability at activation sites. This study explores whether C4d immunohistochemistry (IHC) extends the detection window for complement activation in CNS biopsies of IIDDs and evaluates its usefulness as a fluid biomarker.

Methods: Forty-four IIDD biopsies with active demyelination were analyzed for complement deposition using IHC for C9neo and C4d. C4d levels were also quantified in blood and CSF of patients with IIDDs. The persistence of C4d in CNS tissue was further evaluated in an in vivo NMOSD model.

Results: C4d IHC enhanced the sensitivity to detect complement activation, surpassing C9neo by twofold in NMOSD and by sixfold in ADEM, while remaining undetectable in MS biopsies. Exclusive C4d immunopositivity at the glia limitans distinguished NMOSD from ADEM. Furthermore, CSF C4d levels were significantly elevated in both seronegative and seropositive NMOSD compared with MS.

Discussion: C4d detection extends the window for identifying complement activation in CNS biopsies of IIDDs and emerges as a valuable CSF biomarker, enhancing diagnostic precision, autoantibody target identification, and patient stratification for complement-targeting therapies.

Background and objectives: Interleukin-9 (IL-9) is an immune molecule with multiple roles in a variety of cell types. IL-9-induced cell responses are mediated by the IL-9 receptor (IL-9R). Recent evidence demonstrates that expression of IL-9R in post mortem brain tissues of patients with multiple sclerosis (MS) is associated with a protective, anti-inflammatory role of IL-9 in MS. In this study, we investigated the expression of IL-9R in cells resident in the CNS of patients with MS. We found that astrocytes express IL-9R, indicating their expected responsiveness to IL-9. Astrocytes play a critical role in MS, where the inflammatory environment turns them into reactive cells, which actively contribute to the disease. The transcription factor nuclear factor-kB (NF-kB) regulates the response of reactive astrocytes and their potential pathogenic activities during CNS inflammation.

Methods: To address the role of IL-9 in proinflammatory astrocytes, we used 3 different human in vitro models: (1) human astrocytoma cell line (U-373 MG), (2) primary normal human astrocytes, and (3) induced pluripotent stem cell-derived astrocytes. We used interleukin-1β for their conversion into proinflammatory astrocytes.

Results: We found that IL-9 contributes to the switch of astrocytes from an inflammatory to an anti-inflammatory profile by downregulating NF-kB activation. Moreover, we demonstrated that IL-9 inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF) expression driven by NF-kB.

Discussion: Because GM-CSF production by astrocytes is linked to microglial activation and CNS inflammation, these results indicate that IL-9 regulates the astrocyte-microglia axis and has potential therapeutic anti-inflammatory implications in MS.

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.