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.

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: 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.

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: 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.

Background and objectives: Seronegative autoimmune encephalitis (AE), defined by an appropriate clinical phenotype in the absence of known neuronal autoantibodies, poses diagnostic and therapeutic challenges due to clinical heterogeneity and lack of definitive biomarkers. We conducted a systematic review and meta-analysis of individual patient data to characterize the phenotypes, treatment responses, and prognostic factors in seronegative AE.

Methods: We included 213 cases from 30 studies published between 2014 and 2024 and 11 from a local cohort meeting Graus criteria for seronegative AE. We extracted details on clinical and paraclinical features, immunotherapy, and outcomes measured via the modified Rankin Scale (mRS) and Clinical Assessment Scale for Autoimmune Encephalitis (CASE). Multivariate regression and dimensionality reduction analyses identified prognostic markers.

Results: Of 224 patients (median age 49 years, 50.9% male), 72 (32.1%) had limbic encephalitis (LE) and 152 (67.9%) had antibody-negative probable AE (ANPRA). Good outcome (mRS score ≤2) was more common in LE (49/72, 68.1%) than in ANPRA (76/154, 50.0%) (p < 0.05). Delayed immunotherapy was associated with an increased risk of poor outcome. Additional predictors of poor prognosis included age older than 60 years, the ANPRA subtype, an underlying tumor, striatocapsular or thalamic involvement on MRI, and presentation with refractory status epilepticus. Dimensionality and clustering analysis identified heterogeneity among seronegative AE, with 3 distinct subtypes.

Discussion: Seronegative AE comprises clinically and prognostically distinct subtypes. Early immunotherapy is the key modifiable factor influencing outcome. We advocate for biomarker discovery and prospective, systematically reported cohort studies to improve stratification and treatment strategies in this diagnostically challenging population.

Background and objectives: Multiple sclerosis (MS) is more prevalent in women, with a female-to-male ratio of 3:1. The molecular mechanisms driving this sex difference are still mostly unknown. MS results from immune dysfunction, with an imbalance in effector and regulatory T cells. Among the latter, Type I regulatory T cells (Tr1) are dysfunctional in people with MS (pwMS), secreting less IL-10, a potent anti-inflammatory cytokine, than in healthy donors. Our objectives were to explore the effect of biological sex on Tr1 cell differentiation in healthy donors and pwMS.

Methods: CD4⁺ T cells were isolated from peripheral blood mononuclear cells, and Tr1 differentiation was induced by costimulation with the complement regulator CD46 or IL-27. The frequency of Tr1 cells and their production of IL-10 and IFN-γ were examined. The impact of the PI3K/mTOR pathway on male and female Tr1 cells was also studied.

Results: We found that healthy female Tr1 cells produce less IL-10 than male cells (16 women and 16 men, 18-45 years old, p = 0.0053). This sex difference was only observed when Tr1 cells were differentiated by CD46 costimulation. Mechanistically, this sex difference in IL-10 expression by Tr1 cells was due to the differential activity of a negative feedback loop targeting PI3K signaling in male vs female Tr1 cells. In contrast to findings in healthy donors, no sex difference in IL-10 production was observed when CD4⁺ T cells from pwMS (12 women and 12 men, 18-48 years old) were differentiated to Tr1 cells via the CD46 pathway, further emphasizing the dysregulation of Tr1 generation in MS. However, PI3Kδ inhibition in MS cells also revealed a sex bias, as it reduced IL-10 production by IL-27-induced Tr1 cells only in men (7 men and 5 women, p = 0.0043), while increasing IL-10 levels in the CD46 pathway in both sexes (8 men and 11 women).

Discussion: We demonstrate that sex influences IL-10 production by Tr1 cells via the PI3K pathway, potentially contributing to the greater susceptibility of women to MS. Furthermore, our data suggest that targeting PI3Kδ may represent a novel therapeutic strategy to boost IL-10 production in female pwMS.

Background and objectives: Severe optic neuritis (ON) is a common clinical manifestation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD). Given distinct prognoses and often the necessity of early plasma exchange in NMOSD, prompt differentiation is crucial. In this study, we investigated the utility of optical coherence tomography (OCT) in differentiating between first acute NMOSD-ON and MOGAD-associated optic neuritis (MOGAD-ON), as well as specific factors associated with disc edema.

Methods: In this retrospective multicenter study, 111 adult patients with MOGAD or aquaporin-4 antibody-positive NMOSD who experienced a first ON and underwent OCT within 2 weeks of symptom onset were included from 14 centers across 8 countries. Peripapillary retinal nerve fiber layer (pRNFL) thickness in µm was analyzed, including the average of both eyes in cases of bilateral manifestation.

Results: Eighty-three patients with MOGAD (51 women; 124 ON eyes; bilateral ON 48.2%) and 28 with NMOSD (24 women; 36 ON eyes; bilateral ON 21.4%) were enrolled. A significant increase in pRNFL thickness (>2SD), suggestive of disc edema, was observed in 73.4% of MOGAD-ON eyes and 11.1% of NMOSD-ON eyes (p < 0.001). The pRNFL thickness cutoff of 117.5 µm provided 92.9% specificity and 71.1% sensitivity in distinguishing between MOGAD-ON and NMOSD-ON (area under the curve = 0.838). There was no association between pRNFL thickening and MOG-IgG titer (high vs low), body mass index, or the delay between ON onset and OCT. Simultaneous bilateral MOGAD-ON was associated with significantly more pronounced pRNFL thickening.

Discussion: Acute-stage OCT contributes to the rapid and accurate differentiation between MOGAD-ON and NMOSD-ON prior to antibody confirmation, which can be critical for timely therapeutic decisions.

Objectives: Anti-CD20 therapies for multiple sclerosis (MS) are highly effective at preventing disease activity. Recognizing infectious complications of these therapies is essential.

Methods: Three MS centers shared deidentified clinical data on persons with MS (pwMS) receiving ocrelizumab who developed enterovirus encephalitis.

Results: Five pwMS (4 with relapsing-remitting MS, 1 with secondary progressive MS) on ocrelizumab were identified. At diagnosis, the median age was 34 years (range, 30-57), the median MS duration was 5 years (range, 2-13), and the median ocrelizumab exposure was 3 years (range, 2-7). Four had young children who were recently ill, including 2 with hand, foot, and mouth disease. MRI brain revealed new nonenhancing T2 hyperintensities in the thalamus (2), substantia nigra (2), cerebellum (2), and pons (1). All had CSF pleocytosis (median, 57/mcL; range, 33-175). Enterovirus was detected by reverse-transcription PCR in CSF (4) and blood (2). Hypogammaglobulinemia was present in 4 patients tested; 1 also had neutropenia. Three received IV immunoglobulin. At follow-up (median, 7 months; range, 3-15), 1 patient had fully recovered and 4 had residual symptoms (cognitive, 1; gait impairment, 3).

Discussion: Enterovirus encephalitis is a rare but serious complication in pwMS receiving ocrelizumab; hypogammaglobulinemia may increase risk. Clinician awareness and prompt testing may improve outcomes.