Neurology® Neuroimmunology & Neuroinflammation最新文献

Background and objectives: Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative CNS disorder characterized by a state of "virtual hypoxia." Angiogenesis, one of the main homeostatic responses to hypoxia, has been implicated in the pathophysiology of MS. The study objective was to determine whether angiogenic and hypoxia-related molecules are dysregulated in the serum and CNS of patients with progressive multiple sclerosis (PMS).

Methods: Baseline serum samples were obtained from a phase II trial of Ibudilast in PMS (n = 203 analyzed) and matched to healthy controls (n = 53). Participants on previous therapeutics (interferons or glatiramer acetate) were excluded from analysis (n = 131). Angiogenic factors were measured using a commercially available bead-based multiplex assay, and hypoxia biomarkers were measured using a custom bead-based multiplex assay. To interrogate the expression of selected hypoxia and angiogenic markers in the CNS, we analyzed publicly available transcriptomic databases and in-house generated data from normal appearing white matter of 2 SPMS donors and 2 nonneurologic disease controls.

Results: Circulating markers of hypoxia (such as hypoxia inducible factor-1-a, heme oxygenase-1, and heat shock protein-90) were increased in serum. Conversely, markers of angiogenesis (such as vascular endothelial growth factor-A [VEGF-A], heparin-binding epidermal growth factor, and hepatocyte growth factor) were reduced suggesting a blunting of the angiogenic response. Several of these changes were confirmed in the PMS CNS transcriptome. Lower levels of VEGF-A were associated with disability worsening on the timed-25 foot-walk test at 24 (p = 0.02) and 48 (p = 0.02) weeks and predicted disability worsening (hazard ratio 0.31, 95% CI 0.14-0.69, p = 0.034). Conversely, higher leptin levels trended to predict cognitive worsening on the symbol digit modalities test.

Discussion: Hypoxia-angiogenesis signals are dysregulated in PMS. Increased hypoxia and an insufficient angiogenic adaptive response may play a role in PMS pathophysiology and be a relevant pathway, both in understanding disease mechanisms and as a possible therapeutic target.

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by infection-provoked abrupt-onset obsessive compulsive disorder (OCD) and neurodevelopmental regression. Owing to the neuroimmune hypothesis, we investigated the effects of IV immunoglobulin (IVIg) on cell-specific gene expression.

Methods: Single-cell RNA sequencing of peripheral immune cells was performed in 5 children with PANS (median age 8 (5.5-16) years), before and after administering open-label IVIg, compared with 4 controls (median age 13.5 [IQR 12-15] years).

Results: The index PANS event (age 1.8-13 years) involved abrupt eating restriction (n = 5), developmental regression (n = 4), and OCD (n = 3). A total of 144,470 cells were sequenced and clustered into 11 cell types. Children with PANS before IVIg compared with controls showed downregulated immune pathways (defense response, innate immunity, secretory granules) in most cell types, with natural killer (NK) cells showing upregulated immune pathways (response to corticosteroid), supporting baseline "immune dysregulation." Ribosomal pathways were upregulated in neutrophils and CD8 T cells but downregulated in NK cells. In children with PANS after IVIg, the baseline immune and ribosomal pathway abnormalities were reversed and histone modification pathways (histone methyltransferase, chromatin) were downregulated in neutrophils and NK cells.

Discussion: We propose that PANS is an epigenetic immune brain disorder with cellular epigenetic, ribosomal, and immune dysregulation. Epigenetic and immune-modulating therapies, such as IVIg, may have disease-modifying effects.

Background and objectives: Most patients with myasthenia gravis (MG) suffer from fatigue, which can be defined as a subjective lack of energy and difficulty in initiating or sustaining voluntary activities. This is conceptually different from muscle weakness or muscle fatigability. Fatigue is one of the most reported symptoms in MG and has been hypothesized to be an innate mechanism to minimize muscle activity in order to protect muscles from (further) damage. The exact pathophysiology of fatigue remains unclear, and it is very likely a multifactorial phenomenon. The aim of this study was to provide a better understanding on the pathophysiology of fatigue in MG.

Methods: We analyzed 38 serum biomarkers including various cytokines and myokines in a cohort of 116 anti-acetylcholine receptor-positive patients with MG. A multivariate linear regression analysis for each biomarker was performed in search for a correlation with fatigue. The following preselected covariates were included in the primary analysis: sex, age, disease severity, depression and anxiety scores, nonsteroid immune suppressive medication, and cumulative prednisone dosage in the past 6 months.

Results: Severe fatigue was present in 64% of patients. Results show a robust correlation between fatigue and C-reactive protein (CRP) in the primary analysis. This correlation persisted when additionally adjusting for BMI, strenuous physical activities, and hemoglobulin levels.

Discussion: Our findings suggest that chronic low-grade inflammation, mediated by CRP, contributes to the pathogenesis of fatigue in MG. This aligns with the hypothesis that local peripheral inflammatory processes induce systemic inflammatory cascades responsible for fatigue.

Background and objectives: Differentiating multiple sclerosis (MS) from antibody (Ab)-defined diseases, such as neuromyelitis optica spectrum disorders (NMOSDs), remains challenging, particularly as Ab levels decline. N-glycans play a key role in immunity, with changes in branching and fucosylation linked to T/B-cell function and MS onset while increased N-acetylglucosamine residues correlate with disease progression. Despite growing recognition of glycosylation in neuroinflammation, direct comparisons of the N-glycome between MS and Ab-defined diseases are lacking. This study aims to assess whether plasma N-glycome profiling can effectively differentiate these conditions and their subtypes.

Methods: This cohort study included 120 participants: 30 with relapsing-remitting MS (RRMS), 30 with secondary progressive MS (SPMS), 30 with myelin oligodendrocyte glycoprotein Ab-associated disease (MOGAD), and 30 with aquaporin-4 (AQP4)-Ab NMOSD, recruited from the John Radcliffe Hospital, Oxford University Hospitals National Health System (NHS) Trust. Plasma N-glycans were analyzed using ultra-high-performance (UHPLC) hydrophilic interaction liquid chromatography (HILIC) coupled with high-resolution mass spectrometry. Orthogonal partial least-squares discriminant analysis was applied to identify disease-specific glycomic patterns.

Results: Distinct N-glycome profiles were identified across diseases and phenotypes. Plasma N-glycans differentiated MS from Ab-defined diseases with 80.5% accuracy (±1.5%), MOGAD from AQP4-Ab NMOSD with 77.8% accuracy (±3.1%), and RRMS from SPMS with 75.2% accuracy (±3.6%). Key discriminatory features included increased monosialylation (S1; odds ratio [OR] = 2.57, p < 0.0001), trigalactosylation (G3; OR = 2.70, p < 0.0001), highly branched N-glycans (OR = 2.32, p = 0.0002), and antennary fucosylation (OR = 2.89, p < 0.0001), effectively distinguishing Ab-defined diseases from MS, independent of Ab serostatus at the time of sampling.

Discussion: These findings underscore the potential of plasma N-glycomics as a diagnostic tool for neuroinflammatory diseases. While further research is needed to clarify the mechanistic links between glycomic alterations and disease pathology, our results suggest that plasma N-glycan profiling could improve disease classification. Given its noninvasive and cost-effective nature, this approach holds promise as a complementary diagnostic tool for CNS demyelinating diseases in clinical practice.

Background and objectives: Fc receptor-like 5 (FCRL5) is an IgG-binding receptor frequently reported to be highly expressed on double-negative and atypical memory B cells, both of which are frequently expanded in inflammatory conditions. However, its expression profile in multiple sclerosis (MS) remains unclear. This study aims to characterize FCRL5 expression in CSF, serum, and peripheral blood mononuclear cells (PBMC) of patients with MS and to define the phenotypic and transcriptional features of FCRL5⁺ B cells in MS.

Methods: A proximity extension assay-based proteomic analysis was conducted on the CSF of patients with relapsing-remitting MS (RRMS, n = 59) and controls (n = 29). The observed FCRL5 upregulation was validated using single-molecule array analysis in a cohort comprising patients with RRMS (n = 40), controls (n = 30), and individuals with other inflammatory neurologic diseases (OIND, n = 20). Serum FCRL5 levels were also assessed in a cohort of patients with MS characterized by 3T MRI (n = 58). In addition, flow cytometry-based techniques and RNA sequencing were performed on PBMC from patients with RRMS and controls to investigate the phenotype and transcriptional profiles of FCRL5⁺ B cells. Finally, the effect of Bruton tyrosine kinase inhibitors (BTKi) on FCRL5 regulation was also evaluated in vitro.

Results: FCRL5 was significantly upregulated in the CSF of patients with RRMS compared with that in controls and OIND. Elevated CSF FCRL5 levels were associated with an increased risk of new brain lesions within 24 months. Serum FCRL5 levels were not correlated with CSF measurements but were inversely correlated with the cortical and juxtacortical lesion burdens. Moreover, flow cytometry analysis revealed that peripheral CD19⁺FCRL5⁺ B cells of patients with RRMS differed from those of controls by their strong CD11c expression. The transcriptional profiles of CD19⁺CD11c⁺FCRL5⁺ cells also differed significantly between the 2 groups, characterized by reduced expression of humoral response genes and enhanced inflammatory signaling. In addition, FCRL5 regulation was found to be BTK-dependent.

Discussion: The soluble form of FCRL5 can be measured in the CSF and could serve as a promising biomarker for MS diagnosis and disease activity prediction. In addition, this study highlights that CD19⁺CD11c⁺FCRL5⁺ B cells in MS display a distinct transcriptional profile compared with controls.

Background and objectives: The aim of this study was to elucidate the clinical spectrum and mechanisms of autoimmune nodopathy (AN) with autoantibodies against leucine-rich repeat leucin-rich glioma inactivated 1 (LGI) family member 4 (LGI4) localized at juxtaparanodes and satellite glia in the dorsal root ganglion.

Methods: We developed a live cell-based assay for LGI4-immunoglobulin (Ig) G and surveyed 131 patients with chronic inflammatory demyelinating polyneuropathy. LGI4-IgG, anti-LGI4 antibody-negative CIDP-IgG, or healthy control (HC)-IgG were applied to Schwann cells, and cell proliferation was assayed using 5-bromo-2'-deoxyuridine labeling. Quantitative real-time PCR was used to assess the expression of Krox20 and Prx, both of which independently control peripheral nerve myelination. LGI4-IgG or HC-IgG was intraneurally injected into mouse sciatic nerves, and the effects were immunohistochemically and morphometrically assessed.

Results: Eight anti-LGI4 antibody-positive (LGI4⁺) patients were identified; dominant tissue-binding IgG subclasses were IgG4 in 4 patients and IgG2 and IgG3 in 2 patients each. Patients had a relatively old onset age (median 72 years, range 41-90 years). Four patients had acute/subacute monophasic courses, and 4 had chronic progressive/relapsing courses. Predominant symptoms/signs were motor weakness (8 cases), muscle atrophy (4), deep and superficial sensory impairment (8 and 7, respectively), Romberg sign (4), and hand/finger tremor (5). CSF showed extremely high protein levels (median 253 mg/dL). Three chronic cases had nerve hypertrophy. IVIg and efgartigimod were partially (7/7 patients) and markedly (1/1 patient) effective, respectively. Notably, 1 chronic patient with predominant tissue-binding LGI4-IgG2 but without LGI4-IgG4 showed a moderate reduction in myelinated fibers with endoneurial edema, numerous onion bulbs, and few inflammatory cell infiltrates in the biopsied sural nerve. Electron microscopy demonstrated onion bulb formations around the axons and subtle detachment of myelin terminal loops from axonal membranes in the paranodes. In Schwann cell culture, proliferation was significantly higher, and Krox20 but not Prx mRNA levels were lower after incubation with LGI4-IgG from chronic (but not acute-onset) cases compared with HC-IgG incubation. With intraneural injection, both LGI4-IgG4 and LGI4-IgG2 deposited mainly at the nodes extending toward the paranodes and caused nodal/paranodal alterations.

Discussion: LGI4⁺ AN manifests as acute/subacute monophasic and chronic progressive/relapsing diseases, sometimes exhibiting nerve hypertrophy with onion bulbs through nonmyelinating Schwann cell proliferation.

Background and objectives: Intrathecal synthesis of immunoglobulin G (IgG) is a key feature of multiple sclerosis (MS) and a prognostic marker for the disease course. Although previous studies identified 2 genetic regions-the major histocompatibility complex (MHC) region on chromosome 6 and the immunoglobulin heavy chain constant (IGHC) locus on chromosome 14-associated with intrathecal IgG synthesis in MS, the genetic underpinnings remain insufficiently understood.

Methods: We conducted a genome-wide association study on intrathecal IgG synthesis using the IgG index to identify individuals with (≥0.7) or without (<0.7) quantitative intrathecal synthesis. We used logistic regression models adjusting for sex, age, and population structure. We performed secondary analyses to examine associations between identified loci and the extent of intrathecal IgG synthesis and the presence and extent of intrathecal immunoglobulin A and M synthesis. We further conducted association analyses for imputed human leukocyte antigen alleles and analyzed whether a higher genetic burden for MS risk-quantified through polygenic risk scores-is associated with intrathecal IgG synthesis.

Results: In the discovery cohort (n = 3,934), we identified a novel genome-wide significant association of the intronic variant rs844586 (p = 1.48 × 10^-8) in the sterile alpha motif domain containing 5 (SAMD5) gene on chromosome 6, with intrathecal IgG synthesis. We could confirm this association in a replication cohort (n = 1,094) and demonstrated that it is independent of a previously described association signal at the MHC region. In a subset (n = 1,413), we further identified rs1407 as a potential causal variant (p = 3.80 × 10^-11, posterior inclusion probability = 0.92) for the previously reported association signal at the IGHC locus with the extent of intrathecal IgG synthesis. In addition, we demonstrated that a higher genetic burden for MS susceptibility, both within and outside of the MHC region, is associated with a higher likelihood of and a more pronounced intrathecal IgG synthesis.

Discussion: Our study revealed a previously unknown association between an intronic variant in SAMD5 with intrathecal IgG synthesis and identified a potential causal variant within the IGHC locus. It further provides evidence for possible effects of known MS risk variants on disease severity through their effect on the intrathecal humoral immune response, a prognostic marker for the disease course.