Neurology® Neuroimmunology & Neuroinflammation最新文献

Background and objectives: Paramagnetic rim lesions (PRLs), visible on susceptibility-based imaging (SbI), reflect chronic active inflammation in multiple sclerosis (MS). In adult-onset MS, PRLs are associated with a more aggressive disease course.The objectives of this study were to assess the prevalence of PRLs in children with MS and to examine how baseline PRL count relates to clinical disability and brain tissue volume loss, both cross-sectionally and over short-term follow-up.

Methods: We retrospectively analyzed pediatric patients from 4 UK tertiary neuroimmunology centers who met the 2017 McDonald diagnostic criteria and had 3D T1-weighted, T2-weighted, fluid-attenuated inversion recovery, and SbI MRI available. PRLs were identified per North American Imaging in MS criteria and anatomically classified. Brain volumes were segmented using Mindglide, with z-scores derived from NIH normative data. Associations between baseline PRL burden, clinical variables, and brain volumes were assessed using univariable and multivariable stepwise regression. Linear mixed-effects models evaluated the predictive value of baseline PRL burden on longitudinal brain volume changes.

Results: Fifty-four patients (mean age 14.0 ± 2.2 years; 75.9% female) were included. At least 1 PRL was seen in 74.1% of patients, with a median number of 2 PRLs (interquartile range [IQR] = 0-6), predominantly in periventricular regions, and accounting for 25% of total T2-weighted hyperintense lesions. In multivariable Poisson regression, at baseline, shorter disease duration (incidence rate ratio [IRR] = 0.987, 95% CI 0.975-0.999, p = 0.035), and greater number (IRR 1.045, 95% CI 1.035-1.054, p < 0.001) and volume (IRR 1.018, 95% CI 1.004-1.032, p = 0.012) of T2-hyperintense lesions were associated with higher PRL count. Cross-sectionally, a higher PRL count was associated with lower cortical (β = -0.139, 95% CI -0.231 to -0.047, p = 0.016) and deep (β = -0.096, 95% CI -0.166 to -0.026, p = 0.032) gray matter volume z-scores. No significant association was observed between clinical disability and PRL count. In 45 patients followed up for a median 17 months (IQR 12-24), a higher baseline PRL count predicted greater deep gray matter volume loss over time (β = -0.020, 95% CI -0.034 to -0.006, p = 0.036).

Discussion: PRLs are common in pediatric MS and are linked to greater lesion burden and gray matter atrophy. These findings suggest that PRLs are promising imaging biomarkers of more severe brain tissue damage although their ability to predict future disability requires confirmation in longer term studies.

Background and objectives: Immune reconstitution therapies for multiple sclerosis (MS) are based on selective lymphocyte reduction, followed by repopulation and rescue of immune tolerance. Among these therapies, cladribine is an adenosine analog that interferes with cell division and depletes several lymphocyte subtypes. Regulatory T cells (Tregs), physiologically devoted to immune suppression, are dysfunctional in the context of MS. In this study, we explored the effects of cladribine on Treg dynamics and phenotype.

Methods: In vivo, deep immunophenotyping was conducted on peripheral blood of patients with MS (n = 11), longitudinally collected before and after 6 and 12 months of cladribine therapy. In vitro, expanded Tregs were treated with cladribine and analyzed for their phenotypic, molecular, and metabolic profiles.

Results: In vivo, Tregs were overall less sensitive than conventional T cells (Tconvs) to the depleting effects of cladribine. This phenomenon was particularly evident in the subset of the resting (rest) Tregs. At baseline, while activated (act) Tregs presented markers of proliferation, senescence, and survival, restTregs highly expressed the antiapoptotic protein Bcl2 and the quiescence marker Bach2. In vitro, cladribine strongly reduced Treg viability while inducing a program of senescence and dysfunction and compromising their metabolic fitness. When Treg dynamics were analyzed ex vivo in relation to neuroinflammation and response to therapy, restTregs exhibited resistance to depletion in nonresponders, in association with increasing expression of Bcl2.

Discussion: These results indicate that the efficacy of cladribine therapy may require reduction and repopulation of the Treg compartment, an event that may be hindered by restTreg resistance, which is supported by antiapoptotic signals.

Background and objectives: In multiple sclerosis (MS), a variety of immunosuppressive treatments are available. While effective, these approaches often lead to sustained impairment of essential components of the immune system, posing long-term safety concerns. Consequently, there is a growing interest in alternative therapeutic approaches that selectively limit pathogenic B-cell functions while preserving their physiologic roles. In this study, we investigated the therapeutic potential of inhibiting the enzyme Bruton tyrosine kinase (BTK), a key signaling molecule in both B-cell and myeloid cell activation.

Methods: The effects of the BTK inhibitor evobrutinib were evaluated in various experimental in vivo models of CNS demyelination, each representing different aspects of disease pathology as well as a naïve healthy condition. The impact on disease onset and severity was determined, and phenotypical alterations in different cell populations were assessed via flow cytometry. Furthermore, functional changes in both murine and human myeloid cells induced by BTK inhibition under specific Fc receptor-dependent stimulation were analyzed in in vitro settings using flow cytometry.

Results: In a naïve, healthy environment, evobrutinib promoted the development of regulatory B-cell properties. In various experimental models of CNS demyelination, BTK inhibition limited the differentiation of proinflammatory B cells while supporting their regulatory properties. Beyond modulating B-cell responses, BTK inhibition also attenuated the activation of myeloid cells after Fc receptor-mediated antigen uptake, a process assumed to be of importance in conditions, such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-antibody associated disease. In addition, BTK inhibition was shown to suppress the secretion of proinflammatory cytokines and reduce antigen presentation, further dampening pathogenic immune responses.

Discussion: These findings highlight the potential of BTK inhibition as a selective and sustainable immunomodulatory strategy for both B cells and myeloid cells in the context of chronic CNS inflammation. Despite their efficacy, broad-spectrum immunosuppressive therapies often fail to provide targeted immune modulation. By contrast, BTK inhibition promotes regulatory B-cell properties while leaving other B-cell functions intact, providing the basis for its broad use-potentially in combination with established anti-inflammatory agents.

Background and objectives: Spinal cord leptomeningeal enhancement (LME) can be observed in children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and with seronegative myelitis. We investigated whether the presence of spinal cord LME in MOGAD and seronegative myelitis is associated with distinct clinical, CSF, and MRI findings.

Methods: Study participants were identified among the 490 children and adolescents recruited to the Canadian Pediatric Demyelinating Disease study following an incident attack of CNS demyelination. Inclusion criteria for this study were: (1) evidence of spinal cord lesions on MRI, (2) available postgadolinium MRI sequences, and (3) available MOG and aquaporin-4 (AQP4) antibody results. None of the AQP4 antibody-positive participants met our inclusion criteria and only 1 participant with multiple sclerosis exhibited LME. We therefore focused the study on children with MOGAD and seronegative myelitis and compared the clinical, CSF, and MRI features between participants with and without LME.

Results: Our cohort included 33 participants with MOGAD (median age 5.9 years, 55% women) and 45 with seronegative myelitis (median age 11.9 years, 33% women). Spinal cord LME was detected in 20/33 (61%) participants with MOGAD and 14/45 (31%) with seronegative myelitis. Among children with MOGAD, those with LME were more likely than those without LME to have longitudinally extensive myelitis ([LETM], 19/20 vs 8/13, p = 0.024); H-sign (15/20 vs 5/13, p = 0.036), tumefactive cord lesions (10/20 vs 1/13, p = 0.021); complete cross-sectional involvement (16/20 vs 5/13, p = 0.026); nodular lesional enhancement (7/20 vs 0/13, p = 0.026); and more spinal cord lesions (p = 0.036). LME in MOGAD was not associated with greater CSF protein content or cell count nor predicted relapse rate or clinical recovery. Children with seronegative myelitis and LME were more likely than those without LME to have tumefactive lesions (6/14 vs 4/31, p = 0.048) and complete cross-section involvement (11/14 vs 13/31, p = 0.028) but did not differ in terms of H-sign, LETM, lesional enhancement, or number of lesions.

Discussion: The presence of spinal cord LME is associated with more extensive spinal cord abnormalities on MRI in children with MOGAD and to a lesser extent in those with seronegative myelitis. The biological underpinnings of this finding and its clinical implications should be assessed in further studies.

Objectives: Optical coherence tomography angiography (OCTA) is widely used for evaluating retinal vessels. The aim of this study was to assess the influence of OCTA quality, as measured by the previously introduced OSCAR-MP criteria, on OCTA outcome parameters and the reliability of test-retest results.

Methods: In this prospective longitudinal cohort study, we performed retinal OCTA at baseline and within 24 hours in 54 participants, including 42 healthy individuals and 12 patients with demyelinating CNS disease. We performed reliability testing on OCTA outcome parameters based on QC status according to the OSCAR-MP criteria.

Results: Retinal vessel density measurements remained consistent between baseline and follow-up scans when both passed quality control. By contrast, vessel densities were significantly higher in high-quality images than in paired lower quality ones. Reliability measures, such as intraclass correlation coefficient (ICC) and Pearson r, were higher in pairs where both images met quality standards, with a lower coefficient of repeatability and minimal detectable change observed.

Discussion: Poor OCTA image quality negatively affects retinal vessel density measurements. Implementing OSCAR-MP quality criteria demonstrated strong test-retest reliability in high-quality OCTA images, indicating its potential role as reliable quality criteria for OCTA in future clinical trials and research settings.

Background and objectives: Serum myelin oligodendrocyte glycoprotein (MOG) antibodies are a hallmark of the newly defined neuroinflammatory disease entity MOG antibody-associated disease (MOGAD). Yet, the lack of patient-derived recombinant human MOG (hMOG)-reactive autoantibodies limits investigations into the molecular mechanisms by which these autoantibodies mediate CNS pathology, thereby hindering rational therapeutic approaches. To understand the origins and disease-relevant mechanisms of autoantibodies in MOGAD, we generated and characterized monoclonal anti-hMOG antibodies (MOG-mAbs) from circulating B cells of patients with MOGAD.

Methods: We isolated MOG-specific B-cell receptor (BCR) sequences from unique circulating B-cell clones of 6 patients with MOGAD using an antigen selection approach. BCR sequences were expressed as immunoglobulin (Ig)G1 antibodies, and their molecular features, epitope specificity, and binding to MOG isoforms were investigated. The MOG-mAbs' ability to mediate antibody-dependent cellular phagocytosis (ADCP), natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) toward MOG-expressing cells was assessed by live cell-based assays.

Results: Of the 15 MOG-mAbs generated, 4 revealed evidence of affinity maturation, whereas the remaining 11 were germline encoded. Binding capacities to hMOG varied considerably, with the most frequent putative epitope mapping to a region that includes residue P42. The efficacy of these antibodies in mediating ADCP, ADCC, and CDC of MOG-expressing cells was heterogeneous and associated with their binding characteristics to MOG and its isoforms.

Discussion: Taken together, the molecular characteristics and binding patterns of these patient-derived MOG-mAbs reveal a diverse repertoire of MOG-binding autoantibodies with pathogenic capacity in vitro. Consequently, these well-characterized patient autoantibodies offer a foundation for developing in vivo models of MOGAD, serve as tools to standardize diagnostic assays, and guide development of therapeutic strategies targeting either B cells or autoantibodies and their effector functions.

Background and objectives: Aquaporin (AQP)-4 (AQP4)-seropositive neuromyelitis optica (NMO) frequently coexists with rheumatologic autoimmune conditions, including Sjögren syndrome and systemic lupus erythematosus, 2 conditions that share a common HLA-DRB1 (HLA-DRB1*03:01) association with NMO. AQP4 is a member of a family of ubiquitously expressed water channels. Its immunodominant pathogenic T-cell epitope, which binds MHC II with exceptionally high affinity, is homologous to sequences in other AQPs, including AQP5, a candidate target autoantigen in Sjögren syndrome. Thus, we hypothesized that self-antigen molecular mimicry exists between AQPs and contributes to autoimmunity.

Methods: Previously, we examined binding of AQP4 T-cell epitopes to MHC II (I-A^b) by biochemical assays; we now evaluate interaction of I-A^b and AQPs by molecular modeling. T cells from mice immunized with the immunodominant AQP4 epitope or its homologous AQP5 sequence were examined for proliferation and cross-recognition between AQPs. T-cell receptor (TCR) engagement of individual T cells with AQP-MHC II complexes was examined using AQP4 and AQP5 peptide/MHC II tetramers. The pathogenic potential of AQP4-primed and AQP5-primed T cells was examined by T-cell adoptive transfer into naïve mice.

Results: The immunodominant AQP4 T-cell epitope was predicted to make optimal contacts within the pockets of the MHC II antigen-binding cleft. Like AQP4, the corresponding homologous AQP5 amino acid sequence was predicted to bind MHC II, albeit with modest affinity. In a reciprocal manner, T cells were detected that proliferated to both AQP4 and AQP5. Multi-tetramer analysis of individual T cells demonstrated that the same TCR could engage both AQP4 and AQP5. T cells from mice immunized with AQP4 or AQP5 caused paralysis and CNS inflammation in recipient mice, but not in AQP4-deficient mice, demonstrating that AQP4 expression is obligately required in this model of aquaporin CNS autoimmunity.

Discussion: T cells can express TCRs that recognize multiple AQPs. Autoimmunity can be initiated through molecular mimicry between distinct self-antigens such as AQP4 and AQP5 that are expressed in separate organs. These findings suggest that T-cell self-antigen mimicry may contribute to coexistence of NMO with other autoimmune conditions, such as Sjögren syndrome.