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Frontiers in Immunology 2024The primary treatment for acute relapses in multiple sclerosis (MS) is the intravenous administration of high-dose methylprednisolone (IVMP). However, the mechanisms...
BACKGROUND
The primary treatment for acute relapses in multiple sclerosis (MS) is the intravenous administration of high-dose methylprednisolone (IVMP). However, the mechanisms through which corticosteroid treatment impacts acute neuroinflammation in people with MS (pwMS) remain not fully understood. In particular, the changes induced by glucocorticoids (GCs) on cells of the innate immune system and the differences between patients with distinct immunotherapies have received little attention to date.
METHODS
We conducted immunophenotyping using flow cytometry on peripheral blood mononuclear cells of pwMS who received IVMP treatment during a relapse. We compared the impact of an IVMP treatment on a broad variety of immune cell subsets within three groups: twelve patients who were treatment-naïve to disease modifying therapies (wDMT) to ten patients on platform therapies (PT) and eighteen patients on fingolimod therapy (FTY).
RESULTS
We observed pronounced interindividual short- and intermediate-term effects of IVMP on distinct immune cells subsets. In addition to the well-documented decrease in T-helper cells (Th cells), we detected significant alterations after the first IVMP infusion within the innate immune response among neutrophil, eosinophil and basophil granulocytes, monocytes and plasmacytoid dendritic cells (pDCs). When comparing patients wDMT to the PT and FTY cohorts, we found that IVMP had a similar impact on innate immune cells across all treatment groups. However, we did not observe a significant further decline in T lymphocyte counts during IVMP in patients with pre-existing lymphopenia under FTY treatment. Although T cell apoptosis is considered the main mechanism of action of GCs, patients with FTY still reported symptom improvement following IVMP treatment.
CONCLUSION
In addition to T cell suppression, our data suggests that further immunoregulatory mechanisms of GC, particularly on cells of the innate immune response, are of greater significance than previously understood. Due to the regulation of the adaptive immune cells by DMTs, the impact of GC on these cells varies depending on the underlying DMT. Additional studies involving larger cohorts and cerebrospinal fluid samples are necessary to gain a deeper understanding of the immune response to GC in pwMS with different DMTs during relapse to define and explain differences in clinical response profiles.
Topics: Humans; Female; Male; Adult; Middle Aged; Multiple Sclerosis; Fingolimod Hydrochloride; Immunity, Innate; Methylprednisolone; Immunophenotyping; Leukocytes, Mononuclear; Adrenal Cortex Hormones; Immunosuppressive Agents; Glucocorticoids
PubMed: 38938576
DOI: 10.3389/fimmu.2024.1404316 -
Brain : a Journal of Neurology Jun 2024Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically...
Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically ∼80-95%, of which at least 60% is due to the PMP22 gene duplication. The remainder of CMT1 is more genetically heterogeneous. We used whole exome and whole genome sequencing data included in the GENESIS database to investigate novel causal genes and mutations in a cohort of ∼2,670 individuals with CMT neuropathy. A recurrent heterozygous missense variant p.Thr1424Met in the recently described CMT gene ITPR3, encoding IP3R3 (inositol 1,4,5-trisphosphate receptor 3) was identified. This previously reported p.Thr1424Met change was present in 33 affected individuals from nine unrelated families from multiple populations, representing an unusual recurrence rate at a mutational hotspot, strengthening the gene-disease relationship (GnomADv4 allele frequency 1.76e-6). Sanger sequencing confirmed the co-segregation of the CMT phenotype with the presence of the mutation in autosomal dominant and de novo inheritance patterns, including a four-generation family with multiple affected second-degree cousins. Probands from all families presented with slow nerve conduction velocities, matching the diagnostic category of CMT1. Remarkably, we observed a uniquely variable clinical phenotype for age at onset and phenotype severity in p.Thr1424Met carrying patients, even within families. Finally, we present data supportive of a dominant-negative effect of the p.Thr1424Met mutation with associated changes in protein expression in patient-derived cells.
PubMed: 38938188
DOI: 10.1093/brain/awae206 -
Molecular Therapy : the Journal of the... Jun 2024Galactosyl-ceramidase (GALC) is a ubiquitous lysosomal enzyme crucial for the correct myelination of the mammalian nervous system during early postnatal development....
Deficiency of galactosylceramidase in adult oligodendrocytes worsens the neurological deficits and shortens the survival during chronic experimental allergic encephalomyelitis.
Galactosyl-ceramidase (GALC) is a ubiquitous lysosomal enzyme crucial for the correct myelination of the mammalian nervous system during early postnatal development. However, the physiological consequence of GALC deficiency in the adult brain remains unknown. In this study, we found that mice with conditional ablation of GALC activity in post-myelinating oligodendrocytes were lethally sensitized when challenged with chronic experimental allergic encephalomyelitis (EAE), in contrast to the non-lethal dysmyelination observed in GALC-ablated mice without the EAE challenge. Mechanistically, we found a strong inflammatory demyelination without remyelination and an impaired fusion of lysosomes and autophagosomes with accumulation of myelin debris following a TFEB-dependent increase in the lysosomal autophagosome flux. These results indicate that the physiological impact of GALC deficiency is highly influenced by the cell context (oligodendroglial vs global expression), the presence of inflammation, and the developmental time when it happens (pre-myelination vs post-myelination). We conclude that GALC expression in adult oligodendrocytes is crucial for the maintenance of adult central myelin and to reduce vulnerability to additional demyelinating insults.
PubMed: 38937968
DOI: 10.1016/j.ymthe.2024.06.035 -
Neurological Sciences : Official... Jun 2024Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) presents significant treatment challenges due to its chronic nature, varied clinical presentations, and rarity.... (Review)
Review
BACKGROUND
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) presents significant treatment challenges due to its chronic nature, varied clinical presentations, and rarity. Subcutaneous immunoglobulin (SCIG) has emerged as a maintenance therapy, offering potential advantages in administration and patient experience over the previously recognized intravenous immunoglobulin (IVIG).
METHODS
We included all clinical studies involving CIDP patients treated with SCIG from eleven databases up to March 2024.
RESULTS
50 clinical studies were included in the systematic review, with 22 involved in the meta-analysis. These studies offer clinical data on around 1400 CIDP patients. Almost all studies considered SCIG a maintenance therapy, with the majority of results suggesting it as a viable substitute that may offer comparable or enhanced advantages. Studies covered aspects such as efficacy, safety, quality of life, practicality, economic evaluation, and patient preference. Meta-analysis showed SCIG significantly improved muscle strength and sensory function, had fewer and milder side effects, reduced relapse rates, and received a strong preference.
CONCLUSIONS
Findings suggest that SCIG for CIDP maintenance not only provides a more feasible alternative, with economic evaluations showing considerable cost reductions over time, and patient preference for SCIG being pronounced, but may also deliver comparable or superior health outcomes. Ongoing research lines on formulations, techniques, and direct comparative studies are critical to further illuminate, enhance, and expand SCIG's role in treatment.
PubMed: 38937399
DOI: 10.1007/s10072-024-07640-3 -
Cell Reports Jun 2024Oligodendrocyte death is common in aging and neurodegenerative disease. In these conditions, dying oligodendrocytes must be efficiently removed to allow remyelination...
Oligodendrocyte death is common in aging and neurodegenerative disease. In these conditions, dying oligodendrocytes must be efficiently removed to allow remyelination and to prevent a feedforward degenerative cascade. Removal of this cellular debris is thought to primarily be carried out by resident microglia. To investigate the cellular dynamics underlying how microglia do this, we use a single-cell cortical demyelination model combined with longitudinal intravital imaging of dual-labeled transgenic mice. Following phagocytosis, single microglia clear the targeted oligodendrocyte and its myelin sheaths in one day via a precise, rapid, and stereotyped sequence. Deletion of the fractalkine receptor, CX3CR1, delays the microglial phagocytosis of the cell soma but has no effect on clearance of myelin sheaths. Unexpectedly, deletion of the phosphatidylserine receptor, MERTK, has no effect on oligodendrocyte or myelin sheath clearance. Thus, separate molecular signals are used to detect, engage, and clear distinct sub-compartments of dying oligodendrocytes to maintain tissue homeostasis.
PubMed: 38935500
DOI: 10.1016/j.celrep.2024.114385 -
Neuroreport Jun 2024Recent studies have shown that autophagy is activated in response to nerve damage and occurs simultaneously with the initial stages of Schwann cell-mediated...
Recent studies have shown that autophagy is activated in response to nerve damage and occurs simultaneously with the initial stages of Schwann cell-mediated demyelination. Although several studies have reported that macroautophagy is involved in the peripheral nerve, the role of chaperone-mediated autophagy (CMA) has not yet been investigated in peripheral nerve injury. The present study investigates the role of CMA in the sciatic nerve. Using a mouse model of sciatic nerve injury, the authors employed immunofluorescence analysis to observe the expression of LAMP2A, a critical marker for CMA. RNA sequencing was performed to observe the transcriptional profile of Lamp2a in Schwann cells. Bioinformatics analysis was carried out to observe the hub genes associated with Lamp2a. Expression of Lamp2a, a key gene in CMA, increased following sciatic nerve injury, based on an immunofluorescence assay. To identify differentially expressed genes using Lamp2a, RNA sequence analysis was conducted using rat Schwann cells overexpressing Lamp2a. The nine hub genes (Snrpf, Polr1d, Snip1, Aqr, Polr2h, Ssbp1, Mterf3, Adcy6, and Sbds) were identified using the CytoHubba plugin of Cytoscape. Functional analysis revealed that Lamp2a overexpression affected the transcription levels of genes associated with mitotic spindle organization and mRNA splicing via the spliceosome. In addition, Polr1d and Snrpf1 were downregulated throughout postnatal development but elevated following sciatic nerve injury, according to a bioinformatics study. CMA may be an integral pathway in sciatic nerve injury via mRNA splicing.
PubMed: 38935077
DOI: 10.1097/WNR.0000000000002066 -
Revista de Neurologia Jul 2024The XVI Post-ECTRIMS meeting took place in Seville on 20 and 21 October 2023. This meeting was attended by neurologists specialising in multiple sclerosis (MS) from... (Review)
Review
The XVI Post-ECTRIMS meeting took place in Seville on 20 and 21 October 2023. This meeting was attended by neurologists specialising in multiple sclerosis (MS) from Spain, who shared a summary of the most interesting innovations at the ECTRIMS congress, which had taken place in Milan the previous week. The aim of this article is to summarise new developments related to the pathogenesis, diagnosis and prognosis of MS. The contributions of innate immunity and central nervous system resident cells, including macrophages and microglia in MS pathophysiology and as therapeutic targets were discussed. Compartmentalised intrathecal inflammation was recognised as central to understanding the progression of MS, and the relationship between inflammatory infiltrates and disease progression was highlighted. Perspectives in demyelinating pathologies were reviewed, focusing on neuromyelitis optica and myelin oligodendrocyte glycoprotein antibody-associated disease, highlighting their pathophysiological and diagnostic differences compared to MS. Advances in neuroimaging were also discussed, and especially the analysis of active chronic lesions, such as paramagnetic rim lesions. In the absence of clinical improvements in trials of remyelinating treatments, methodological strategies to optimise the design of future studies were proposed. Breakthroughs in detecting the prodromal phase of MS, the use of biomarkers in body fluids to assess activity, progression and treatment response, and research on progression independent of flares were addressed. The need to define criteria for radiologically isolated syndrome and to clarify the concept was also discussed.
Topics: Humans; Multiple Sclerosis; Congresses as Topic
PubMed: 38934946
DOI: 10.33588/rn.7901.2024170 -
Frontiers in Immunology 2024B cell depleting anti-CD20 monoclonal antibodies (aCD20 mAbs) are highly effective in treatment of multiple sclerosis (MS) but fail to halt the formation of meningeal...
Single-cell profiling indicates a high similarity between immune cells in the cerebrospinal fluid and in meningeal ectopic lymphoid tissue in experimental autoimmune encephalomyelitis.
BACKGROUND AND OBJECTIVES
B cell depleting anti-CD20 monoclonal antibodies (aCD20 mAbs) are highly effective in treatment of multiple sclerosis (MS) but fail to halt the formation of meningeal ectopic lymphoid tissue (mELT) in the murine model experimental autoimmune encephalomyelitis (EAE). While mELT can be examined in EAE, it is not accessible in MS patients. Our key objectives were to compare the immune cells in cerebrospinal fluid (CSF), which is accessible in patients, with those in mELT, and to study the effects of aCD20 mAbs on CSF and mELT in EAE.
METHODS
Applying single cell RNA sequencing, we compared gene expression profiles in immune cells from (1) CSF with mELT and (2) aCD20 mAbs treated with control treated mice in a spontaneous 2D2xTh EAE model.
RESULTS
The immune cell composition in CSF and mELT was very similar. Gene expression profiles and pathway enrichment analysis revealed no striking differences between the two compartments. aCD20 mAbs led not only to a virtually complete depletion of B cells in the CSF but also to a reduction of naïve CD4+ T cells and marked increase of macrophages. No remarkable differences in regulated genes or pathways were observed.
DISCUSSION
Our results suggest that immune cells in the CSF may serve as a surrogate for mELT in EAE. Future studies are required to confirm this in MS patients. The observed increase of macrophages in B cell depleted CSF is a novel finding and requires verification in CSF of aCD20 mAbs treated MS patients. Due to unresolved technical challenges, we were unable to study the effects of aCD20 mAbs on mELT. This should be addressed in future studies.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Mice; Single-Cell Analysis; Meninges; B-Lymphocytes; Female; Tertiary Lymphoid Structures; Mice, Inbred C57BL; Antibodies, Monoclonal; Transcriptome; Gene Expression Profiling; Antigens, CD20; Cerebrospinal Fluid; Disease Models, Animal; Multiple Sclerosis
PubMed: 38933267
DOI: 10.3389/fimmu.2024.1400641 -
Vaccines May 2024Following mass vaccinations for the control of the COVID-19 epidemic, a spectrum of cardiac and neurological disorders was reported among vaccinated individuals. This... (Review)
Review
Following mass vaccinations for the control of the COVID-19 epidemic, a spectrum of cardiac and neurological disorders was reported among vaccinated individuals. This study examined the range of complications documented and factors related to their occurrence. Three electronic databases were searched for case reports and case series with descriptions of cardiac and/or neurological complications in COVID-19 vaccine recipients. A total of 698 vaccinees were included in this review, of which 259 (37.1%) had cardiac and 439 (62.9%) had neurological complications. Inflammatory conditions were the commonest among the cardiac complications; while polyneuropathy, demyelinating diseases and cerebrovascular disorders were the more common neurological complications. The mean age of those with cardiac complications (33.8 years) was much younger than those with neurological complications (49.7 years). There was no notable difference in the gender distribution between these two groups of vaccine recipients. mRNA vaccines (all brands) were associated with almost 90.0% of the cardiac complications, whereas viral vector vaccines were associated with slightly over half (52.6%) of the neurological complications. With regard to the dose, cardiac complications were more common after the second (69.1%), whereas neurological complications were more common after the first dose (63.6%). The majority of the cases had an uncomplicated clinical course. Nevertheless, 5.9% of cases with neurological complications and 2.5% of those with cardiac complications were fatal, underscoring the significance of the consistent surveillance and vigilant monitoring of vaccinated individuals to mitigate these occurrences.
PubMed: 38932303
DOI: 10.3390/vaccines12060575 -
Journal of Clinical Medicine Jun 2024: Myelin oligodendrocyte glycoprotein (MOG) is exclusively expressed in the central nervous system (CNS) and is found on the outer surface of oligodendrocytes.... (Review)
Review
: Myelin oligodendrocyte glycoprotein (MOG) is exclusively expressed in the central nervous system (CNS) and is found on the outer surface of oligodendrocytes. Antibodies to MOG are associated with CNS demyelination, whereas peripheral nervous system (PNS) demyelination is seldom reported to be related to MOG-IgG. : The database of patients seen in our neurological academic center was searched for MOG-IgG seropositivity and concomitant demyelinating polyneuropathy. For the purpose of the review, in March 2024, we searched for case reports and case series in the following databases: PubMed, Scopus, Cochrane, and ScienceDirect. Inclusion criteria were MOG-IgG seropositivity and demyelinating polyneuropathy. Exclusion criteria were type of publication other than case reports and case series, unconfirmed diagnosis of demyelinating polyneuropathy, and other diseases causing demyelination in either the CNS or PNS. Critical appraisal of the selected case reports and case series was realized by JBI. : Four new cases were identified with MOG-IgG and confirmed demyelinating polyneuropathy. This review identified 22 cases that have been published since 2018. Clinical, imaging, neurophysiological, and immunological characteristics, as well as treatment options and outcomes are presented and compared to those of other cases with combined central and peripheral demyelination (CCPD). : The pathogenetic mechanism is unclear; thus, different hypotheses are discussed. New case reporting and large cohort studies will help further the exploration of the underlying mechanism and guide more effective therapeutic interventions.
PubMed: 38930142
DOI: 10.3390/jcm13123604