Background and Aims:
The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, ...the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs.
Methods:
We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated.
Results:
Protective humoral immunity of 97.9%, 100%, 100%, 22.7%, and 3.8%, was observed in COVID-19 vaccinated healthy subjects (N = 47), untreated MS patients (N = 32), and MS patients treated with cladribine (N = 23), ocrelizumab (N = 44), and fingolimod (N = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5–55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination.
Conclusions:
Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.
Pediatric onset multiple sclerosis patients (POMS) are defined as multiple sclerosis with an onset before the age of 18 years. Compared to adult onset multiple sclerosis (AOMS), POMS has more severe ...disease activity at onset, but better recovery. Little is known about the molecular mechanism responsible for the differences in the clinical presentations.
Peripheral Blood Mononuclear Cells samples were taken from 22 POMS patients (mean age 14.1 ± 2.4 years, 15 females, 7 male), and 16 AOMS patients, (mean age 30.8 ± 6.1 years,10 females, 6 males), and gene-expression were analyzed using Affymetrix Inc. HU-133-A2 microarrays. Differentially Expressed Genes (DEGs) that significantly distinguished between POMS and AOMS with pvalue <0.05 after false discovery rate correction were evaluated using Partek software. Twenty-one matched age and gender control was applied to clarify age-related changes. Clinical assessment was performed by analysis of expanded disability status scale (EDSS) and brain MRI lesion loads. Gene functional analysis was performed by Ingenuity Pathway Analysis software.
Compared to AOMS, POMS had higher EDSS (3.0 IQR 2.0–3.0 and 2.0 IQR 2.0–3.0, p = 0.005), volume of T1 (2.72 mm3, IQR 0.44–8.39 mm3 and 0.5 mm3 IQR 0–1.29 mm3 respectively, p = 0.04) and T2 (3.70 mm3, IQR 1.3–9.6 and 0.96 mm3, IQR 0.24–4.63 respectively, p = 0.02) brain MRI lesions. The POMS transcriptional profile was characterized by 551 DEGs, enriched by cell cycling, B lymphocyte signaling and senescent pathways (p < 0.02). Of these, 183 DEGs significantly correlated with T2 lesions volume. The POMS MRI correlated DEGs (n = 183) and their upstream regulators (n = 718) has overlapped with age related DEGs obtained from healthy subjects (n = 497). This evaluated common DEGs (n = 29) defined as POMS age-related regulators, suggesting to promote effect on disease severity.
Our finding of higher transcriptional levels of genes involved in cell cycle, cell migration and B cell proliferation that promoted by transcriptional level of age-associated genes and transcription factors allows better understanding of the more aggressive clinical course that defines the POMS.
•Pediatric onset multiple sclerosis (POMS) has more severe course than adults.•POMS has more active inflammatory blood transcription profile than adult patients.•POMS disease activity is promoted by age-related blood transcriptional mechanism.
Although the causes of multiple sclerosis are largely unknown, genetic and environmental components play an important role. Geographic distribution, varying with latitude, reflects both genetic and ...environmental influences. We conducted a retrospective exploratory observational study to characterize the disability progression of 2396 Jewish patients with relapsing-remitting multiple sclerosis, followed at the Sheba Multiple Sclerosis Center, Tel-Aviv, Israel; 188 patients who originated in Iraq and 2207 patients who originated in northern Europe. Peripheral blood microarray gene expression analysis was performed in a subgroup of patients to identify molecular pathways associated with faster disability progression. During a follow-up period of 18.8 and 19.8 years, respectively, 51.6% of patients with an Iraqi origin progressed to moderate disability defined as expanded disability status scale (EDSS) score of 3.0 to 5.5, compared to 44.2% of patients with a northern European origin (odds ratio 1.347, 95% CI 1.0-1.815, p = 0.049). An Iraqi origin was associated with increased risk of progression to moderate disability adjusted for sex, disease duration, age at onset, and treatment with immunomodulatory drugs (hazard ratio 1.323; 95% CI, 1.049-1.668, p = 0.02), but not to severe disability defined as EDSS score > = 6.0 (i.e., walking aids are required for a distance of 100 meters, (hazard ratio 1.311; 95% CI, 0.918-1.874, p = 0.136). Gene expression analysis disclosed 98 differentially expressed genes (79 over-expressed and 19 under-expressed) between relapsing-remitting multiple sclerosis patients of Iraqi origin (N = 17) and northern European (N = 34) origin. Interestingly, this gene expression was enriched with genes related to neuronal pathways associated with morphology of axons, branching of neurites, proliferation of neocortical neurons, and formation of myelin sheath, suggesting an augmented process of neurodegeneration in relapsing-remitting multiple sclerosis patients with an Iraqi origin. The study results suggest that relapsing-remitting multiple sclerosis patients with an Iraqi origin progress faster to disability possibly due to an enhanced process of neurodegeneration.
•COVID-19 convalescents displayed an adaptive immune response for up to 7 months.•The T cell response is characterized by IFN-γ-, IL2-, and IFN-γ+IL2-secreting memory T cells.•Waning anti-SARS-CoV-2 ...IgG is associated with robust memory B cell and memory T cell responses.•The SNMO peptide pools elicited the strongest memory T cell response.
Antiviral adaptive immunity involves memory B cells (MBC) and memory T cells (MTC). The dynamics of MBC and MTC in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescents warrant further investigation.
In this cross-sectional and longitudinal study, blood-derived MBC and MTC responses were evaluated in 68 anti-spike IgG-positive mild coronavirus disease 2019 (COVID-19) convalescents at visit 1, between 1 and 7 months (median 4.1 months) after disease onset. SARS-CoV-2 anti-spike IgG was determined by ELISA, MBC by SARS-CoV-2-specific receptor binding domain (RBD) ELISpot, and interferon gamma (IFN-γ)-, interleukin 2 (IL2)-, and IFN-γ+IL2-secreting MTC by IFN-γ and IL2 SARS-CoV-2 FluoroSpot. For 24 patients sampled at the first visit, the IgG, MBC, and MTC analyses were also performed 3 months later at the second visit.
Seventy-two percent of convalescents were both MBC- and MTC-positive, 18% were MBC-positive and MTC-negative, and 10% were MTC-positive and MBC-negative. The peak MBC response level was detected at 3 months after COVID-19 onset and persisted up to 7 months post infection. Significant MTC levels were detected 1 month after onset in response to S1, S2_N, and SNMO peptide pools. The frequency and magnitude of the MTC response to SNMO was higher than those to S1 and S2_N. Longitudinal analysis demonstrated that even when specific humoral immunity declined, the cellular immunity persisted.
The study findings demonstrate the durability of adaptive cellular immunity at least for 7 months after SARS-CoV-2 infection, suggesting long-lasting protection.
In this study, we introduce an artificial intelligent method for addressing the batch effect of a transcriptome data. The method has several clear advantages in comparison with the alternative ...methods presently in use. Batch effect refers to the discrepancy in gene expression data series, measured under different conditions. While the data from the same batch (measurements performed under the same conditions) are compatible, combining various batches into 1 data set is problematic because of incompatible measurements. Therefore, it is necessary to perform correction of the combined data (normalization), before performing biological analysis. There are numerous methods attempting to correct data set for batch effect. These methods rely on various assumptions regarding the distribution of the measurements. Forcing the data elements into pre-supposed distribution can severely distort biological signals, thus leading to incorrect results and conclusions. As the discrepancy between the assumptions regarding the data distribution and the actual distribution is wider, the biases introduced by such “correction methods” are greater. We introduce a heuristic method to reduce batch effect. The method does not rely on any assumptions regarding the distribution and the behavior of data elements. Hence, it does not introduce any new biases in the process of correcting the batch effect. It strictly maintains the integrity of measurements within the original batches.
Abstract Multiple sclerosis (MS) is characterized in most patients by a relapsing-remitting disease course. However, the trigger of relapse and the transformation that switches relapse into remission ...are not clearly understood. To evaluate the key molecular pathways operating in MS relapse and remission we performed peripheral blood gene-expression profiling in 123 MS patients either in relapse (n = 34) or remission (n = 89) and in comparison with 41 matched healthy subjects using Affymetrix microarray technology. Our findings suggest that the relapsing-remitting pattern of MS is an ongoing process where inflammation is persistently active in the background of a changing magnitude of processes associated with TBX21-mediated immune suppression and activation of BDNF-related neuroprotection.
Abstract
Background
Targeting RNA polymerase-1 (POL1) machinery is a new strategy for suppression of multiple sclerosis (MS) relapse activity. Oral administration of POL1 inhibitor RAM-589.555, which ...is characterized by high permeability and bioavailability in naïve mice, ameliorates proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) by suppressing activated autoreactive lymphocytes. We assessed the accessibility of RAM-589.555 to the central nervous system (CNS) of EAE-mice and further investigated its immunomodulatory effects on CNS-resident astro- and micro-glial cells in-vitro and in-vivo.
Methods
Effects of RAM-589.555 on activated microglia and astrocyte viability, proliferation, and secretion of neurotrophic factors were assessed in-vitro. The pharmacokinetic of RAM-589.555 was evaluated in the blood and central nervous system (CNS) of EAE-affected mice. High-dimensional single-cell mass cytometry was applied to characterize the effect of RAM-589.555 on EAE-affected mice’s CNS-resident micro- and astroglial cells and CNS-infiltrating immune cells, which were obtained seven days after RAM-589.555 administration at EAE onset. Simultaneously, the expression level of pre-rRNA, the POL1 end product, was assessed in blood cells, microglia, and astrocytes to monitor RAM-589.555 effects.
Results
RAM-589.555 demonstrated blood and CNS permeability in EAE mice. In-vitro, incubation with 400 nM of RAM-589.555 significantly reduced viability and proliferation of lipopolysaccharide (LPS)-activated microglia by 70% and 45% (
p
< 0.05), respectively, while tumor necrosis factor α (TNFα)-activated astrocytes were not affected. The secretion of neurotrophic factors was preserved. Furthermore, 7 days after administration of RAM-589.555 at EAE onset, the level of pre-rRNA transcript in peripheral blood mononuclear cells (PBMC) was decreased by 38.6% (
p
= 0.02), while levels of pre-rRNA transcript in microglia and astrocytes remained unchanged. The high-dimensional single-cell mass cytometry analysis showed decreased percentages of CNS-resident microglia and astrocytes, diminished pro-inflammatory cytokines (IL-1β, IL-6, IL-12, IL-17, TNFα, and IFNγ), and an increase of their anti-inflammatory cytokines (IL-4, IL-10, and TGFβ) in RAM-589.555-treated compared to vehicle-treated mice (
p
< 0.05).
Conclusions
These data correlate RAM-589.555-induced clinical amelioration and its CNS-permeability to decreased CNS-inflammation, and decreased micro- and astrogliosis, while restoring micro- and astroglial anti-inflammatory and neuroprotective capacity.
Background: Eccentric muscle contractions elicit distinct physiological responses, including modulation of the cytokine profile. Although relevant for rehabilitation, the effect of eccentric muscle ...training on the immune system has never been investigated in multiple sclerosis (MS). Objectives: Examine the immediate cytokine response of interleukin-4 (IL-4), IL-6, IL-10, IL-17a, interferon-gamma, and tumor necrosis factor-alpha after a moderate eccentric training session in individuals with MS. Additionally, further investigate the association between systemic cytokine levels at rest and clinical measures of mobility and lower limb functional strength. Design: Observational study. Methods: The first session included blood sampling for baseline cytokine measures. Subsequently, the participant completed a battery of clinical assessments related to mobility and lower limb strength, that is, the Timed-Up-and-Go Test, Five-Repetition-Sit-to-Stand-Test (5STS), Four-Square-Step-Test, and Two-Minute-Walk-Test. The second session included the eccentric exercise training session, followed by a second blood sampling to assess the acute cytokine response to the eccentric training bout. This session comprised 10 exercises concentrating on the strength of the trunk and lower extremities. Results: Twenty-seven people with MS (pwMS), with a mean age of 40.1 years, participated in the study. No difference was demonstrated in the cytokine concentration values between baseline and immediately after the eccentric training session. The 5STS explained 30.3% of the variance associated with interferon-gamma, 14.8% with IL-4, and 13.8% with IL-10. Conclusion: An eccentric training bout does not impact cytokine concentration in the blood and, consequently, does not boost a pro-inflammatory response, thus, it can be performed on pwMS in a rehabilitation setting.
Plain language summary A strength-lengthening exercise session doesn’t affect inflammation markers in people with multiple sclerosis The article explores how a specific type of exercise, called eccentric muscle training, affects people with multiple sclerosis (MS). Eccentric muscle training involves exercises where the muscle lengthens under tension, like when you slowly lower a heavy object. This type of exercise is known for causing unique physical responses, including changes in certain proteins in the blood that help control the immune system and inflammation. The main goal of the study was to see if a session of eccentric muscle training would change the levels of these proteins, called cytokines, in the blood of people with MS immediately after exercise. The cytokines studied included IL-4, IL-6, IL-10, IL-17a, INF-γ, and TNF-α. These proteins are important because they help regulate inflammation and immune responses. The researchers also wanted to know if there was any connection between the levels of these proteins at rest and measures of mobility and leg strength. Twenty-seven people with MS took part in the study. Their average age was 40.1 years. In the first session, blood samples were taken to measure the baseline levels of these proteins, and various tests were conducted to assess mobility and leg strength. In the second session, participants completed an eccentric training session, and another blood sample was taken immediately after to see if there were any immediate changes in the protein levels. The results showed no significant differences in the protein levels before and after the exercise session. This suggests that a single session of eccentric muscle training does not cause an immediate inflammatory response in the blood. Therefore, this type of exercise can be safely included in rehabilitation programs for people with MS without the risk of causing harmful inflammation. Overall, the study supports the safety of eccentric muscle training for people with MS and provides valuable insights into its immediate effects on the immune system.
Abstract Molecular mechanisms that influence susceptibility to multiple sclerosis are poorly understood. We analyzed peripheral blood gene expression profiles in nine healthy subjects up to nine ...years before the onset of multiple sclerosis in comparison with 11 age-, gender-, and origin-matched healthy subjects who remained multiple sclerosis-free, and 31 subjects during the first clinical episode of multiple sclerosis. Within the 1051 highly variable genes that differentiated between multiple sclerosis-to-be and multiple sclerosis-free subjects, we identified activation of TCR signaling that triggered the Cbl and MAPK cascade in concert with downstream synergic over-expression of NFAT and MEF2B, but failed to augment the expression of the nuclear receptor gene family members NR4A1, NR2F1, VDR and MEF2B, that further resulted in impaired apoptotic machinery. Comparison between multiple sclerosis-to-be and first clinical onset of multiple sclerosis operating module networks demonstrated the evolution of altered regulation of nuclear receptor-dependent apoptosis. Our findings demonstrating a silent multiple sclerosis trait that is associated with suppressed expression of the nuclear receptor network and inhibited apoptosis of activated T-cells support the role of these transcription signals in the evolution of the autoimmune processes that operate in the pre-disease stage of multiple sclerosis.
Multiple sclerosis (MS) is an immune-mediated disease whose precise etiology is unknown. Several studies found alterations in the microbiome of individuals with MS, but the mechanism by which it may ...affect MS is poorly understood. Here we analyze the microbiome of 129 individuals with MS and find that they harbor distinct microbial patterns compared with controls. To study the functional consequences of these differences, we measure levels of 1,251 serum metabolites in a subgroup of subjects and unravel a distinct metabolite signature that separates affected individuals from controls nearly perfectly (AUC = 0.97). Individuals with MS are found to be depleted in butyrate-producing bacteria and in bacteria that produce indolelactate, an intermediate in generation of the potent neuroprotective antioxidant indolepropionate, which we found to be lower in their serum. We identify microbial and metabolite candidates that may contribute to MS and should be explored further for their causal role and therapeutic potential.
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Gut microbiota and metabolites profiles of individuals with MS differ from healthy controlsIndividuals with MS have reduced serum levels of indolepropionateIndividuals with MS have reduced serum levels of indolelactate and its producing bacteriaIndividuals with MS have lower levels of species and genes involved in butyrate production
Levi et al. perform a coupled analysis of gut microbiota, untargeted metabolomics, gene expression, nutritional records, and clinical data of individuals with MS. The results suggest that increasing the levels of butyrate-producing species and the levels of the tryptophan metabolites indolepropionate and indolelactate in individuals with MS may have potential benefits.
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