B cell targeting therapies in MS patients during the SARS-CoV-2 pandemic — when immunosuppression meets infection?

Introduction. Research into the mechanisms of autoimmune demyelination have highlighted B cells in this process. Therapies targeting this population were a recent addition to the multiple sclerosis (MS) drugs portfolio. The SARS-CoV-2 pandemic and the risk of severe COVID-19 have challenged the safety of B cell depletion in MS patients.State of the art. Selective depletion of B cells by monoclonal antibodies as monotherapy in MS has been shown to profoundly suppress disease activity among relapsing-remitting MS patients. Furthermore ocrelizumab, a humanised anti-CD20 monoclonal antibody, was the first licensed therapy in primary progressive MS. Based on the concept of the role of B cells in MS, many therapeutic approaches are emerging as novel ways to treat autoimmune demyelination. However, during the SARS-CoV-2 pandemic, a conservative approach toward limiting immune suppression in MS patients has been proposed.Clinical implications. Emerging evidence does not support the notion of increased susceptibility among MS patients to the SARS-CoV-2 infection, or any predisposition toward greater severity of COVID-19. This also does not appear to be the case for MS patients undergoing B cell depletion therapies. Thus, any decision to withhold immune suppression in MS patients during the SARS-CoV-2 pandemic is probably incorrect. MS therapeutic decision-making should focus on the danger of poorly controlled autoimmune demyelination rather than perceived risks from COVID-19.Future directions. The current pandemic highlights the need to develop more selective and safer methods of immunomodulation in MS. B cells represent several functionally different populations. Further research into the different role of these cells during autoimmune demyelination should yield better, safer strategies to control the encephalitogenic process

Intrathecal administration of mesenchymal stem cells in patients with adrenomyeloneuropathy

Background and objectivesX-linked adrenomyeloneuropathy (AMN) is an inherited neurodegenerative disorder associated with mutations in the ABCD1 gene and the accumulation of very long-chain fatty acids (VLFCAs) in plasma and tissues. Currently, there is no effective treatment for AMN. We have aimed to evaluate the therapeutic effects of mesenchymal stem cell (MSC) transplantation in patients with AMN.MethodsThis is a small cohort open-label study with patients with AMN diagnosed and treated at the University Hospital in Olsztyn, Poland. All patients met clinical, biochemical, MRI, and neuropsychological criteria for AMN. MSCs derived from Wharton jelly, 20 × 106 cells, were administered intrathecally three times every 2 months, and patients were followed up for an additional 3 months. The primary outcome measures included a blinded assessment of lower limb muscle strength with the Medical Research Council Manual Muscle Testing scale at baseline and on every month visits until the end of the study. Additional outcomes included measurements of the timed 25-feet walk (T25FW) and VLFCA serum ratio.ResultsThree male patients with AMN with an age range of 26–37 years participated in this study. All patients experienced increased muscle strength in the lower limbs at the end of the study versus baseline. The power grade increased by 25–43% at the baseline. In addition, all patients showed an improvement trend in walking speed measured with the T25FW test. Treatment with MSCs in patients with AMN appeared to be safe and well tolerated.DiscussionThe results of this study demonstrated that intrathecal administration of WJ-MSC improves motor symptoms in patients with AMN. The current findings lend support to the safety and feasibility of MSC therapy as a potentially viable treatment option for patients with AMN

NCF1 gene and pseudogene pattern: association with parasitic infection and autoimmunity

<p>Abstract</p> <p>Background</p> <p>Neutrophil cytosolic factor 1, p47^phox(NCF1) is a component of the leukocyte NADPH oxidase complex mediating formation of reactive oxygen intermediates (ROI) which play an important role in host defense and autoimmunity. An individual genomic pattern of <it>ncf1 </it>and its two types of pseudogenes (reflected by the ΔGT/GTGT ratio) may influence the individual capacity to produce ROI.</p> <p>Methods</p> <p>NCF1ΔGT/GTGT ratios were correlated with clinical parameters and ROI production during <it>Plasmodium falciparum </it>malaria and with susceptibility to the autoimmune disease multiple sclerosis (MS).</p> <p>Results</p> <p>Among Gabonese children with severe malaria, ROI production from peripheral blood tended to be higher in individuals with a ΔGT/GTGT ratio ≤ 1:1. ΔGT/GTGT ratios were not associated with susceptibility to MS, but to age-of-onset among MS patients.</p> <p>Conclusion</p> <p>The genomic pattern of <it>NCF1 </it>and its pseudogenes might influence ROI production but only marginally influence susceptibility to and outcome of malaria and MS.</p

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

microRNA and exosome profiling in multiple sclerosis

New DNA sequencing technologies have uncovered non-coding RNA (ncRNA) as a major player in regulating cellular processes and can no longer be dismissed as "junk" or "dark" RNA. Among the ncRNA, microRNA (miRNA) is arguably the most extensively characterized category and a number of studies have implicated them in regulating critical functions that can influence autoimmune demyelination. Of specific interest to multiple sclerosis (MS), miRNA have been implicated in both regulating immune responses and myelination, thus making them an attractive candidate for both pharmacological intervention and as disease biomarkers. In addition, exosomes, small vesicles secreted by most cell types and present in all body fluids, have been also shown to play roles in immune signaling, inflammation and angiogenesis. Therefore, exosomes are also being explored as tools for therapeutic delivery and as biomarkers. This article reviews the recent advances in miRNA and exosome profiling in MS and experimental models

The Heat Shock Protein HSP70 Promotes Th17 Genes’ Expression via Specific Regulation of microRNA

T helper cells type 17 (Th17) are orchestrators of autoimmune conditions, including multiple sclerosis (MS), but mechanisms of Th17 pathogenicity remain unknown. MicroRNAs (miRNA) are known to control T cells. To understand the function of miRNA in Th17, we have established a T cell line, EL4-TCR+, that resembles the expression pattern of the Th17 cells. Subsequently, we have evaluated the crosstalk between miRNA and Th17 genes&rsquo; expression using a combination of gene expression profiling, gene expression manipulation, RNA and protein immunoprecipitation, as well as confocal microscopy. We have found that Th17-related miRNA were strongly expressed in EL4-TCR+ cells following the binding of the cluster of differentiation 3 (CD3) component of the T cell receptor (TCR). Furthermore, a specific inhibition of these miRNA resulted in downregulation of the critical Th17 genes&rsquo; expression. Surprisingly, this mechanism relied on the function of the stress signal regulator heat shock protein 70 (HSP70). Upon activation, HSP70 co-localized intracellularly with miRNA processing proteins. Precipitation of HSP70 resulted in enrichment of the Th17-associated miRNA. Finally, HSP70 inhibition led to downregulation of the Th17 genes&rsquo; expression and ameliorated development of autoimmune demyelination. Our study demonstrated that HSP70 facilitates specific miRNA function leading to Th17 genes&rsquo; expression, a mechanism linking stress and autoimmunity