Myelin Antigens Research Articles

Ocrelizumab Alters Cytotoxic Lymphocyte Function While Reducing EBV-Specific CD8+ T-Cell Proliferation in Patients With Multiple Sclerosis.

The role of B cells in the pathogenic events leading to relapsing multiple sclerosis (R-MS) has only been recently elucidated. A pivotal step in defining this role has been provided by therapeutic efficacy of anti-CD20 monoclonal antibodies. Indeed, treatment with anti-CD20 can also alter number and function of other immune cells not directly expressing CD20 on their cell surface, whose activities can contribute to unknown aspects influencing therapeutic efficacy. We examined the phenotype and function of cytotoxic lymphocytes and Epstein-Barr virus (EBV)-specific immune responses in people with R-MS before and after ocrelizumab treatment. In this prospective study, we collected blood samples from people with R-MS (n = 41) before and 6 and 12 months after initiating ocrelizumab to assess the immune phenotype and the indirect impact on cytotoxic functions of CD8+ T and NK cells. In addition, we evaluated the specific anti-EBV proliferative responses of both CD8+ T and NK lymphocytes as surrogate markers of anti-EBV activity. We observed that while ocrelizumab depleted circulating B cells, it also reduced the expression of activation and migratory markers on both CD8+ T and NK cells as well as their in vitro cytotoxic activity. A comparable pattern in the modulation of immune molecules by ocrelizumab was observed in cytotoxic cells even when patients with R-MS were divided into groups based on their prior disease-modifying treatment. These effects were accompanied by a significant and selective reduction of CD8+ T-cell proliferation in response to EBV antigenic peptides. Taken together, our findings suggest that ocrelizumab-while depleting B cells-affects the cytotoxic function of CD8+ and NK cells, whose reduced cross-activity against myelin antigens might also contribute to its therapeutic efficacy during MS.

Prevalence of anti-myelin oligodendrocyte glycoprotein antibodies across neuroinflammatory and neurodegenerative diseases

Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.

Lactate Dehydrogenase-Elevating Virus Infection Inhibits MOG Peptide Presentation by CD11b+CD11c+ Dendritic Cells in a Mouse Model of Multiple Sclerosis.

Infections may affect the course of autoimmune inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis (MS). Infections with lactate dehydrogenase-elevating virus (LDV) protected mice from developing experimental autoimmune encephalomyelitis (EAE), a mouse counterpart of MS. Uninfected C57BL/6 mice immunized with the myelin oligodendrocyte glycoprotein peptide (MOG35-55) experienced paralysis and lost weight at a greater rate than mice who had previously been infected with LDV. LDV infection decreased the presentation of the MOG peptide by CD11b+CD11c+ dendritic cells (DC) to pathogenic T lymphocytes. When comparing non-infected mice to infected mice, the histopathological examination of the CNS showed more areas of demyelination and CD45+ and CD3+, but not Iba1+ cell infiltration. These results suggest that the protective effect of LDV infection against EAE development is mediated by a suppression of myelin antigen presentation by a specific DC subset to autoreactive T lymphocytes. Such a mechanism might contribute to the general suppressive effect of infections on autoimmune diseases known as the hygiene hypothesis.

Sustained effects on immune cell subsets and autoreactivity in multiple sclerosis patients treated with oral cladribine.

Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS). Recently, we showed that one year after the initiation of cladribine treatment, T and B cell crosstalk was impaired, reducing potentially pathogenic effector functions along with a specific reduction of autoreactivity to RAS guanyl releasing protein 2 (RASGRP2). In the present study we conducted a longitudinal analysis of the effect of cladribine treatment in patients with RRMS, focusing on the extent to which the effects observed on T and B cell subsets and autoreactivity after one year of treatment are maintained, modulated, or amplified during the second year of treatment. In this case-control exploratory study, frequencies and absolute counts of peripheral T and B cell subsets and B cell cytokine production from untreated patients with relapsing-remitting MS (RRMS) and patients treated with cladribine for 52 (W52), 60 (W60), 72 (W72) and 96 (W96) weeks, were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay. We found a substantial reduction in circulating memory B cells and proinflammatory B cell responses. Furthermore, we observed reduced T cell responses to autoantigens possibly presented by B cells (RASGRP2 and a-B crystallin (CRYAB)) at W52 and W96 and a further reduction in responses to the myelin antigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) after 96 weeks. We conclude that the effects of cladribine observed after year one are maintained and, for some effects, even increased two years after the initiation of a full course of treatment with cladribine tablets.

Autoreactive T cells target peripheral nerves in Guillain–Barré syndrome

Guillain–Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness1. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4+ cells, that show a cytotoxic T helper 1 (TH1)-like phenotype, and rare CD8+ T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3β lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRβ clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.

Circular RNAs: A New Approach to Multiple Sclerosis.

Multiple sclerosis, a condition characterised by demyelination and axonal damage in the central nervous system, is due to autoreactive immune cells that recognise myelin antigens. Alteration of the immune balance can promote the onset of immune deficiencies, loss of immunosurveillance, and/or development of autoimmune disorders such as MS. Numerous enzymes, transcription factors, signal transducers, and membrane proteins contribute to the control of immune system activity. The "transcriptional machine" of eukaryotic cells is a complex system composed not only of mRNA but also of non-coding elements grouped together in the set of non-coding RNAs. Recent studies demonstrate that ncRNAs play a crucial role in numerous cellular functions, gene expression, and the pathogenesis of many immune disorders. The main purpose of this review is to investigate the role of circular RNAs, a previously unknown class of non-coding RNAs, in MS's pathogenesis. CircRNAs influence post-transcriptional control, expression, and functionality of a microRNA and epigenetic factors, promoting the development of typical MS abnormalities such as neuroinflammation, damage to neuronal cells, and microglial dysfunction. The increase in our knowledge of the role of circRNAs in multiple sclerosis could, in the future, modify the common diagnostic-therapeutic criteria, paving the way to a new vision of this neuroimmune pathology.

Relapsing/remitting multiple sclerosis: A speculative model and its implications for a novel treatment.

The clinical pattern in relapsing/remitting multiple sclerosis may be accounted for if an autoreactive immune response can transition back and forth between inflammatory, pathogenic, and non-inflammatory, non-pathogenic modes. Such 'back-and-forth' immune responses are rare. I speculate how such back-and-forth immune responses may arise. Understanding the nature of these different modes, and what controls their mutual transition, may help in designing strategies to favour the nonpathogenic mode, thus constituting treatment. Antigen dose is known to be critical in determining the class/subclass of primary immune responses. Observations have led us to suggest the level of antigen also similarly influences the class/subclass of on-going immune responses. I propose the relapsing, inflammatory and the remitting modes are respectively sustained by relatively low and high amounts of the responsible autoantigens, as is the case, for example, for Th1 and Th2 responses to foreign antigens. In addition, I propose more self-antigens are released during an inflammatory than during a remitting mode. The decrease in the amount of antigen released, as the response transitions from an inflammatory to a remitting mode, results in time in a decreased level of antigen and so the response again evolves towards the inflammatory mode. The inflammatory mode then leads to an increased release of antigen and so, in time, to remission. This model thus explains the transition between different modes. I outline non-invasive, testable predictions of the hypothesis. If confirmed, it may be ethical to examine whether the non-inflammatory mode can be sustained by administering myelin antigens during the remitting phase.

IAstrocytes do not restrain T cell proliferation in vitro

The cross-talk between T cells and astrocytes occurring under physiological and, even more, neuroinflammatory conditions may profoundly impact the generation of adaptive immune responses in the nervous tissue. In this study, we used a standardized in vitro co-culture assay to investigate the immunomodulatory properties of astrocytes differing for age, sex, and species. Mouse neonatal astrocytes enhanced T cell vitality but suppressed T lymphocyte proliferation in response to mitogenic stimuli or myelin antigens, regardless of the Th1, Th2 or Th17 T cell phenotype. Studies comparing glia cells from adult and neonatal animals showed that adult astrocytes were more efficient in inhibiting T lymphocyte activation than neonatal astrocytes, regardless of their sex. Differently from primary cultures, mouse and human astrocytes derived from reprogrammed fibroblasts did not interfere with T cell proliferation. Overall, we describe a standardized astrocyte-T cell interaction in vitro assay and demonstrate that primary astrocytes and iAstrocytes may differ in modulating T cell function.

Neuropathic-like Nociception and Spinal Cord Neuroinflammation Are Dependent on the TRPA1 Channel in Multiple Sclerosis Models in Mice.

Background: Transient receptor potential ankyrin 1 (TRPA1) activation is implicated in neuropathic pain-like symptoms. However, whether TRPA1 is solely implicated in pain-signaling or contributes to neuroinflammation in multiple sclerosis (MS) is unknown. Here, we evaluated the TRPA1 role in neuroinflammation underlying pain-like symptoms using two different models of MS. Methods: Using a myelin antigen, Trpa1+/+ or Trpa1-/- female mice developed relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) (Quil A as adjuvant) or progressive experimental autoimmune encephalomyelitis (PMS)-EAE (complete Freund's adjuvant). The locomotor performance, clinical scores, mechanical/cold allodynia, and neuroinflammatory MS markers were evaluated. Results: Mechanical and cold allodynia detected in RR-EAE, or PMS-EAE Trpa1+/+ mice, were not observed in Trpa1-/- mice. The increased number of cells labeled for ionized calcium-binding adapter molecule 1 (Iba1) or glial fibrillary acidic protein (GFAP), two neuroinflammatory markers in the spinal cord observed in both RR-EAE or PMS-EAE Trpa1+/+ mice, was reduced in Trpa1-/- mice. By Olig2 marker and luxol fast blue staining, prevention of the demyelinating process in Trpa1-/- induced mice was also detected. Conclusions: Present results indicate that the proalgesic role of TRPA1 in EAE mouse models is primarily mediated by its ability to promote spinal neuroinflammation and further strengthen the channel inhibition to treat neuropathic pain in MS.

Clostridium epsilon toxin is excessive in multiple sclerosis and provokes multifocal lesions in mouse models.

Multiple sclerosis (MS) is an inflammatory disease of the CNS. In this issue of the JCI, Ma and Sannino et al. show that two strains of intestinal Clostridium perfringens, known to produce epsilon toxin (ETX), were frequently found in patients with MS. Tiny amounts of this toxin added to immunization with myelin antigens provoked MS-like brain lesions in mice. The distribution of these lesions was diffuse, as in MS, in contrast to the spinal cord-restricted lesions of most animal models. ETX bound to endothelial cells of the CNS to enhance immune cell trafficking through the blood-brain barrier into inflammatory brain lessons. ETX also binds to human, but not murine, white blood cells, perhaps altering immune responses. Barrier disruption and changes in immunity due to the toxin could alter the benefits of immune-modulatory MS therapies and are likely to interact with the complex genetics and environmental influences seen in MS.

Antigen clearance at the peak of the primary immune response induces experimental autoimmune encephalomyelitis.

Autoimmune demyelinating diseases can be induced by an immune response against myelin peptides; however, the exact mechanism underlying the development of such diseases remains unclear. In experimental autoimmune encephalomyelitis, we found that the clearance of exogenous myelin antigen at the peak of the primary immune response is key to the pathogenesis of the disease. The generation of effector T cells requires continuous antigen stimulation, whereas redundant antigen traps and exhausts effector T cells in the periphery, which induces resistance to the disease. Moreover, insufficient antigenic stimulation fails to induce disease efficiently owing to insufficient numbers of effector T cells. When myelin antigen is entirely cleared, the number of effector T cells reaches a peak, which facilitatesinfiltration of more effector T cells into the central nervous system. The peripheral antigen clearance initiates the first wave of effector T cell entry into the central nervous system and induces chronic inflammation. The inflamed central nervous system recruits the second wave of effector T cells that worsen inflammation, resulting in loss of self-tolerance. These findings provide new insights into the mechanism underlying the development of autoimmune demyelinating diseases, which may potentially impact future treatments.

A review on Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a kind of inflammatory neuropathy that has a gradual start and symmetrical sensory involvement. However, there are several clinical variances, suggesting that CIDP may represent a spectrum of linked disorders rather than a single disease entity. While the prevailing idea of CIDP pathogenesis is that cell-mediated and humoral processes interact in an abnormal immune response to damage peripheral neurons, the proportional roles of T cell and autoantibody responses are yet unknown. T cell responses to specified myelin antigens are responsible in animal models of spontaneous inflammatory neuropathy. Antibodies to Schwann cell, compact myelin, and nodal antigens have been found in different human inflammatory neuropathies. The roles of the cellular and humoral immune systems in the development of CIDP are discussed in this review. It is believed that, in the future, the identification of clinical phenotypes and the underlying disease processes would aid in the development of diagnostic and therapy options for CIDP.

Immunosenescence and Multiple Sclerosis: A Literature Review

Introduction: Multiple sclerosis is a chronic inflammatory disorder characterized by the demyelination of central nervous system neurons, giving rise to various motor and non-motor impairments. Aging has been strongly associated with inflammation and immunosenescence, and it is believed that the dysfunction of regulatory T-cells is the central complication in the maintenance of peripheral immunity. CD4+ T-cells and Th17 cells seem to play a crucial role in autoimmune inflammation and are important in the pathophysiology underlying multiple sclerosis. In this systematic review, the link between aging and T-cell function will be explored as well as its implication in MS pathophysiology. Methods: A literature review was conducted using databases such as PubMed, NCBI, and Scopus. Relevant primary literature describing theories or results of an experiment and review papers were selected. Data from primary articles were analyzed to explore the association between aging and MS, as well as its contribution to immunosenescence. Results: There exists a strong association between aging and the pathophysiology of MS which was suggested by a multitude of laboratory studies. Animal models of experimental autoimmune encephalomyelitis have demonstrated the immunological mechanisms of this disease by highlighting differences in T-cell presence and function in healthy people versus MS patients. Discussion: According to numerous studies, chronic inflammation is recognized as a sign of aging, rendering it one of the key contributors to neurodegenerative diseases like MS. The implication of regulatory T-cells in MS is crucial due to its necessity for the maintenance of immunosuppressive activity, which has been found to deteriorate with age. Myelin antigens supplied by microglial cells reactivate autoreactive CD4+ T-cells infiltrating the CNS, producing a cascade of immunological responses that lead to demyelination and tissue death. Conclusion: This literature review finds that MS is largely T-cell mediated and that the aging process heightens chronic inflammation, leading to the destruction of neurons in the CNS.

A plausible contributor to multiple sclerosis; presentation of antigenic myelin protein epitopes by major histocompatibility complexes

BackgroundMultiple sclerosis (MS) can be induced upon successful presentation of myelin antigens by MHC I/II. Antigenic similarity between the myelin and viral proteins may worsen the immunological responses. MethodologyAntigenic regions within myelin proteins; PLP1, MBP, MOG, and MAG were analyzed using SVMTrip and EMBOSS. Homology search identified sequence similarity between the predicted host epitopes and viral proteins. NetMHCpan predicted MHC I/II binding followed by peptide-protein docking through the HPEPDOCK server. Thereafter we analyzed conformational flexibility and stability of 15 protein-peptide complexes based on high docking scores. The binding free energy was calculated using conventional (MD) and Gaussian accelerated molecular dynamics simulation. ResultsPLP1, MBP, MAG and MOG contained numerous antigenic epitopes. MBP and MOG epitopes had sequence similarity to HHV-6 BALF5; EBNA1 and CMV glycoprotein M (gM), and EBV LMP2B, gp350/220; HHV-8 ORFs respectively. Many herpes virus proteins like tegument, envelope glycoproteins, and ORFs of EBV, CMV, HHV-6, and HHV-8 demonstrated sequence similarity with MAG and PLP1. Some antigenic peptides were also linear B-cell epitopes and influenced cytokine production by T-cell. MHC I allele HLA-B*57:01 bound to PLP1 peptide and HLA-A*68:02 bound to a MAG peptide strongly. MHC II alleles HLA-DRB1*04:05 and HLA-DR1*01:01 associated with MAG- and MOG-derived peptides, respectively, demonstrating high HPEPDOCK scores. MD simulations established stable binding of certain peptides with the MHC namely HLA-B*51:01-MBP(DYKSAHKGFKGVDAQGTLSKIFKL), HLA-B*57:01-PLP1(PDKFVGITYALTVVWLLVFACSAVPVYIYF), HLA-DR1*01:01-MOG(VEDPFYWVSPGVLVLLAVLPVLLLQITVGLVFLCLQYR) and HLA-DRB1*04:05-MAG(TWVQVSLLHFVPTREA). ConclusionsCross-reactivity between self-antigens and pathogen derived immunodominant epitopes may induce MS. Our study supported the role of specific MHC alleles as a contributing MS risk factor.

Major depression favors the expansion of Th17-like cells and decrease the proportion of CD39+Treg cell subsets in response to myelin antigen in multiple sclerosis patients.

Mood disorders have been associated with risk of clinical relapses in multiple sclerosis (MS), a demyelinating disease mediated by myelin-specific T cells. We aimed to investigate the impact of major depressive disorder (MDD) and cytokine profile of T-cells in relapsing remitting MS patients. For our study, plasma and PBMC were obtained from 60 MS patients (30 with lifetime MDD) in remission phase. The PBMC cultures were stimulated with anti-CD3/anti-CD28 beads or myelin basic protein (MBP), and effector and regulatory T cell phenotypes were determined by flow cytometry. The cytokine levels, both in the plasma or in the supernatants collected from PBMC cultures, were quantified by Luminex. In some experiments, the effect of serotonin (5-HT) was investigated. Here, higher Th17-related cytokine levels in response to anti-CD3/anti-CD28 and MBP were quantified in the plasma and PBMC cultures of the MS/MDD group in comparison with MS patients. Further, elevated frequency of CD4+ and CD8+ T cells capable of producing IL-17, IL-22 and GM-CSF was observed in depressed patients. Interestingly, the percentage of myelin-specific IFN-γ+IL-17+ and IFN-γ+GM-CSF+ CD4+ T cells directly correlated with neurological disabilities. In contrast, the occurrence of MDD reduced the proportion of MBP-specific CD39+Tregs subsets. Notably, the severity of both neurological disorder and depressive symptoms inversely correlated with these Tregs. Finally, the addition of 5-HT downregulated the release of Th17-related cytokines in response to anti-CD3/anti-CD28 and myelin antigen. In summary, our findings suggested that recurrent major depression, by favoring imbalances of effector Th17 and Treg cell subsets, contributes to MS severity.

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Experimental Autoimmune Encephalomyelitis Animal Models Induced by Different Myelin Antigens Exhibit Differential Pharmacologic Responses to Anti-Inflammatory Drugs

Background and objective Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for studying autoimmune-mediated myelin degradation in multiple sclerosis (MS). Here, we evaluated the pharmacologic responses of several anti-inflammatory drugs with varying mechanisms of actions (MOAs) using EAE models induced by different MOG immunogens to reveal differential pharmacologic characteristics of the disease models and provide a general guidance in animal model selection for MS research. Methods The pharmacologic responses of anti-inflammatory drugs with different mechanisms of actions (MOAs) were evaluated using EAE models induced by either myelin oligodendrocyte glycoprotein p35-55 （MOG35-55）or p1-128 (MOG1-128). EAE animal models were developed in mice with C57BL/6 background. The animals were treated with different anti-MS medications, including 3 B cell-mediated agents and 2 T cell-mediated agents, respectively. Clinical symptoms were monitored and scored, and pharmacodynamic markers including cytokine secretion, inflammatory cell infiltration, and demyelination in spinal cord were analyzed. Results In MOG35-55 peptide-induced EAE model, T cell modulating agents Secukinumab and Fingolimod significantly alleviated clinical symptoms, while B cell-depleting agents, BTK inhibitors PRN2246 and Telitacicept, displayed minimal therapeutic effects or even exacerbated disease progression. In contrast, both T cell-modulating agents and B cell-depleting agents ameliorated disease severity in MOG1-128-induced EAE model. T cell and B cell infiltration in spinal cord increased with disease progression in MOG1-128-induced EAE model. Conclusions Our results demonstrated that induction of EAE by different myelin antigens resulted in differential pharmacologic responses to drugs with specific MOAs. The MOG35-55 peptide-induced EAE model only responded to T cell-modulating drugs, whereas the MOG1-128 protein-induced EAE model exhibited therapeutic sensitivity to both T cell- and B cell-modulating agents. These data suggest the MOG35-55 peptide-induced EAE model is suitable for assessing T cell-modulating agents while MOG1-128 protein-induced model can be employed to evaluate both T cell- and B cell-modulating agents.

Long Non-Coding RNA- Associated Competing Endogenous RNA Axes in T-Cells in Multiple Sclerosis.

Multiple sclerosis (MS) is an immune-mediated demyelinating and degenerative disease with unknown etiology. Inappropriate response of T-cells to myelin antigens has an essential role in the pathophysiology of MS. The clinical and pathophysiological complications of MS necessitate identification of potential molecular targets to understand the pathogenic events of MS. Since the functions and regulatory mechanisms of long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) in MS are yet uncertain, we conducted a bioinformatics analysis to explain the lncRNA-associated ceRNA axes to clarify molecular regulatory mechanisms involved in T-cells responses in MS. Two microarray datasets of peripheral blood T-cell from subjects with relapsing-remitting MS and matched controls containing data about miRNAs (GSE43590), mRNAs and lncRNAs (GSE43591) were downloaded from the Gene Expression Omnibus database. Differentially expressed miRNAs (DEmiRNAs), mRNAs (DEmRNAs), and lncRNAs (DElncRNAs) were identified by the limma package of the R software. Protein-protein interaction (PPI) network and module were developed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and the Molecular Complex Detection (MCODE) Cytoscape plugin, respectively. Using DIANA-LncBase and miRTarBase, the lncRNA-associated ceRNA axes was constructed. We conducted a Pearson correlation analysis and selected the positive correlations among the lncRNAs and mRNAs in the ceRNA axes. Lastly, DEmRNAs pathway enrichment was conducted by the Enrichr tool. A ceRNA regulatory relationship among Small nucleolar RNA host gene 1 (SNHG1), hsa-miR-197-3p, YOD1 deubiquitinase (YOD1) and zinc finger protein 101 (ZNF101) and downstream connected genes was identified. Pathway enrichment analysis showed that DEmRNAs were enriched in “Protein processing in endoplasmic reticulum” and “Herpes simplex virus 1 infection” pathways. To our knowledge, this would be the first report of a possible role of SNHG1/hsa-miR-197-3p/YOD1/ZNF101 axes in the pathogenesis of MS. This research remarks on the significance of ceRNAs and prepares new perceptions for discovering the molecular mechanism of MS.

Antigen-presenting innate lymphoid cells orchestrate neuroinflammation.

Pro-inflammatory T cells in the central nervous system (CNS) are causally associated with multiple demyelinating and neurodegenerative diseases1-6, but the pathways that control these responses remain unclear. Here we define a population of inflammatory group 3 innate lymphoid cells (ILC3s) that infiltrate the CNS in a mouse model of multiple sclerosis. These ILC3s are derived from the circulation, localize in proximity to infiltrating T cells in the CNS, function as antigen-presenting cells that restimulate myelin-specific T cells, and are increased in individuals with multiple sclerosis. Notably, antigen presentation by inflammatory ILC3s is required to promote T cell responses in the CNS and the development of multiple-sclerosis-like disease in mouse models. By contrast, conventional and tissue-resident ILC3s in the periphery do not appear to contribute to disease induction, but instead limit autoimmune T cell responses and prevent multiple-sclerosis-like disease when experimentally targeted to present myelin antigen. Collectively, our data define a population of inflammatory ILC3s that is essential for directly promoting T-cell-dependent neuroinflammation in the CNS and reveal the potential of harnessing peripheral tissue-resident ILC3s for the prevention of autoimmune disease.

Recombinant myelin oligodendrocyte glycoprotein quality modifies evolution of experimental autoimmune encephalitis in macaques

Experimental autoimmune encephalitis (EAE) is a well-recognized model for the study of human acquired demyelinating diseases (ADD), a group of inflammatory disorders of the central nervous system (CNS) characterized by inflammation, myelin loss, and neurological impairment of variable severity. In rodents, EAE is typically induced by active immunization with a combination of myelin-derived antigen and a strong adjuvant as complete Freund's adjuvant (CFA), containing components of the mycobacterial wall, while myelin antigen alone or associated with other bacterial components, as lipopolysaccharides (LPS), often fails to induce EAE. In contrast to this, EAE can be efficiently induced in non-human primates by immunization with the recombinant human myelin oligodendrocyte glycoprotein (rhMOG), produced in Escherichia coli (E. coli), purified and formulated with incomplete Freund's adjuvant (IFA), which lacks bacterial elements. Here, we provide evidence indicating how trace amounts of bacterial contaminants within rhMOG may influence the course and severity of EAE in the cynomolgus macaque immunized with rhMOG/IFA. The residual amount of E. coli contaminants, as detected with mass spectrometry within rhMOG protein stocks, were found to significantly modulate the severity of clinical, radiological, and histologic hallmarks of EAE in macaques. Indeed, animals receiving the purest rhMOG showed milder disease severity, increased numbers of remissions, and reduced brain damage. Histologically, these animals presented a wider diversity of lesion types, including changes in normal-appearing white matter and prephagocytic lesions. Non-human primates EAE model with milder histologic lesions reflect more accurately ADD and permits to study of the pathogenesis of disease initiation and progression.The authors describe quantitatively and qualitatively different forms of experimental autoimmune encephalitis (EAE) in cynomolgus macaques. They found that bacterial contaminants within recombinant human myelin oligodendrocyte glycoprotein seemed to aggravate disease evolution. They provide anatomopathological features of fulminant and progressive forms of EAE, allowing them to distinguish specific factors influencing the evolution of this model of autoimmune demyelinating disease.