Central Nervous System Autoimmunity Research Articles

Mitochondrial Strokes: Diagnostic Challenges and Chameleons.

Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected in anyone with an acute/subacute onset of focal neurological symptoms at any age and are usually driven by seizures. Suggestive features of an underlying mitochondrial pathology include evolving MRI lesions, often originating within the posterior brain regions, the presence of multisystemic involvement, including diabetes, deafness, or cardiomyopathy, and a positive family history. The diagnosis of MELAS has important implications for those affected and their relatives, given it enables early initiation of appropriate treatment and genetic counselling. However, the diagnosis is frequently challenging, particularly during the acute phase of an event. We describe four cases of mitochondrial strokes to highlight the considerable overlap that exists with other neurological disorders, including viral and autoimmune encephalitis, ischemic stroke, and central nervous system (CNS) vasculitis, and discuss the clinical, laboratory, and imaging features that can help distinguish MELAS from these differential diagnoses.

Clinicoradiological comparative study of Aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody associated disease (MOGAD): A prospective observational study and review of literature

Neuromyelitis Optica spectrum disorders (NMOSD) are autoimmune inflammatory central nervous system diseases. NMOSD patients typically have recurrent attacks of severe optic neuritis or/and myelitis with majority of them having autoantibodies against the aquaporin-4 (AQP4). In the recent past, a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations had been demonstrated. MOG-IgG antibody associated disease (MOGAD) is now considered as a disease entity in its own right, distinct from classic MS and from AQP4-IgG-positive NMOSD. Here, we compared the clinical, laboratory, radiological features and treatment outcomes of patients with Aquaporin-4-IgG seropositive NMOSD and MOGAD. Relatively younger age at onset, lesser number of relapses, better response to treatment and favorable clinical outcomes were found in MOGAD group in comparison to AQP4-IgG-positive NMOSD group.

Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway.

ObjectiveTo determine whether the metabolites of Kynurenine pathway (KP) could serve as biomarkers for distinguishing between viral CNS infections and autoimmune neuroinflammatory diseases, especially anti‐N‐methyl‐D‐aspartate receptor encephalitis (NMDARE) and herpes virus encephalitis (HSE).MethodsThis study enrolled CSF samples from 76 patients with viral CNS infections, autoimmune neuroinflammatory, and non‐inflammatory neurological diseases. We measured cerebrospinal fluid (CSF) concentrations of tryptophan (Trp) and kynurenine (Kyn) by ELISA.ResultsKyn concentrations and Kyn/Trp ratios were highly increased (p < 0.001, viral vs. autoimmune) in viral CNS infections, whereas patients with autoimmune neuroinflammatory and non‐inflammatory diseases exhibited low concentrations. Furthermore, Kyn concentrations and Kyn/Trp ratio turned out to be excellent biomarkers to distinguish between herpes simplex encephalitis (HSE) and NMDARE (AUC 0.920 and AUC 0.906), whereas Trp concentrations were similar in all three groups.InterpretationThe results suggest that elevated CSF Kyn concentrations and Kyn/Trp ratio may serve as biomarkers for distinguishing viral CNS infections from autoimmune neuroinflammatory diseases. In particular, the distinction between HSE and NMDARE is of great clinical relevance. Further studies are warranted to investigate the potential of CSF Kyn levels and Kyn/Trp ratio as routine parameters in patients with CNS diseases.

Crosstalk of Microorganisms and Immune Responses in Autoimmune Neuroinflammation: A Focus on Regulatory T Cells.

Regulatory T cells (Tregs) are the major determinant of peripheral immune tolerance. Many Treg subsets have been described, however thymus-derived and peripherally induced Tregs remain the most important subpopulations. In multiple sclerosis, a prototypical autoimmune disorder of the central nervous system, Treg dysfunction is a pathogenic hallmark. In contrast, induction of Treg proliferation and enhancement of their function are central immune evasion mechanisms of infectious pathogens. In accordance, Treg expansion is compartmentalized to tissues with high viral replication and prolonged in chronic infections. In friend retrovirus infection, Treg expansion is mainly based on excessive interleukin-2 production by infected effector T cells. Moreover, pathogens seem also to enhance Treg functions as shown in human immunodeficiency virus infection, where Tregs express higher levels of effector molecules such as cytotoxic T-lymphocyte-associated protein 4, CD39 and cAMP and show increased suppressive capacity. Thus, insights into the molecular mechanisms by which intracellular pathogens alter Treg functions might aid to find new therapeutic approaches to target central nervous system autoimmunity. In this review, we summarize the current knowledge of the role of pathogens for Treg function in the context of autoimmune neuroinflammation. We discuss the mechanistic implications for future therapies and provide an outlook for new research directions.

Selected transient receptor potential channel genes' expression in peripheral blood mononuclear cells of multiple sclerosis.

Transient receptor potential channels have responsibilities in many cellular processes such as cytokine production, cell differentiation, and cytotoxicity by affecting intracellular cation levels or intracellular signal pathways. Multiple sclerosis is a chronic autoimmune central nervous system (CNS) disease caused by environmental and genetic factors. In this study, we aim to investigate TRPV1-TRPV4, TRPM2, TRPM4, TRPM7, TRPC6, and TRPA1 mRNA expression levels, which are associated with the inflammatory process, in the peripheral blood mononuclear cells (PBMCs) of relapsing-remitting multiple sclerosis (RRMS) patients. Thirty-five healthy controls and age-gender matched thirty patients with RRMS were involved in the study. TRPC6, TRPA1, TRPM2, TRPM4, TRPM7, TRPV1, TRPV2, TRPV3, and TRPV4 PBMCs mRNA expression levels were determined by qPCR. In the present study, the TRPC6, TRPM7, TRPV1, TRPV3, and TRPV4 mRNA expressions of RRMS patients in PBMCs decreased at a significant level compared to the healthy control group (p = .000, p = .000, p = .044, p = .000, p = .004, respectively). The decreased expression of TRPC6, TRPM7, TRPV1, TRPV3, and TRPV4 in PBMCs may be associated with the pathogenesis of MS. Further studies are required to understand the mechanism of the relation between these TRP channels and MS and other autoimmune diseases.

Mechanisms of brain protection against autoimmune inflammation

A significant number of unique antigens expressed in the brain can activate an adaptive immune response, increasing the risk of autoimmune inflammation in the central nervous system (CNS). As a result, a complex protection system exists in the CNS to prevent autoimmune reactions. In addition to the blood-brain- and blood-cerebrospinal fluid-barriers, we discuss complex systems of antigen drainage and circulation of antigen-presenting cells in the CNS. Moreover, the interaction of the CNS with the peripheral immune system typically occurs in specific areas (choroid plexuses, perivascular spaces, and brain meninges), and resident cells of the innate immune system (macrophages, microglia, astrocytes) have limited opportunities for antigen presentation and do not migrate to regional lymph nodes. There are signs of activation of adaptive immunity against CNS antigens in normal conditions, which, however, do not lead to autoimmune diseases. The review covers the mechanisms of maintaining natural immune self-tolerance in the CNS and their failure in autoimmune CNS pathology.

Vaccination in acute immune-mediated/inflammatory disorders of the central nervous system.

This review article covers the vaccination related issues in autoimmune disorders of central nervous system (CNS) including narcolepsy, anti-NMDAR encephalitis, Rasmussen encephalitis and febrile infection related epilepsy syndrome (FIRES). Beyond these conditions the immune mediated epilepsies related with autoimmune CNS disorders are discussed and indications and contraindications of vaccinations in these cases are also considered.

The CXCL13/CXCR5-chemokine axis in neuroinflammation: evidence of CXCR5+CD4 T cell recruitment to CSF

BackgroundC-X-C chemokine ligand 13 (CXCL13) is frequently elevated in cerebrospinal fluid (CSF) in a variety of inflammatory central nervous system (CNS) diseases, has been detected in meningeal B cell aggregates in brain tissues of multiple sclerosis patients, and proposedly recruits B cells into the inflamed CNS. Besides B cells also follicular helper T (Tfh) cells express the cognate receptor C-X-C chemokine receptor type 5 (CXCR5) and follow CXCL13 gradients in lymphoid tissues. These highly specialized B cell helper T cells are indispensable for B cell responses to infection and vaccination and involved in autoimmune diseases. Phenotypically and functionally related circulating CXCR5+CD4 T cells occur in blood. Their co-recruitment to the inflamed CSF is feasible but unresolved.MethodsWe approached this question with a retrospective study including data of all patients between 2017 and 2019 of whom immune phenotyping data of CXCR5 expression and CSF CXCL13 concentrations were available. Discharge diagnoses and CSF laboratory parameters were retrieved from records. Patients were categorized as pyogenic/aseptic meningoencephalitis (ME, n = 29), neuroimmunological diseases (NIMM, n = 22), and non-inflammatory neurological diseases (NIND, n = 6). ANOVA models and Spearman’s Rank-Order correlation were used for group comparisons and associations of CXCL13 levels with immune phenotyping data.ResultsIn fact, intrathecal CXCL13 elevations strongly correlated with CXCR5+CD4 T cell frequencies in the total cohort (p < 0.0001, r = 0.59), and ME (p = 0.003, r = 0.54) and NIMM (p = 0.043, r = 0.44) patients. Moreover, the ratio of CSF-to-peripheral blood (CSF/PB) frequencies of CXCR5+CD4 T cells strongly correlated with CXCL13 levels both in the total cohort (p = 0.001, r = 0.45) and ME subgroup (p = 0.005, r = 0.50), indicating selective accumulation. ME, NIMM and NIND groups differed with regard to CSF cell counts, albumin quotient, intrathecal IgG, CXCL13 elevations and CXCR5+CD4 T cells, which were higher in inflammatory subgroups.ConclusionThe observed link between intrathecal CXCL13 elevations and CXCR5+CD4 T cell frequencies does not prove but suggests recruitment of possible professional B cell helpers to the inflamed CSF. This highlights CSF CXCR5+CD4 T cells a key target and potential missing link to the poorly understood phenomenon of intrathecal B cell and antibody responses with relevance for infection control, chronic inflammation and CNS autoimmunity.

Treatment of Neuromyelitis Optica Spectrum Disorders.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune central nervous system (CNS) inflammatory disorder that can lead to serious disability and mortality. Females are predominantly affected, including those within the reproductive age. Most patients develop relapsing attacks of optic neuritis; longitudinally extensive transverse myelitis; and encephalitis, especially brainstem encephalitis. The majority of NMOSD patients are seropositive for IgG autoantibodies against the water channel protein aquaporin-4 (AQP4-IgG), reflecting underlying aquaporin-4 autoimmunity. Histological findings of the affected CNS tissues of patients from in-vitro and in-vivo studies support that AQP4-IgG is directly pathogenic in NMOSD. It is believed that the binding of AQP4-IgG to CNS aquaporin-4 (abundantly expressed at the endfoot processes of astrocytes) triggers astrocytopathy and neuroinflammation, resulting in acute attacks. These attacks of neuroinflammation can lead to pathologies, including aquaporin-4 loss, astrocytic activation, injury and loss, glutamate excitotoxicity, microglial activation, neuroinflammation, demyelination, and neuronal injury, via both complement-dependent and complement-independent pathophysiological mechanisms. With the increased understanding of these mechanisms underlying this serious autoimmune astrocytopathy, effective treatments for both active attacks and long-term immunosuppression to prevent relapses in NMOSD are increasingly available based on the evidence from retrospective observational data and prospective clinical trials. Knowledge on the indications and potential side effects of these medications are essential for a clear evaluation of the potential benefits and risks to NMOSD patients in a personalized manner. Special issues such as pregnancy and the coexistence of other autoimmune diseases require additional concern and meticulous care. Future directions include the identification of clinically useful biomarkers for the prediction of relapse and monitoring of the therapeutic response, as well as the development of effective medications with minimal side effects, especially opportunistic infections complicated by long-term immunosuppression.

Immunotherapy‐responsive brainstem lesion accompanied with anti‐galactocerebroside antibody

AbstractBackgroundBrainstem lesions are a diagnostic challenge and clinicians have to differentiate between many diseases including acute disseminated encephalomyelitis, multiple sclerosis (MS), Bickerstaff brainstem encephalitis (BBE) and brain tumors. The anti‐galactocerebroside (Gal‐C) antibody is an anti‐glycolipid antibody that is often detected in autoimmune peripheral neuropathy. However, anti‐Gal‐C antibody is rarely detected in autoimmune central nervous system diseases. Here, we report the case of an anti‐Gal‐C antibody‐positive patient who had a brainstem lesion that mimicked MS and responded to immunotherapy.Case presentationWe report a 32‐year‐old woman who presented with subacute numbness of the right lower extremities and hemiataxia. Her cerebrospinal fluid examination showed an elevated myelin basic protein level and an oligoclonal band. Brain magnetic resonance imaging showed a T2 high‐intensity lesion from the left brainstem to the cerebellum. She was treated with steroid pulse therapy, but internuclear ophthalmoplegia and left peripheral facial palsy developed. Her brain magnetic resonance imaging showed an enlargement of the brainstem lesion. Therefore, plasma exchange therapy and high‐dose immunoglobulin therapy were administered, and her symptoms eventually ameliorated. First, we diagnosed her with MS and started dimethyl fumarate. After anti‐GM2 and anti‐Gal‐C antibody positivity was revealed, we diagnosed an anti‐Gal‐C antibody‐related brainstem lesion. There have been few reports of anti‐Gal‐C antibody‐positive central nervous system diseases.ConclusionsThe present case highlights that an anti‐Gal‐C positivity can cause brainstem inflammatory lesions, which should be differentiated from acute disseminated encephalomyelitis, Bickerstaff brainstem encephalitis and MS. The patient’s symptoms improved with intense immunotherapy, and antibody measurement led to the discontinuation of unnecessary disease‐modifying drugs.

Matrine treatment induced an A2 astrocyte phenotype and protected the blood-brain barrier in CNS autoimmunity

Type 1 astrocytes (A1), which are highly proinflammatory and neurotoxic, are prevalent in multiple sclerosis (MS). In addition, in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), immune cells must cross the blood-brain barrier (BBB) and infiltrate into the parenchyma of the central nervous system (CNS) in order to induce neurological deficits. We have previously reported that treatment of EAE with matrine (MAT), a quinazine alkaloid derived from Sophorae Flavescens, effectively inhibited CNS inflammation and promoted neuroregeneration. However, the impact of MAT treatment on astrocyte phenotype is not known. In the present study, we showed that MAT treatment inhibited the generation of neurotoxic A1 astrocytes and promoted neuroprotective A2 astrocytes in the CNS of EAE, most likely by inhibiting production of the A1-inducing cytokine cocktail. MAT also downregulated the expression of vascular endothelial growth factor-A (VEGF-A) and upregulated tight junction proteins Claudin 5 and Occludin, thus protecting the BBB from CNS inflammation-induced damage. Moreover, MAT treatment promotes the formation of astrocyte tight junctions at glia limitans, thereby limiting parenchymal invasion of the CNS by immune cells. Taken together, the inhibition of A1 astrogliogenesis, and the dual effects on the BBB and astrocytic glia limitans, may be the mechanisms whereby MAT significantly improves EAE clinical scores and neuroprotection.

Antibody-Mediated Autoimmune Diseases of the CNS: Challenges and Approaches to Diagnosis and Management.

Antibody-mediated disorders of the central nervous system (CNS) are increasingly recognized as neurologic disorders that can be severe and even life-threatening but with the potential for reversibility with appropriate treatment. The expanding spectrum of newly identified autoantibodies targeting glial or neuronal (neural) antigens and associated clinical syndromes (ranging from autoimmune encephalitis to CNS demyelination) has increased diagnostic precision, and allowed critical reinterpretation of non-specific neurological syndromes historically associated with systemic disorders (e.g., Hashimoto encephalopathy). The intracellular vs. cell-surface or synaptic location of the different neural autoantibody targets often helps to predict the clinical characteristics, potential cancer association, and treatment response of the associated syndromes. In particular, autoantibodies targeting intracellular antigens (traditionally termed onconeural autoantibodies) are often associated with cancers, rarely respond well to immunosuppression and have a poor outcome, although exceptions exist. Detection of neural autoantibodies with accurate laboratory assays in patients with compatible clinical-MRI phenotypes allows a definite diagnosis of antibody-mediated CNS disorders, with important therapeutic and prognostic implications. Antibody-mediated CNS disorders are rare, and reliable autoantibody identification is highly dependent on the technique used for detection and pre-test probability. As a consequence, indiscriminate neural autoantibody testing among patients with more common neurologic disorders (e.g., epilepsy, dementia) will necessarily increase the risk of false positivity, so that recognition of high-risk clinical-MRI phenotypes is crucial. A number of emerging clinical settings have recently been recognized to favor development of CNS autoimmunity. These include antibody-mediated CNS disorders following herpes simplex virus encephalitis or occurring in a post-transplant setting, and neurological autoimmunity triggered by TNFα inhibitors or immune checkpoint inhibitors for cancer treatment. Awareness of the range of clinical and radiological manifestations associated with different neural autoantibodies, and the specific settings where autoimmune CNS disorders may occur is crucial to allow rapid diagnosis and early initiation of treatment.

Neuroinflammation-Driven Lymphangiogenesis in CNS Diseases.

The central nervous system (CNS) undergoes immunosurveillance despite the lack of conventional antigen presenting cells and lymphatic vessels in the CNS parenchyma. Additionally, the CNS is bathed in a cerebrospinal fluid (CSF). CSF is continuously produced, and consequently must continuously clear to maintain fluid homeostasis despite the lack of conventional lymphatics. During neuroinflammation, there is often an accumulation of fluid, antigens, and immune cells to affected areas of the brain parenchyma. Failure to effectively drain these factors may result in edema, prolonged immune response, and adverse clinical outcome as observed in conditions including traumatic brain injury, ischemic and hypoxic brain injury, CNS infection, multiple sclerosis (MS), and brain cancer. Consequently, there has been renewed interest surrounding the expansion of lymphatic vessels adjacent to the CNS which are now thought to be central in regulating the drainage of fluid, cells, and waste out of the CNS. These lymphatic vessels, found at the cribriform plate, dorsal dural meninges, base of the brain, and around the spinal cord have each been implicated to have important roles in various CNS diseases. In this review, we discuss the contribution of meningeal lymphatics to these processes during both steady-state conditions and neuroinflammation, as well as discuss some of the many still unknown aspects regarding the role of meningeal lymphatics in neuroinflammation. Specifically, we focus on the observed phenomenon of lymphangiogenesis by a subset of meningeal lymphatics near the cribriform plate during neuroinflammation, and discuss their potential roles in immunosurveillance, fluid clearance, and access to the CSF and CNS compartments. We propose that manipulating CNS lymphatics may be a new therapeutic way to treat CNS infections, stroke, and autoimmunity.

IFN-β Acts on Monocytes to Ameliorate CNS Autoimmunity by Inhibiting Proinflammatory Cross-Talk Between Monocytes and Th Cells.

IFN-β has been the treatment for multiple sclerosis (MS) for almost three decades, but understanding the mechanisms underlying its beneficial effects remains incomplete. We have shown that MS patients have increased numbers of GM-CSF+ Th cells in circulation, and that IFN-β therapy reduces their numbers. GM-CSF expression by myelin-specific Th cells is essential for the development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. These findings suggested that IFN-β therapy may function via suppression of GM-CSF production by Th cells. In the current study, we elucidated a feedback loop between monocytes and Th cells that amplifies autoimmune neuroinflammation, and found that IFN-β therapy ameliorates central nervous system (CNS) autoimmunity by inhibiting this proinflammatory loop. IFN-β suppressed GM-CSF production in Th cells indirectly by acting on monocytes, and IFN-β signaling in monocytes was required for EAE suppression. IFN-β increased IL-10 expression by monocytes, and IL-10 was required for the suppressive effects of IFN-β. IFN-β treatment suppressed IL-1β expression by monocytes in the CNS of mice with EAE. GM-CSF from Th cells induced IL-1β production by monocytes, and, in a positive feedback loop, IL-1β augmented GM-CSF production by Th cells. In addition to GM-CSF, TNF and FASL expression by Th cells was also necessary for IL-1β production by monocyte. IFN-β inhibited GM-CSF, TNF, and FASL expression by Th cells to suppress IL-1β secretion by monocytes. Overall, our study describes a positive feedback loop involving several Th cell- and monocyte-derived molecules, and IFN-β actions on monocytes disrupting this proinflammatory loop.

911-P: New-Onset Diabetes and Cerebellar Ataxia in a Child: What Does GAD-65 Have to Do with It?

Glutamic acid decarboxylase isotype 65 (GAD-65) antibodies have been associated with several conditions including type 1 diabetes (T1D), stiff-man syndrome and autoimmune cerebellar ataxia. GAD-65 antibody-associated cerebellar ataxia has been described in multiple case reports, mostly in adult women, but rarely in children, as reported here. An 11-year-old female presented with two weeks of polyuria and polydipsia and one week of abnormal speech and difficulty walking. Labs were consistent with new onset diabetes with mild ketoacidosis. Neurological exam localized her lesion to the cerebellum. Several type 1 diabetes-related antibodies were positive, including zinc transporter 8, GAD-65, and ICA512. Insulin autoantibody was negative. Serum Pediatric Autoimmune Central Nervous System Disorders Evaluation (Mayo Clinic) showed only elevated levels of GAD-65 antibody to 41.6 nmol/L (≤ 0.02). CSF studies showed oligoclonal bands, without evidence of infection. CSF GAD-65 antibody testing (Mayo Clinic) was elevated to 13.7 nmol/L (≤ 0.02). MRI showed no cerebellar pathology. Thyroglobulin and thyroid peroxidase antibodies were normal. Because of the constellation of findings, she was diagnosed with GAD-65 antibody-associated cerebellar ataxia. Her symptoms improved after a short course of steroids and IVIG. She is planned for monthly IVIG for at least 6 months. Elevated serum GAD-65 antibody levels are found in the majority of patients newly diagnosed with T1D. GAD-65 CSF levels are noted to be higher in patients that develop autoimmune cerebellar ataxia, stiff-man syndrome or autoimmune polyendocrine syndromes (≤20 nmol/L), as seen in this patient (41.6 nmol/L). Patients presenting with new onset T1D and cerebellar ataxia should prompt evaluation for GAD-65 antibody-associated cerebellar ataxia. Disclosure K. Chan: None. M. Sweat: None. M. R. Zimbric: None. R. S. Newfield: Consultant; Self; Merck Sharp &amp; Dohme Corp.

Autoantibodies in neurological disease.

The realization that autoantibodies can contribute to dysfunction of the brain has brought about a paradigm shift in neurological diseases over the past decade, offering up important novel diagnostic and therapeutic opportunities. Detection of specific autoantibodies to neuronal or glial targets has resulted in a better understanding of central nervous system autoimmunity and in the reclassification of some diseases previously thought to result from infectious, ‘idiopathic’ or psychogenic causes. The most prominent examples, such as aquaporin 4 autoantibodies in neuromyelitis optica or NMDAR autoantibodies in encephalitis, have stimulated an entire field of clinical and experimental studies on disease mechanisms and immunological abnormalities. Also, these findings inspired the search for additional autoantibodies, which has been very successful to date and has not yet reached its peak. This Review summarizes this rapid development at a point in time where preclinical studies have started delivering fundamental new data for mechanistic understanding, where new technologies are being introduced into this field, and — most importantly — where the first specifically tailored immunotherapeutic approaches are emerging.

"Antibody of Unknown Significance" (AUS): The Issue of Interpreting Antibody Test Results.

"Antibody of Unknown Significance" (AUS): The Issue of Interpreting Antibody Test Results.

Dysregulated follicular regulatory T cells and antibody responses exacerbate CNS autoimmunity

Abstract Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. Here we show that mice with a FoxP3-specific ablation of the transcription factor Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of unstable regulatory T cells (Tregs) into IL-17A/GM-CSF-producing effector T-cells associated with increased TFH-Ab responses, more IgE deposition in the central nervous system (CNS) and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells and EAE. Moreover, compared to healthy controls, a small group of MS patients had fewer circulating Tregs and TFR cells that expressed reduced levels of Blimp1, associated with elevated serum IgE. These findings suggest that Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE, and that dysregulated TFR cells and Ab responses promote CNS autoimmunity.

Dectin-1 limits CNS autoimmunity through a non-canonical pathway

Abstract Innate immunity mediates both damage and repair of the central nervous system (CNS) in neurologic disorders. Although pathologic roles for innate immunity are well-described in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), protective aspects of the immune response are less understood. In this study, we sought to identify the function of Dectin-1, a C-type lectin receptor (CLR), in CNS autoimmunity. We found that Dectin-1 limited neuroinflammation in EAE while its canonical signaling mediator, Card9, promoted disease. Myeloid cells from the bone-marrow mediated the regulatory function of Dectin-1 in EAE and upregulated expression of Oncostatin M (Osm), a neuroprotective cytokine, through a non-canonical Card9-independent Dectin-1 signaling pathway. We found that the Osm receptor (OsmR) functioned specifically in astrocytes to reduce EAE severity. RNA-seq profiling of the Card9-independent Dectin-1 transcriptional program identified multiple targets with neuroprotective functions, including Osm, which were regulated by NFAT signaling. Our data describe a new mechanism of neuroprotective myeloid-astrocyte crosstalk regulated by a non-canonical Dectin-1 pathway.

ILC3, a Central Innate Immune Component of the Gut-Brain Axis in Multiple Sclerosis.

Gut immune cells have been increasingly appreciated as important players in the central nervous system (CNS) autoimmunity in animal models of multiple sclerosis (MS). Among the gut immune cells, innate lymphoid cell type 3 (ILC3) is of special interest in MS research, as they represent the innate cell counterpart of the major pathogenic cell population in MS, i.e. T helper (Th)17 cells. Importantly, these cells have been shown to stimulate regulatory T cells (Treg) and to counteract pathogenic Th17 cells in animal models of autoimmune diseases. Besides, they are also well known for their ability to stabilize the intestinal barrier and to shape the immune response to the gut microbiota. Thus, proper maintenance of the intestinal barrier and the establishment of the regulatory milieu in the gut performed by ILC3 may prevent activation of CNS antigen-specific Th17 cells by the molecular mimicry. Recent findings on the role of ILC3 in the gut-CNS axis and their relevance for MS pathogenesis will be discussed in this paper. Possibilities of ILC3 functional modulation for the benefit of MS patients will be addressed, as well.