Central Nervous System Autoimmunity Research Articles

Susceptibility-weighted imaging in the differential diagnosis of autoimmune central nervous system vasculitis and multiple sclerosis

ObjectivesTo determine the differentiating features of autoimmune central nervous system (CNS) vasculitis and multiple sclerosis (MS) on susceptibility-weighted imaging (SWI). MethodsSeventy-three patients (27 with autoimmune CNS vasculitis and 46 with MS) who underwent magnetic resonance imaging with SWI sequence were included. The features of lesions and distinct SWI findings were investigated in both diseases. ResultsOn SWI, autoimmune CNS vasculitis presented with a higher prevalence of multiple microbleeds (48.1%), cortical superficial siderosis (70.4%), and tortuosity of the vascular route (59.3%) than were found in MS (p < 0.001, p < 0.001, and p = 0.001, respectively). Multivariable logistic analysis showed that multiple microbleeds and cortical superficial siderosis were associated with a much higher probability of a diagnosis of autoimmune CNS vasculitis than of MS (OR 19.09, 95% CI 1.13–321.18, p = 0.041; and OR 13.20, 95% CI 2.22–78.30, p = 0.005, respectively). The presence of more than eleven lesions was associated with a lower probability of a diagnosis of autoimmune CNS vasculitis than of MS (OR 0.14, 95% CI 0.03–0.73, p = 0.020). ConclusionsSWI may be a useful adjunct in distinguishing autoimmune CNS vasculitis from MS. The identification of multiple microbleeds and cortical superficial siderosis can point to a diagnosis of autoimmune CNS vasculitis.

Interleukin 22 ameliorates neuropathology and protects from central nervous system autoimmunity

IL-22 has opposing effects in different tissues, from pro-inflammatory (skin, joints) to protective (liver, intestine) but little is known about its effects on neuroinflammation. We examined the effect of IL-22 on retinal tissue by using the model of experimental autoimmune uveitis (EAU) in IL-22−/− mice, as well as by intraocular injections of recombinant IL-22 or anti-IL-22 antibodies in wild type animals. During EAU, IL-22 was produced in the eye by CD4+ eye-infiltrating T cells. EAU-challenged IL-22−/− mice, as well as WT mice treated systemically or intraocularly with anti-IL-22 antibodies during the expression phase of disease, developed exacerbated retinal damage. Furthermore, IL-22−/− mice were more susceptible than WT controls to glutamate-induced neurotoxicity, whereas local IL-22 supplementation was protective, suggesting direct or indirect neuroprotective effects. Mechanistic studies revealed that retinal glial Müller cells express IL-22rα1 in vivo, and in vitro IL-22 enhanced their ability to suppress proliferation of effector T cells. Finally, IL-22 injected into the eye concurrently with IL-1, inhibited the (IL-1-induced) expression of multiple proinflammatory and proapoptotic genes in retinal tissue. These findings suggest that IL-22 can function locally within the retina to reduce inflammatory damage and provide neuroprotection by affecting multiple molecular and cellular pathways.

Type 2 Inflammatory Responses in Autoimmune Demyelination of the Central Nervous System: Recent Advances.

Type 2 immunity has long been confined to a restricted spectrum of responses, mostly including allergic reactions to innocuous environmental triggers. However, growing evidence suggests that cells and mediators typically associated with type 2 inflammation are involved in several physiopathological conditions, such as defense against toxic substances, anticancer immunity, and autoimmune diseases. In neuromyelitis optica, an autoimmune demyelinating disorder of the spinal cord and optic nerve, eosinophils extensively infiltrate lesions in the central nervous system (CNS) and promote tissue pathology in experimental models of this disease. Next-generation sequencing of CD4+ T cells isolated from a specific subtype of multiple sclerosis plaque has uncovered an unexpectedly Th2 profile of these cells. Even mast cells and other allergic mediators have been implicated in the modulation and/or effector mechanisms of autoimmune reactions against the CNS. In this review article, the most recent developments showing the involvement of type 2 inflammatory components in CNS autoimmunity are summarised and possible lines of further investigation are discussed.

Contribution of Protein Arginine Methyltransferase (PRMT)5 to House Dust Mite Asthma

Abstract Severe asthma affects 2.4 million Americans and 23.8 million people worldwide and accounts for the majority of total asthma hospital costs. Most severe asthma is mediated by Th17/neutrophilic responses, alone or combined with Th2 and/or Th1 responses. In contrast, Treg responses are deficient. Protein Arginine Methyl Transferase (PRMT) 5 catalyzes symmetric dimethylation (SDM) of arginine on histones and other proteins, thereby regulating gene expression. PRMT5 promotes murine Th1/Th17 responses in central nervous system autoimmunity. However, its impact on asthma has not been established. We evaluated the role of PRMT5 on mouse models of house dust mite (HDM) asthma. PRMT5 and its symmetric demethylation activity were increased in lung infiltrating cells during Th2/Th17-mediated HDM severe asthma, suggesting a role for PRMT5 in asthma pathogenesis. To determine the contribution of PRMT5 to HDM asthma pathogenesis, we used first-in-class PRMT5-specific inhibitors developed at The Ohio State University. PRMT5 inhibitor HLCL65 modulated Th1, Th2 and Th17 differentiation and suppressed airway hyperreactivity in Th2/Th17 models of house dust mite (HDM)-induced asthma. Overall, these results support a role for PRMT5 in severe asthma pathogenesis.

Interactions between the host genome and the gut microbiome determine susceptibility to CNS autoimmune disease

Abstract Multiple sclerosis (MS) is a chronic autoimmune central nervous system (CNS) disease and the leading cause of non-traumatic neurological disability in young adults. The etiology of MS is multifactorial and polygenic, with 30% of risk genetic and 70% environmental. Recent studies identified an imbalance in the human gut microbiome within MS patients, including depletion of the Lactobacillus genus. Animal models support a causal role of the gut microbiome in MS, though the mechanisms remain unclear. Here, we leverage natural genetic variation in wild-derived PWD/PhJ (PWD) mice as compared to classic C57BL/6J (B6) mice, modeling human genetic diversity to identify host genome and gut microbiome interactions governing disease susceptibility. In a model of MS, experimental autoimmune encephalomyelitis (EAE), 27 consomic strains carrying PWD chromosomes on the B6 background demonstrated that PWD-derived loci exhibit bidirectional and sex-specific effects on disease severity. 16S rRNA gene sequencing of the gut microbiome in consomic and parental strains identified strain-specific profiles and metabolic functions associated with differential susceptibility to EAE. Functionally, manipulation of the gut microbiome by co-housing or transplantation, demonstrated direct host genotype-dependent effects of the microbiome on EAE susceptibility, with transfer of signature Lactobacillus species associated with changes in circulating indole metabolites and altered EAE severity. These studies reveal the presence of complex bidirectional interactions between the host genome and gut microbiome that modulate susceptibility to CNS autoimmunity, and identify specific microbiome constituents as potential therapeutic candidates.

Linking diet, gut microbiota and autoimmunity: A phytoestrogen diet alters the gut microbiota and influences Experimental Autoimmune Encephalomyelitis (EAE)

Abstract The etiology of multiple sclerosis (MS) involves genetic predisposition and an unknown environmental trigger. The gut microbiome may be an environmental contributing factor. Previously, we have shown that certain gut bacteria especially those with ability to metabolize phytoestrogen are less abundant in MS patients compared to healthy individuals. We hypothesize that phytoestrogen metabolism via microbial flora induces an anti-inflammatory state in the intestine. Therefore their reduced levels might predispose to disease development and/or severity. To test this, we placed C57Bl/6 mice on a diet with or without phytoestrogens and induced Experimental Autoimmune Encephalomyelitis (EAE), an experimental model of MS. We observed that mice on a phytoestrogen diet developed milder disease compared to those on a phytoestrogen free diet; a phenomenon dependent on the presence of phytoestrogen-metabolizing bacteria in the gut. We also found that a phytoestrogen diet alters the gut microbiota compared to a phytoestrogen-free diet with the gut microbiota of phytoestrogen group closely resembling the gut microbiota of healthy individuals. The gut microbiota of mice on a phytoestrogen-free diet closely resembles the gut microbiota of MS patients. Furthermore, mice on a phytoestrogen-diet exhibit an altered immune profile in the colonic lamina propria and mesenteric lymph nodes. Finally, we found that phytoestrogen-metabolites altered the cytokine-producing function of human colonic epithelial cells in vitro. Our results suggest that dietary phytoestrogen metabolites produced by commensal bacteria can alter the phenotype and function of the intestinal immune system, which may influence central nervous system autoimmunity.

Accuracy of MRI Sequences in Detecting Multiple Sclerosis (MS) Lesions: A Systematic Review

Introduction: Multiple sclerosis (MS) is one of the chronic autoimmune central nervous system disorder that characterized by demyelination of axon in brain cortex and the other grey and white matter regions and it makes several symptoms. Magnetic Resonance Imaging (MRI) with high sensitivity is the most important preclinical tool for the diagnosis of MS. The aim is to conduct systematic review studies carried out on accuracy of MRI sequences in detecting Multiple Sclerosis (MS) lesions. Methods: This study was systematic review. The related studies accomplished about using MRI in detecting MS lesions in worldwide included by searching in database and journal websites, including PubMed, Google Scholar and Medline. These articles searched by main keywords such as MRI, MS, lesions, sequence, and detecting. Conclusion: Our reviewing study showed that Double Inversion Recovery (DIR) Sequence in MRI has a high sensitivity to detect of lesion of MS. Furthermore, we recommend that the physicians add DIR sequence in routine MR protocols for diagnostic MS in patients.

Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation

The molecular events underlying the transition from initial inflammatory flares to the progressive phase of multiple sclerosis (MS) remain poorly understood. Here, we report that the microtubule-associated protein (MAP) Tau exerts a gender-specific protective function on disease progression in the MS model experimental autoimmune encephalomyelitis (EAE). A detailed investigation of the autoimmune response in Tau-deficient mice excluded a strong immunoregulatory role for Tau, suggesting that its beneficial effects are presumably exerted within the central nervous system (CNS). Spinal cord transcriptomic data show increased synaptic dysfunctions and alterations in the NF-kB activation pathway upon EAE in Tau-deficient mice as compared to wildtype animals. We also performed the first comprehensive characterization of Tau post-translational modifications (PTMs) in the nervous system upon EAE. We report that the methylation levels of the conserved lysine residue K306 are significantly decreased in the chronic phase of the disease. By combining biochemical assays and molecular dynamics (MD) simulations, we demonstrate that methylation at K306 decreases the affinity of Tau for the microtubule network. Thus, the down-regulation of this PTM might represent a homeostatic response to enhance axonal stability against an autoimmune CNS insult. The results, altogether, position Tau as key mediator between the inflammatory processes and neurodegeneration that seems to unify many CNS diseases.

Diagnosis and Management of Autoimmune Dementia.

To describe the clinical, laboratory, and MRI features that characterize cognitive decline in the setting of central nervous system (CNS) autoimmunity, and provide an overview of current treatment modalities. The field of autoimmune neurology is rapidly expanding due to the increasing number of newly discovered autoantibodies directed against specific CNS targets. The clinical syndromes associated with these autoantibodies are heterogeneous but frequently share common, recognizable clinical, and MRI characteristics. While the detection of certain autoantibodies strongly suggest the presence of an underlying malignancy (onconeural autoantibodies), a large proportion of cases remain idiopathic. Cognitive decline and encephalopathy are common manifestations of CNS autoimmunity, and can mimic neurodegenerative disorders. Recent findings suggest that the frequency of autoimmune encephalitis in the population is higher than previously thought, and potentially rivals that of infectious encephalitis. Moreover, emerging clinical scenarios that may predispose to CNS autoimmunity are increasingly been recognized. These include autoimmune dementia/encephalitis post-herpes simplex virus encephalitis, post-transplant and in association with immune checkpoint inhibitor treatment of cancer. Early recognition of autoimmune cognitive impairment is important given the potential for reversibility and disability prevention with appropriate treatment. Autoimmune cognitive impairment is treatable and may arise in a number of different clinical settings, with important treatment implications. Several clinical and para-clinical clues may help to differentiate these disorders from dementia of other etiologies.

The Different Clinical Features Between Autoimmune and Infectious Status Epilepticus

Objective: The prognosis of status epilepticus (SE) is highly related to the underlying etiology. Inflammation of the central nervous system (CNS), including infection and autoimmune encephalitis, is one of the treatable conditions causing SE. The initial presentation of infectious and autoimmune CNS disorders can be quite similar, which may be difficult to differentiate at the beginning. However, treatment for these entities can be quite different. In this study, we aim to identify the differences in clinical features among patients with infectious and autoimmune SE, which could help the clinicians to select initial investigation and ensuing therapies that may improve overall outcomes.Methods: This was a retrospective study that included 501 patients with SE within a period of 10.5-years. Patients with inflammatory etiology were collected and separated into infectious and autoimmune SE. The symptoms at onset, SE semiology, status epilepticus severity score, and END-IT score at admission, treatment for SE, and outcome (modified Rankin Scale) on discharge and last follow-up were recorded. Data on the first cerebrospinal fluid, electroencephalography, and magnetic resonance imaging were also collected.Results: Forty-six (9.2%) of the 501 patients had SE with inflammatory etiology. Twenty-five (5%) patients were autoimmune SE and 21 (4.2%) were infectious SE. Patients with autoimmune SE have younger age and female predominance. As for clinical presentations, psychosis, non-convulsive SE, and super refractory SE were more common in patients with autoimmune SE. Nevertheless, the prognosis showed no difference between the two groups.Conclusion: The different initial clinical presentations and patient characteristics may provide some clues about the underlying etiology of SE. When inflammatory etiology is suspected in patients with SE, younger age, female sex, psychosis, non-convulsive SE, and super refractory SE are clinical features that suggest an autoimmune etiology.

Combination Therapy With Fingolimod and Neural Stem Cells Promotes Functional Myelination in vivo Through a Non-immunomodulatory Mechanism.

Myelination, which occurs predominantly postnatally and continues throughout life, is important for proper neurologic function of the mammalian central nervous system (CNS). We have previously demonstrated that the combination therapy of fingolimod (FTY720) and transplanted neural stem cells (NSCs) had a significantly enhanced therapeutic effect on the chronic stage of experimental autoimmune encephalomyelitis, an animal model of CNS autoimmunity, compared to using either one of them alone. However, reduced disease severity may be secondary to the immunomodulatory effects of FTY720 and NSCs, while whether this therapy directly affects myelinogenesis remains unknown. To investigate this important question, we used three myelination models under minimal or non-inflammatory microenvironments. Our results showed that FTY720 drives NSCs to differentiate into oligodendrocytes and promotes myelination in an ex vivo brain slice culture model, and in the developing CNS of healthy postnatal mice in vivo. Elevated levels of neurotrophic factors, e.g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, were observed in the CNS of the treated infant mice. Further, FTY720 and NSCs efficiently prolonged the survival and improved sensorimotor function of shiverer mice. Together, these data demonstrate a direct effect of FTY720, beyond its known immunomodulatory capacity, in NSC differentiation and myelin development as a novel mechanism underlying its therapeutic effect in demyelinating diseases.

Autoimmune glial fibrillary acidic protein astrocytopathy.

Purpose of reviewTo describe a recently characterized autoimmune, inflammatory central nervous system (CNS) disorder known as autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy.Recent findingsAffected patients present with symptoms of one or more of meningitis (headache and neck ache), encephalitis (delirium, tremor, seizures, or psychiatric symptoms), and myelitis (sensory symptoms and weakness). Optic disc papillitis (blurred vision) is common. CNS inflammation is evident in characteristic T1 postgadolinium enhancement of GFAP-enriched CNS regions, and lymphocytic cerebrospinal fluid (CSF) white cell count elevation. CSF is more reliable than serum for GFAP-immunoglobulin G (IgG) testing. Ovarian teratoma commonly coexists, particularly among patients with accompanying N-methyl-D-aspartate receptor or aquaporin-4 autoimmunity. Parainfectious autoimmunity is suspected in some other patients, though the culprit organism is rarely verified. Pathophysiologic relevance of T cells is underscored by neuropathology and cases of dysregulated T-cell function (HIV or checkpoint inhibitor cancer therapy). Corticosteroid-responsiveness is a hallmark of the disease. Relapses occur in approximately 20% of patients, necessitating transition to a steroid-sparing drug. Reported outcomes vary, though in the authors’ experience, early and sustained intervention usually portends recovery.SummaryAutoimmune GFAP astrocytopathy is a treatable autoimmune CNS disease diagnosable by GFAP-IgG testing in CSF. This disease presents opportunities to explore novel mechanisms of CNS autoimmunity and inflammation.

CNS inflammation and neurodegeneration: sequelae of peripheral inoculation with spinal cord tissue in rat.

Recent research demonstrates that victims of spinal cord injury (SCI) are at increased risk for dementia and that encephalitis can occur as a consequence of isolated SCI. We theorize that autoimmunity to the central nervous system (CNS) could explain these phenomena and undertook this study to determine whether peripheral inoculation with spinal cord homogenate on 1 or 2 occasions is associated with CNS-directed autoimmunity and neurodegeneration in a rat model. Rats were subcutaneously inoculated with saline or 75 mg of allogeneic spinal cord tissue on 1 or 2 occasions. Animals underwent Morris Water Maze testing, and serial serum samples were collected. Animals were sacrificed 8 weeks following the first inoculation. Autoantibody titers to myelin antigens MAG and GM1 were measured in serum. Immunohistochemistry was used to identify autoantibodies targeting NeuN-labeled neurons and CC1-labeled oligodendrocytes. Quantitative real-time polymerase chain reaction (qPCR) and western blotting were performed for pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and the cell death marker caspase 3 as well as the neurodegenerative proteins tau and β-amyloid in both brain and spinal cord. Fluoro-Jade B was used to stain degenerating neurons, facilitating counting. Animals inoculated with spinal cord homogenate exhibited increased titers of autoantibodies to MAG and GM1 and autoantibodies binding to neurons and oligodendrocytes. Double-inoculated animals demonstrated a significant increase in the expression of pro-inflammatory cytokines in the brain (TNF-α, p = 0.016; IL-6, p = 0.009) as well as the spinal cord (TNF-α, p = 0.024; IL-6, p = 0.002). The number of degenerating neurons was significantly increased in the brain and spinal cord of inoculated animals (p < 0.0001 and p = 0.028, respectively). Elevated expression of tau and β-amyloid was seen in brain of double-inoculated animals (p = 0.003 and p = 0.009, respectively). Inflammatory marker expression in the brain was positively correlated with anti-myelin autoimmune antibody titers and with tau expression in the brain. Inoculated animals showed impaired memory function in Morris Water Maze testing (p = 0.043). The results of these experiments demonstrate that peripheral exposure to spinal cord antigens is associated with CNS-directed autoimmunity and inflammation in the brain and spinal cord as well as degeneration of CNS cells, memory impairment, and production of neurodegenerative proteins particularly when this exposure is repeated. These data support CNS autoimmunity as a candidate mechanism for the dementia that can follow SCI and perhaps other posttraumatic dementias such as chronic traumatic encephalopathy.

Exploiting the Therapeutic Potential of Endogenous Immunomodulatory Systems in Multiple Sclerosis-Special Focus on the Peroxisome Proliferator-Activated Receptors (PPARs) and the Kynurenines.

Multiple sclerosis (MS) is a progressive neurodegenerative disease, characterized by autoimmune central nervous system (CNS) demyelination attributable to a disturbed balance between encephalitic T helper 1 (Th1) and T helper 17 (Th17) and immunomodulatory regulatory T cell (Treg) and T helper 2 (Th2) cells, and an alternatively activated macrophage (M2) excess. Endogenous molecular systems regulating these inflammatory processes have recently been investigated to identify molecules that can potentially influence the course of the disease. These include the peroxisome proliferator-activated receptors (PPARs), PPARγ coactivator-1alpha (PGC-1α), and kynurenine pathway metabolites. Although all PPARs ameliorate experimental autoimmune encephalomyelitis (EAE), recent evidence suggests that PPARα, PPARβ/δ agonists have less pronounced immunomodulatory effects and, along with PGC-1α, are not biomarkers of neuroinflammation in contrast to PPARγ. Small clinical trials with PPARγ agonists have been published with positive results. Proposed as immunomodulatory and neuroprotective, the therapeutic use of PGC-1α activation needs to be assessed in EAE/MS. The activation of indolamine 2,3-dioxygenase (IDO), the rate-limiting step of the kynurenine pathway of tryptophan (Trp) metabolism, plays crucial immunomodulatory roles. Indeed, Trp metabolites have therapeutic relevance in EAE and drugs with structural analogy to kynurenines, such as teriflunomide, are already approved for MS. Further studies are required to gain deeper knowledge of such endogenous immunomodulatory pathways with potential therapeutic implications in MS.

Interferon β-Mediated Protective Functions of Microglia in Central Nervous System Autoimmunity.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and axonal damage. It often affects young adults and can lead to neurological disability. Interferon β (IFNβ) preparations represent widely used treatment regimens for patients with relapsing-remitting MS (RRMS) with therapeutic efficacy in reducing disease progression and frequency of acute exacerbations. In mice, IFNβ therapy has been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS while genetic deletion of IFNβ or its receptor augments clinical severity of disease. However, the complex mechanism of action of IFNβ in CNS autoimmunity has not been fully elucidated. Here, we review our current understanding of the origin, phenotype, and function of microglia and CNS immigrating macrophages in the pathogenesis of MS and EAE. In addition, we highlight the emerging roles of microglia as IFNβ-producing cells and vice versa the impact of IFNβ on microglia in CNS autoimmunity. We finally discuss recent progress in unraveling the underlying molecular mechanisms of IFNβ-mediated effects in EAE.

Deterioro cognitivo en pacientes con esclerosis múltiple

La esclerosis múltiple es una enfermedad inflamatoria, autoinmune y neurodegenerativa del sistema nervioso central caracterizada por pérdida de la función motora y sensitiva; es considerada una de las principales causas de discapacidad en el adulto joven. Recientemente, se le ha dado gran importancia al deterioro cognitivo, por ser un síntoma frecuente y discapacitante. Este deterioro está presente en un 40 a 65% de los pacientes y afecta la velocidad de procesamiento de información, atención compleja, memoria de trabajo, memoria visual y verbal, fluencia verbal y funciones ejecutivas. Se puede presentar en el síndrome radiológico aislado, en el síndrome clínico aislado y en las diferentes fases de la enfermedad; además, es el responsable de la dependencia de algunos pacientes y de las dificultades para mantener o conseguir empleo. Este déficit cognitivo se asocia a atrofia del tálamo y se ha observado una correlación con las medidas de atrofia y con el volumen lesional cerebral. Existen diferentes herramientas para su evaluación; hay pruebas de cribado breves de 5 minutos de duración, hasta baterías extensas de 90 minutos. Respecto al tratamiento de las alteraciones cognitivas, no existe un tratamiento farmacológico específico; sin embargo, se considera que los fármacos modificadores de la enfermedad podrían tener una influencia favorable en la función cognitiva por sus efectos en la reducción de la actividad inflamatoria y la atrofia cerebral. En cuanto a la estimulación cognitiva, no existen datos concluyentes por las diferentes técnicas empleadas y las distintas medidas utilizadas para evaluar los resultados de las intervenciones.

Bacteria-Host Interactions in Multiple Sclerosis.

Multiple sclerosis (MS) is caused by a complex interaction of genetic and environmental factors. Numerous causative factors have been identified that play a role in MS, including exposure to bacteria. Mycobacteria, Chlamydia pneumoniae, Helicobacter pylori, and other bacteria have been proposed as risk factors for MS with different mechanisms of action. Conversely, some pathogens may have a protective effect on its etiology. In terms of acquired immunity, molecular mimicry has been hypothesized as the mechanism by which bacterial structures such as DNA, the cell wall, and intracytoplasmic components can activate autoreactive T cells or produce autoantibodies in certain host genetic backgrounds of susceptible individuals. In innate immunity, Toll-like receptors play an essential role in combating invading bacteria, and their activation leads to the release of cytokines or chemokines that mediate effective adaptive immune responses. These receptors may also be involved in central nervous system autoimmunity, and their contribution depends on the infection site and on the pathogen. We have reviewed the current knowledge of the influence of bacteria on MS development, emphasizing the potential mechanisms of action by which bacteria affect MS initiation and/or progression.

Mycophenolate mofetil in the treatment of pediatric autoimmune central nervous system disease.

This commentary is on the original article by Nosadini et al. on pages 458–468 of this issue.

Antigen-presenting cell diversity for T cell reactivation in central nervous system autoimmunity.

Autoreactive T cells are considered the major culprits in the pathogenesis of many autoimmune diseases like multiple sclerosis (MS). Upon activation in the lymphoid organs, autoreactive T cells migrate towards the central nervous system (CNS) and target the myelin sheath-forming oligodendrocytes, resulting in detrimental neurological symptoms. Despite the availability of extensively studied systems like the experimental autoimmune encephalomyelitis (EAE) model, our understanding of this disease and the underlying pathogenesis is still elusive. One vividly discussed subject represents the T cell reactivation in the CNS. In order to exert their effector functions in the CNS, autoreactive T cells must encounter antigen-presenting cells (APCs). This interaction provides an antigen-restricted stimulus in the context of major histocompatibility complex class II (MHC-II) and other co-stimulatory molecules. Peripherally derived dendritic cells (DCs), B cells, border-associated macrophages (BAM), CNS-resident microglia, and astrocytes have the capacity to express molecules required for antigen presentation under inflammatory conditions. Also, endothelial cells can fulfill these prerequisites in certain situations. Which of these cells in fact act as APCs for T cell reactivation and to which extent they can exert this function has been studied intensively, but unfortunately with no firm conclusion. In this review, we will summarize the findings that support or question the antigen presenting capacities of the mentioned cell types of CNS-localized T cell reactivation.

Myeloid-derived suppressor cells control B cell accumulation in the central nervous system during autoimmunity.

PMN-MDSCs (polymorphonuclear myeloid-derived suppressor cells) have been characterized in the context of malignancies. Here we found that PMN-MDSCs had the unique ability to restrain B cell accumulation during central nervous system (CNS) autoimmunity. Ly6G+ cells were recruited to the CNS during experimental autoimmune encephalomyelitis (EAE), interacted with B cells that produced the cytokines GM-CSF and IL-6, and acquired properties of PMN-MDSCs in the CNS in a manner dependent on the signal transducer STAT3. Depletion of Ly6G+ cells or dysfunction of Ly6G+ cells through conditional ablation of STAT3 resulted in the selective accumulation of GM-CSF-producing B cells in the CNS compartment, which in turn promoted an activated microglial phenotype and failure to recover from EAE. The frequency of CD138+ B cells in the cerebrospinal fluid (CSF) of human patients with multiple sclerosis negatively correlated with the frequency of PMN-MDSCs in the CSF. Thus, PMN-MDSCs might selectively control the accumulation and cytokine secretion of B cells within the inflamed CNS.