• ADAP1/CentA1
• autoimmunity
• experimental autoimmune encephalomyelitis
• multiple sclerosis

• Animals
• Encephalomyelitis, Autoimmune, Experimental/immunology
• Encephalomyelitis, Autoimmune, Experimental/metabolism
• Encephalomyelitis, Autoimmune, Experimental/genetics
• Encephalomyelitis, Autoimmune, Experimental/pathology
• Mice
• Mice, Inbred C57BL
• Multiple Sclerosis/immunology
• Multiple Sclerosis/metabolism
• Mice, Knockout
• Female
• Microfilament Proteins/genetics
• Microfilament Proteins/metabolism
• Autoimmunity

• The Wooten Family Initiative for Brain Health Research
• East Carolina University Startup Funds

• Alzheimer's disease
• NK cells
• cytotoxicity
• immunosenescence

• Humans
• Animals
• Natural Killer T-Cells/immunology
• Alzheimer Disease/immunology
• Alzheimer Disease/pathology
• Alzheimer Disease/therapy
• Immunosenescence
• Brain/immunology
• Brain/pathology
• Brain/physiopathology
• Cognition Disorders/immunology
• Cognition Disorders/physiopathology

• 451-03-65/2024-03/200113 Ministry of Science, Technological Development, and Innovation of the Republic of Serbia

• Alzheimer’s Disease
• Biomarkers
• Natural killer cell

• Humans
• Alzheimer Disease/therapy
• Alzheimer Disease/cerebrospinal fluid
• Alzheimer Disease/immunology
• Male
• Female
• Aged
• Killer Cells, Natural/transplantation
• Middle Aged
• Aged, 80 and over
• Biomarkers/cerebrospinal fluid
• Treatment Outcome
• tau Proteins/cerebrospinal fluid

• NKGen Biotech, Inc.

• neuroimmunology
• immune system

• Meninges/immunology
• Animals
• Skull/immunology
• Skull/anatomy & histology
• Humans
• Bone Marrow/immunology
• Bone Marrow/anatomy & histology
• Central Nervous System/immunology
• Immunologic Surveillance

• This work was supported by grants from the National Natural Science Foundation of China (No. 82271399), the Project of Tianjin Applied Basic and Multiple Support Research (No. 21JCZDJC00910), the Tianjin Health Care Elite Prominent Young Doctor Development Program, the Young and Middle-aged Backbone Innovative Talent Program, and Clinical Talent Training “123” Climbing Plan of Tianjin Medical University.

• Diagnosis
• MS
• MiRNAs
• Multiple sclerosis
• Pathogenesis

• Humans
• MicroRNAs/metabolism
• Multiple Sclerosis/diagnosis
• Multiple Sclerosis/genetics
• Multiple Sclerosis/therapy
• Drug Resistance, Neoplasm

• Alzheimer’s disease
• cytotoxicity
• innate immunity
• natural killer cell
• single cell sequencing

• Humans
• CD56 Antigen/genetics
• CD56 Antigen/analysis
• Transcriptome
• Alzheimer Disease/genetics
• Immunity, Innate
• Killer Cells, Natural

Multiple sclerosis (MS) is a highly debilitating autoimmune disease affecting millions of individuals worldwide. Although classically viewed as T-cell mediated disease, the role of innate lymphoid cells (ILC) such as natural killer (NK) cells and ILC 1-3s has become a focal point as several findings implicate them in the disease pathology. The role of ILCs in MS is still not completely understood as controversial findings have been reported assigning them either a protective or disease-accelerating role. Recent findings in experimental autoimmune encephalomyelitis (EAE) suggest that ILCs infiltrate the central nervous system (CNS), mediate inflammation, and have a disease exacerbating role by influencing the recruitment of autoreactive T-cells. Elucidating the detailed role of ILCs and altered signaling pathways in MS is essential for a more complete picture of the disease pathology and novel therapeutic targets. We here review the current knowledge about ILCs in the development and progression of MS and preclinical models of MS and discuss their potential for therapeutic applications.

• Animals
• Encephalomyelitis, Autoimmune, Experimental
• Humans
• Immunity, Innate
• Killer Cells, Natural/pathology
• Multiple Sclerosis/pathology
• T-Lymphocytes/pathology

• Austrian Science Fund

The transcription factor STAT1 plays a critical role in modulating the differentiation of CD4⁺ T cells producing IL-17 and GM-CSF, which promote the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The protective role of STAT1 in MS and EAE has been largely attributed to its ability to limit pathogenic Th cells and promote Tregs. Using mice with selective deletion of STAT1 in T cells (STAT1^CD4-Cre), we identified a potentially novel mechanism by which STAT1 regulates neuroinflammation independently of Foxp3⁺ Tregs. STAT1-deficient effector T cells became the target of NK cell–mediated killing, limiting their capacity to induce EAE. STAT1-deficient T cells promoted their own killing by producing more IL-2 that, in return, activated NK cells. Elimination of NK cells restored EAE susceptibility in STAT1^CD4-Cre mice. Therefore, our study suggests that the STAT1 pathway can be manipulated to limit autoreactive T cells during autoimmunity directed against the CNS.

• Autoimmunity
• Cytokines
• Multiple sclerosis
• T cells

• choroid plexus
• human
• immunology
• inflammation
• multiple sclerosis
• natural killer cells
• neuroscience
• periventricular
• septum
• single-cell mass cytometry

• CD56 Antigen/metabolism
• Granzymes
• Humans
• Killer Cells, Natural
• Multiple Sclerosis/metabolism
• Neural Cell Adhesion Molecules/metabolism
• T-Lymphocytes

• Stichting MS Research

Studies investigating the immunopathology of multiple sclerosis (MS) have largely focused on adaptive T and B lymphocytes. However, in recent years there has been an increased interest in the contribution of innate immune cells, amongst which the natural killer (NK) cells. Apart from their canonical role of controlling viral infections, cell stress and malignancies, NK cells are increasingly being recognized for their modulating effect on the adaptive immune system, both in health and autoimmune disease. From different lines of research there is now evidence that NK cells contribute to MS immunopathology. In this review, we provide an overview of studies that have investigated the role of NK cells in the pathogenesis of MS by use of the experimental autoimmune encephalomyelitis (EAE) animal model, MS genetics or through ex vivo and in vitro work into the immunology of MS patients. With the advent of modern hypothesis-free technologies such as single-cell transcriptomics, we are exposing an unexpected NK cell heterogeneity, increasingly blurring the boundaries between adaptive and innate immunity. We conclude that unravelling this heterogeneity, as well as the mechanistic link between innate and adaptive immune cell functions will lay the foundation for the use of NK cells as prognostic tools and therapeutic targets in MS and a myriad of other currently uncurable autoimmune disorders.

• autoimmune disorders
• experimental autoimmune encephalomyelitis (EAE)
• immune cell heterogeneity
• multiple sclerosis
• multiple sclerosis genetics
• natural killer (NK) cells

• B cells
• IL-10
• MS
• NK cells
• NMOSD

• Iran University of Medical Sciences

• Aging
• CNS and lymphoid tissues
• FoxP3+ regulatory T cells
• Multiple sclerosis
• Self-reactive conventional T cells
• Sex difference

The pathological hallmark of multiple sclerosis (MS) is the formation of multifocal demyelinating lesions in the central nervous system (CNS). Stimulation of innate receptors has been shown to suppress experimental autoimmune encephalomyelitis (EAE), an MS-like disease in mice. Specifically, targeting Toll-like receptor 9 (TLR9) and NOD-like receptor 2 (NOD2) significantly reduced disease severity. In the present work we have developed a novel focal EAE model to further study the effect of innate signaling on demyelinating pathology. Focal lesions were induced by stereotactic needle insertion into the corpus callosum (CC) of mice previously immunized for EAE. This resulted in focal pathology characterized by infiltration and demyelination in the CC. We find that intrathecal delivery of MIS416, a TLR9 and NOD2 bispecific innate ligand, into the cerebrospinal fluid reduced focal lesions in the CC. This was associated with upregulation of type I and II interferons, interleukin-10, arginase-1, CCL-2 and CXCL-10. Analysis of draining cervical lymph nodes showed upregulation of type II interferons and interleukin 10. Moreover, intrathecal MIS416 altered the composition of early CNS infiltrates, increasing proportions of myeloid and NK cells and reducing T cells at the lesion site. This study contributes to an increased understanding of how innate immune responses can play a protective role, which in turn may lead to additional therapeutic strategies for the prevention and treatment of demyelinating pathologies.

• NK cells
• T-cells
• demyelination
• focal EAE
• innate signaling
• myeloid cells
• neuroinflammation

• autoimmunity
• cytokines
• cytotoxicity
• innate immunity
• natural killer cells

• Animals
• Autoimmune Diseases/immunology
• Autoimmunity
• Cytotoxicity, Immunologic
• Humans
• Immunity, Innate
• Killer Cells, Natural/immunology

The exact aetiology of multiple sclerosis (MS) remains elusive, although several environmental and genetic risk factors have been implicated to varying degrees. Among the environmental risk factors, viral infections have been suggested as strong candidates contributing to MS pathology/progression. Viral recognition and control are largely tasked to the NK cells via TLR recognition and various cytotoxic and immunoregulatory functions. Additionally, the complex roles of different TLRs in MS pathology are highlighted in multiple, often contradictory, studies. The present work aims to analyse the TLR expression profile of NK cells isolated from MS patients. Highly purified CD56⁺CD3⁻ NK cells isolated from peripheral blood of MS patients (n = 19) and healthy controls (n = 20) were analysed via flow cytometry for their expression of viral antigen-recognizing TLRs (TLR2, TLR3, TLR7, and TLR9).

No difference was noted in TLR expression between MS patients and healthy controls. These results aim to supplement previous findings which study expressional or functional differences in TLRs present in various subsets of the immune system in MS, thus aiding in a better understanding of MS as a complex multifaceted disease.

• Flow cytometry
• Multiple sclerosis
• Natural killer cells
• Toll-like receptor

Natural killer (NK) cells, influencing dendritic cell (DC)-mediated CD4+ lymphocyte priming in draining lymph nodes (dLNs) and controlling spinal cord (SC) infiltration with encephalitogenic CD4+T lymphocytes, modulate EAE (multiple sclerosis model). This study examined their putative contribution to age-related differences in EAE development in Dark Agouti (DA) (exhibiting age-related decrease in EAE susceptibility) and Albino Oxford (AO) (becoming susceptible to EAE with aging) rats. Aging increased NK cell number in dLNs from rats of both strains. In AO rats, but not in DA ones, it also increased the numbers of IFN-γ-producing NK cells (important for DC activation) and activated/matured DCs, thereby increasing activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated CD25+Foxp3-CD4+ cell number. Aging in DA rats diminished activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated Foxp3-CD4+ cell number. However, MBP-stimulated CD4+ cell proliferation did not differ in dLN cell cultures from young and aged AO rats (as more favorable activated/matured DC/Foxp3-CD4+ cell ratio was abrogated by lower intrinsic CD4+ cell proliferative capacity and a greater regulatory CD25+Foxp3+CD4+ lymphocyte frequency), but was lower in those from aged compared with young DA rats. At SC level, aging shifted Foxp3-CD4+/cytotoxic CX3CR1+ NK cell ratio towards the former in AO rats, so it was less favorable in aged AO rats exhibiting prolonged neurological deficit compared with their DA counterparts. The study showed strain and age differences in number of IFN-γ-producing NK cells in EAE rat dLNs, and suggested that their pathogenetic relevance depends on frequency and/or activity of other cells involved in CD4+ T cell (auto)immune response.

• EAE
• NK cells
• aging
• dendritic cells
• strain differences

• ILC1s
• central nervous system (CNS)
• experimental autoimmune encephalomyelitis (EAE)
• innate lymphoid cells (ILCs)
• mouse
• natural killer (NK) cells

• Adaptive lymphocytes
• Experimental autoimmune encephalomyelitis
• Innate lymphoid cells
• Innate-like T and B cells
• Innate-like lymphocytes
• Multiple sclerosis

• Adaptive Immunity
• Animals
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental/immunology
• Humans
• Immunity, Innate
• Multiple Sclerosis/immunology
• T-Lymphocytes/immunology

• P30 DK058404 NIDDK NIH HHS
• R25 GM062459 NIGMS NIH HHS
• R01 DK104817 NIDDK NIH HHS
• T32 AR059039 NIAMS NIH HHS
• T32 HL069765 NHLBI NIH HHS
• U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)
• U.S. Department of Defense (United States Department of Defense)
• National Multiple Sclerosis Society (National MS Society)

Daclizumab (DAC) is a humanized, monoclonal antibody that blocks CD25, a critical element of the high-affinity interleukin-2 receptor (IL-2R). DAC HYP blockade of CD25 inhibits effector T cell activation, regulatory T cell expansion and survival, and activation-induced T-cell apoptosis. Because CD25 blockade reduces IL-2 consumption by effector T cells, it increases IL-2 bioavailability allowing for greater interaction with the intermediate-affinity IL-2R, and therefore drives the expansion of CD56^bright natural killer (NK) cells. Furthermore, there appears to be a direct correlation between CD56^bright NK cell expansion and DAC HYP efficacy in reducing relapses and MRI evidence of disease activity in patients with RMS in phase II and phase III double-blind, placebo- and active comparator-controlled trials. Therapeutic efficacy was maintained during open-label extension studies. However, treatment was associated with an increased risk of rare adverse events, including cutaneous inflammation, autoimmune hepatitis, central nervous system Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) syndrome, and autoimmune Glial Fibrillary Acidic Protein (GFAP) alpha immunoglobulin-associated encephalitis. As a result, DAC HYP was removed from clinical use in 2018. The lingering importance of DAC is that its use led to a deeper understanding of the underappreciated role of innate immunity in the potential treatment of autoimmune disease.

• CD25
• DRESS
• autoimmunity
• daclizumab
• drug reaction with eosinophilia systemic symptoms
• innate immune system
• interleukin-2
• relapsing multiple sclerosis

Quinoline-3-carboxamides, such as laquinimod, ameliorate CNS autoimmunity in patients and reduce tumor cell metastasis experimentally. Previous studies have focused on the immunomodulatory effect of laquinimod on myeloid cells. The data contained herein suggest that quinoline-3-carboxamides improve the immunomodulatory and anti-tumor effects of NK cells by upregulating the adhesion molecule DNAX accessory molecule-1 (DNAM-1).

We explored how NK cell activation by laquinimod inhibits CNS autoimmunity in experimental autoimmune encephalomyelitis (EAE), the most utilized model of MS, and improves immunosurveillance of experimental lung melanoma metastasis. Functional manipulations included in vivo NK and DC depletion experiments and in vitro assays of NK cell function. Clinical, histological, and flow cytometric read-outs were assessed.

We demonstrate that laquinimod activates natural killer (NK) cells via the aryl hydrocarbon receptor and increases their DNAM-1 cell surface expression. This activation improves the cytotoxicity of NK cells against B16F10 melanoma cells and augments their immunoregulatory functions in EAE by interacting with CD155⁺ dendritic cells (DC). Noteworthy, the immunosuppressive effect of laquinimod-activated NK cells was due to decreasing MHC class II antigen presentation by DC and not by increasing DC killing.

This study clarifies how DNAM-1 modifies the bidirectional crosstalk of NK cells with CD155⁺ DC, which can be exploited to suppress CNS autoimmunity and strengthen tumor surveillance.

The online version of this article (10.1186/s12974-019-1437-0) contains supplementary material, which is available to authorized users.

• Aryl hydrocarbon receptor
• B16F10 melanoma cells
• CNS autoimmunity
• DNAM-1/CD155 interactions
• Dendritic cells
• Experimental autoimmune encephalomyelitis
• Laquinimod
• Natural killer cells
• Quinoline-3-carboxamide

• Alzheimer disease
• Parkinson’s disease
• blood-brain barrier
• brain tumors
• inflammation
• innate immunity
• macrophage polarization
• multiple sclerosis
• neurodegeneration

• Animals
• Blood-Brain Barrier/pathology
• Humans
• Immunity, Innate
• Nervous System/blood supply
• Nervous System/cytology
• Nervous System/immunology

In autoimmunity, the balance of different helper T (Th) cell subsets can influence the tissue damage caused by autoreactive T cells. Pro-inflammatory Th1 and Th17 T cells are implicated as mediators of several human autoimmune conditions such as multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (aHSCT) has been tested in phase 2 clinical trials for MS patients with aggressive disease. Abrogation of new clinical relapses and brain lesions can be seen after ablative aHSCT, accompanied by significant reductions in Th17, but not Th1, cell populations and activity. The cause of this selective decrease in Th17 cell responses following ablative aHSCT is not completely understood. We identified an increase in the kinetics of natural killer (NK) cell reconstitution, relative to CD4⁺ T cells, in MS patients post-aHSCT, resulting in an increased NK cell:CD4⁺ T cell ratio that correlated with the degree of decrease in Th17 responses. Ex vivo removal of NK cells from post-aHSCT peripheral blood mononuclear cells resulted in higher Th17 cell responses, indicating that NK cells can regulate Th17 activity. NK cells were also found to be cytotoxic to memory Th17 cells, and this toxicity is mediated through NKG2D-dependent necrosis. Surprisingly, NK cells induced memory T cells to secrete more IL-17A. This was preceded by an early rise in T cell expression of RORC and IL17A mRNA, and could be blocked with neutralizing antibodies against CD58, a costimulatory receptor expressed on NK cells. Thus, NK cells provide initial co-stimulation that supports the induction of a Th17 response, followed by NKG2D-dependent cytotoxicity that limits these cells. Together these data suggest that rapid reconstitution of NK cells following aHSCT contribute to the suppression of the re-emergence of Th17 cells. This highlights the importance of NK cells in shaping the reconstituting immune system following aHSCT in MS patients.

• CD58
• NKG2D
• Th17 cells
• aHSCT
• multiple sclerosis
• natural killer cells

• immunogenetics
• neurological disease

• Animals
• Genetic Variation/genetics
• Genetic Variation/immunology
• Humans
• Immunogenetics
• Nervous System Diseases/genetics
• Nervous System Diseases/immunology

• R01 AI128775 NIAID NIH HHS
• R01 NS102153 NINDS NIH HHS
• U19 NS095774 NINDS NIH HHS

• Chemokine receptor
• Chemokines
• Innate lymphoid cells
• Migration
• Neurodegeneration
• Tissue localization

• autoimmune encephalomyelitis
• immune system
• monoclonal antibody
• multiple sclerosis

• Autoimmunity
• DMARDs
• KIR genes
• pharmacogenetics
• treatment response

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by loss of motor and sensory function that results from immune-mediated inflammation, demyelination, and subsequent axonal damage.

Clinically, most MS patients experience recurrent episodes (relapses) of neurological impairment, but in most cases (60–80%) the course of the disease eventually becomes chronic and progressive, leading to cumulative motor, sensory, and visual disability, and cognitive deficits.

The course of the disease is largely unpredictable and its clinical presentation is variable, but its predilection for certain parts of the CNS, which includes the optic nerves, the brain stem, cerebellum, and cervical spinal cord, provides a characteristic constellation of signs and symptoms. Several variants of MS have been nowadays defined with variable immunopathogenesis, course and prognosis. Many new treatments targeting the immune system have shown efficacy in preventing the relapses of MS and have been introduced to its management during the last decade.

• daclizumab
• disease-modifying therapy
• humanized monoclonal antibody
• relapsing multiple sclerosis
• therapeutic use

• CX3CR1
• Chemokines
• EAE
• NK cells
• Neuroinflammation

The role of interferon (IFN)-γ in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), has remained as an enigmatic paradox for more than 30 years. Several studies attribute this cytokine a prominent proinflammatory and pathogenic function in these pathologies. However, accumulating evidence shows that IFN-γ also plays a protective role inducing regulatory cell activity and modulating the effector T cell response. Several innate and adaptive immune cells also develop opposite functions strongly associated with the production of IFN-γ in EAE. Even the suppressive activity of different types of regulatory cells is dependent on IFN-γ. Interestingly, recent data supports a stage-specific participation of IFN-γ in EAE providing a plausible explanation for previous conflicting results. In this review, we will summarize and discuss such literature, emphasizing the protective role of IFN-γ on immune cells. These findings are fundamental to understand the complex role of IFN-γ in the pathogenesis of these diseases and can provide basis for potential stage-specific therapy for MS targeting IFN-γ-signaling or IFN-γ-producing immune cells.

• adaptive immunity
• experimental autoimmune encephalomyelitis
• innate immunity
• interferon-gamma
• multiple sclerosis
• neuroinflammation

• IL-17
• NK cells
• autoimmunity
• experimental autoimmune encephalomyelitis
• multiple sclerosis
• γ δ T cells

• Genetics
• Human leukocyte antigen
• Killer-cell immunoglobulin-like receptor
• Multiple sclerosis

• CSF
• innate immunity
• multiple sclerosis
• natural killer cells
• neuroinflammation

• NK cells
• cytotoxic T lymphocytes
• ischemic stroke
• perforin

To assess the relationship between CD56^bright natural killer (NK) cells and multiple sclerosis (MS) disease activity in patients with relapsing-remitting MS treated with daclizumab high-yield process (DAC HYP).

Data were from patients enrolled in a 52-week randomized, double-blind, placebo-controlled study of DAC HYP and its extension study. Assessments included relationships of CD56^bright NK cell numbers (identified using fluorescence-activated cell sorting) at weeks 4 and 8 with the numbers of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 and the annualized relapse rate.

In DAC HYP–treated patients but not placebo-treated patients, the numbers of CD56^bright NK cells increased over 52 weeks of treatment, and their numbers at weeks 4 and 8 predicted the number of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 of treatment (p ≤ 0.005 for each comparison). Similar but nonsignificant trends were observed between CD56^bright NK cell counts and the annualized relapse rate in DAC HYP–treated patients. DAC HYP–treated patients who showed lower levels of expansion of CD56^bright NK cells still developed fewer new or newly enlarging T2-hyperintense lesions than placebo-treated patients during the first year of treatment.

CD56^bright NK cells appear to mediate some of the treatment-related effects of DAC HYP, but their numbers do not account for the full effect of DAC HYP on MS-related outcomes.

• Immunotherapy
• NK cells and HIV1
• NK cells and autoimmunity
• NK cells and cancer
• Natural killer (NK) cells

• Acquired Immunodeficiency Syndrome/immunology
• Acquired Immunodeficiency Syndrome/pathology
• Acquired Immunodeficiency Syndrome/therapy
• Animals
• Asthma/immunology
• Asthma/pathology
• Asthma/therapy
• Autoimmune Diseases/immunology
• Autoimmune Diseases/pathology
• Autoimmune Diseases/therapy
• Humans
• Immunotherapy/methods
• Killer Cells, Natural/cytology
• Killer Cells, Natural/immunology
• Killer Cells, Natural/pathology
• Neoplasms/immunology
• Neoplasms/pathology
• Neoplasms/therapy
• Virus Diseases/immunology
• Virus Diseases/pathology
• Virus Diseases/therapy

Numerous neurological disorders are characterized by central nervous system (CNS) vascular permeability. However, the underlying contribution of inflammatory-derived factors leading to pathology associated with blood-brain barrier (BBB) disruption remains poorly understood. In order to address this, we developed an inducible model of BBB disruption using a variation of the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis. This peptide induced fatal syndrome (PIFS) model is initiated by virus-specific CD8 T cells and results in severe CNS vascular permeability and death in the C57BL/6 mouse strain. While perforin is required for BBB disruption, the cellular source of perforin has remained unidentified. In addition to CD8 T cells, various innate immune cells also express perforin and therefore could also contribute to BBB disruption. To investigate this, we isolated the CD8 T cell as the sole perforin-expressing cell type in the PIFS model through adoptive transfer techniques. We determined that C57BL/6 perforin^−/− mice reconstituted with perforin competent CD8 T cells and induced to undergo PIFS exhibited: 1) heightened CNS vascular permeability, 2) increased astrocyte activation as measured by GFAP expression, and 3) loss of linear organization of BBB tight junction proteins claudin-5 and occludin in areas of CNS vascular permeability when compared to mock-treated controls. These results are consistent with the characteristics associated with PIFS in perforin competent mice. Therefore, CD8 T cells are sufficient as a sole perforin-expressing cell type to cause BBB disruption in the PIFS model.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterised by widespread areas of focal demyelination. Its aetiology and pathogenesis remain unclear despite substantial insights gained through studies of animal models, most notably experimental autoimmune encephalomyelitis (EAE). MS is widely believed to be immune-mediated and pathologically attributable to myelin-specific autoreactive CD4+ T cells. In recent years, MS research has expanded beyond its focus on CD4+ T cells to recognise the contributions of multiple immune and glial cell types to the development, progression, and amelioration of the disease. This review summarises evidence of T and B lymphocyte, natural killer cell, macrophage/microglial, astrocytic, and oligodendroglial involvement in both EAE and MS and the intercommunication and influence of each cell subset in the inflammatory process. Despite important advances in the understanding of the involvement of these cell types in MS, many questions still remain regarding the various subsets within each cell population and their exact contribution to different stages of the disease.

• Autoimmunity
• Experimental autoimmune encephalomyelitis/multiple sclerosis
• Heat shock protein
• Neuroimmunology
• Tolerance/Suppression

Multiple sclerosis (MS) is a complex disease with many different immune cells involved in its pathogenesis, and in particular T cells as the most recognized cell type. Recently, the innate immune system has also been researched for its effect on the disease. Hence, cells of the immune system play vital roles in either ameliorating or exacerbating the disease. The genetic and environmental factors, as well as the etiology and pathogenesis are of utmost importance for the development of MS. An insight into the roles play by T cells, B cells, natural killer cells, and dendritic cells in MS and the animal model experimental autoimmune encephalomyelitis, will be presented. Understanding the mechanisms of action for current therapeutic modalities should help developing new therapeutic tools to treat this disease and other autoimmune diseases.

• Multiple sclerosis
• Experimental autoimmune encephalomyelitis
• Chemokines
• Chemokine receptors
• Glatiramer acetate
• Central nervous system
• T cells
• B cells
• Natural killer cells
• Dendritic cells

• cell differentiation
• human natural killer cells

• Cytokines
• Dendritic cells
• Experimental autoimmune neuritis
• NKR-P1(+) cells
• Statins

• Animals
• Atorvastatin
• Cattle
• Cytokines/metabolism
• Dendritic Cells/drug effects
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Female
• Heptanoic Acids/pharmacology
• Heptanoic Acids/therapeutic use
• NK Cell Lectin-Like Receptor Subfamily B/immunology
• NK Cell Lectin-Like Receptor Subfamily B/metabolism
• Neuritis, Autoimmune, Experimental/drug therapy
• Neuritis, Autoimmune, Experimental/immunology
• Neuritis, Autoimmune, Experimental/metabolism
• Pyrroles/pharmacology
• Pyrroles/therapeutic use
• Rats
• Rats, Inbred Lew
• T-Lymphocytes, Regulatory/drug effects
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• Th1 Cells/drug effects
• Th1 Cells/immunology
• Th1 Cells/metabolism
• Th17 Cells/drug effects
• Th17 Cells/immunology
• Th17 Cells/metabolism
• Up-Regulation/drug effects
• Up-Regulation/physiology

• HLA-E
• KLRC2
• NKG2C
• natural killer
• psoriasis

• Alleles
• Case-Control Studies
• Cohort Studies
• Gene Deletion
• Genetic Predisposition to Disease
• Genetic Variation
• Genotype
• Histocompatibility Antigens Class I/metabolism
• Humans
• Inflammation
• Killer Cells, Natural/cytology
• Ligands
• NK Cell Lectin-Like Receptor Subfamily C/genetics
• NK Cell Lectin-Like Receptor Subfamily C/metabolism
• Polymerase Chain Reaction
• Polymorphism, Genetic
• Psoriasis/genetics
• Risk Factors
• HLA-E Antigens

• R01 AR050266 NIAMS NIH HHS
• 5K08AR057763 NIAMS NIH HHS
• R01 AR065174 NIAMS NIH HHS
• K08 AR057763 NIAMS NIH HHS
• AR050266 NIAMS NIH HHS