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1.
Nat Med ; 25(12): 1873-1884, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806906

RESUMO

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-ß renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/ß stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.


Assuntos
Encefalite por Herpes Simples/genética , Herpesvirus Humano 1/genética , Neurônios/imunologia , RNA Nucleolar Pequeno/genética , Adulto , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Pré-Escolar , Encefalite por Herpes Simples/imunologia , Encefalite por Herpes Simples/patologia , Encefalite por Herpes Simples/virologia , Feminino , Predisposição Genética para Doença , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Humanos , Imunidade/genética , Lactente , Masculino , Metagenoma/genética , Metagenoma/imunologia , Pessoa de Meia-Idade , Neurônios/virologia , RNA Nucleolar Pequeno/imunologia
2.
Nat Commun ; 10(1): 5779, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852955

RESUMO

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8+ T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.


Assuntos
Sistema Nervoso Central/irrigação sanguínea , Endotélio Vascular/patologia , Microvasos/patologia , Síndrome de Susac/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Animais , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Feminino , Humanos , Integrina alfa4/antagonistas & inibidores , Integrina alfa4/metabolismo , Masculino , Camundongos Transgênicos , Microvasos/efeitos dos fármacos , Microvasos/imunologia , Pessoa de Meia-Idade , Natalizumab/farmacologia , Natalizumab/uso terapêutico , Síndrome de Susac/sangue , Síndrome de Susac/tratamento farmacológico , Adulto Jovem
3.
PLoS Pathog ; 15(10): e1007856, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31648279

RESUMO

Toxoplasma gondii is an intracellular parasite that persistently infects the CNS and that has genetically distinct strains which provoke different acute immune responses. How differences in the acute immune response affect the CNS immune response is unknown. To address this question, we used two persistent Toxoplasma strains (type II and type III) and examined the CNS immune response at 21 days post infection (dpi). Contrary to acute infection studies, type III-infected mice had higher numbers of total CNS T cells and macrophages/microglia but fewer alternatively activated macrophages (M2s) and regulatory T cells (Tregs) than type II-infected mice. By profiling splenocytes at 5, 10, and 21 dpi, we determined that at 5 dpi type III-infected mice had more M2s while type II-infected mice had more pro-inflammatory macrophages and that these responses flipped over time. To test how these early differences influence the CNS immune response, we engineered the type III strain to lack ROP16 (IIIΔrop16), the polymorphic effector protein that drives the early type III-associated M2 response. IIIΔrop16-infected mice showed a type II-like neuroinflammatory response with fewer infiltrating T cells and macrophages/microglia and more M2s and an unexpectedly low CNS parasite burden. At 5 dpi, IIIΔrop16-infected mice showed a mixed inflammatory response with more pro-inflammatory macrophages, M2s, T effector cells, and Tregs, and decreased rates of infection of peritoneal exudative cells (PECs). These data suggested that type III parasites need the early ROP16-associated M2 response to avoid clearance, possibly by the Immunity-Related GTPases (IRGs), which are IFN-γ- dependent proteins essential for murine defenses against Toxoplasma. To test this possibility, we infected IRG-deficient mice and found that IIIΔrop16 parasites now maintained parental levels of PECs infection. Collectively, these studies suggest that, for the type III strain, rop16III plays a key role in parasite persistence and influences the subacute CNS immune response.


Assuntos
Sistema Nervoso Central/imunologia , Macrófagos/imunologia , Proteínas Tirosina Quinases/imunologia , Proteínas de Protozoários/imunologia , Linfócitos T/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/imunologia , Animais , Sistema Nervoso Central/parasitologia , GTP Fosfo-Hidrolases/genética , Camundongos , Camundongos Knockout , Microglia/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas de Protozoários/genética , Toxoplasma/classificação , Toxoplasma/genética
4.
Immunology ; 158(2): 61-62, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31515802

RESUMO

Immunologists are sometimes guilty of describing the innate immune response as 'non-specific'. What we really mean is that the pattern recognition receptors of innate immune cells are not able to recombine and mutate to bind the spectacular range of molecular patterns that can be recognised by B and T cells. So, while it may be accurate to describe the innate immune response as less specific than adaptive immunity, even this belies the emerging complexity of the receptors and receptor complexes that control inflammatory responses. This complexity is necessary to recognise danger, and therefore successfully initiate proportionate inflammatory responses to cellular damage or against potential pathogens.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Imunidade Inata , Glicoproteínas de Membrana/imunologia , Receptores de Complemento/imunologia , Linfócitos T/imunologia , Receptor Toll-Like 9/imunologia , Animais , Células Apresentadoras de Antígenos/microbiologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/microbiologia , Ilhas de CpG , Regulação da Expressão Gênica , Humanos , Glicoproteínas de Membrana/genética , Receptores de Complemento/genética , Linfócitos T/microbiologia , Receptor Toll-Like 9/genética
5.
Blood ; 134(12): 946-950, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31366619

RESUMO

Tetraspanin CD37 is predominantly expressed on the cell surface of mature B lymphocytes and is currently being studied as novel therapeutic target for B-cell lymphoma. Recently, we demonstrated that loss of CD37 induces spontaneous B-cell lymphoma in Cd37-knockout mice and correlates with inferior survival in patients with diffuse large B-cell lymphoma (DLBCL). Here, CD37 mutation analysis was performed in a cohort of 137 primary DLBCL samples, including 44 primary immune-privileged site-associated DLBCL (IP-DLBCL) samples originating in the testis or central nervous system. CD37 mutations were exclusively identified in IP-DLBCL cases (10/44, 23%) but absent in non-IP-DLBCL cases. The aberrations included 10 missense mutations, 1 deletion, and 3 splice-site CD37 mutations. Modeling and functional analysis of CD37 missense mutations revealed loss of function by impaired CD37 protein expression at the plasma membrane of human lymphoma B cells. This study provides novel insight into the molecular pathogenesis of IP-DLBCL and indicates that anti-CD37 therapies will be more beneficial for DLBCL patients without CD37 mutations.


Assuntos
Antígenos de Neoplasias/genética , Privilégio Imunológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Tetraspaninas/genética , Antígenos de Neoplasias/química , Antígenos de Neoplasias/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/patologia , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Frequência do Gene , Inativação Gênica , Humanos , Privilégio Imunológico/genética , Linfoma Difuso de Grandes Células B/epidemiologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Mutação , Neoplasias Testiculares/genética , Neoplasias Testiculares/imunologia , Neoplasias Testiculares/patologia , Testículo/imunologia , Testículo/patologia , Tetraspaninas/química , Tetraspaninas/imunologia , Evasão Tumoral/genética , Evasão Tumoral/imunologia
6.
Nat Commun ; 10(1): 3887, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467299

RESUMO

Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.


Assuntos
Antígenos/imunologia , Sistema Nervoso Central/imunologia , Doenças Desmielinizantes/imunologia , Células Precursoras de Oligodendrócitos/imunologia , Células Precursoras de Oligodendrócitos/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Astrócitos/metabolismo , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Caspase 3/metabolismo , Caspase 7/metabolismo , Diferenciação Celular , Sistema Nervoso Central/metabolismo , Citocinas/genética , Citocinas/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Expressão Gênica , Antígenos de Histocompatibilidade Classe I , Humanos , Interferon gama , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/patologia , Oligodendroglia/metabolismo , Ovalbumina/metabolismo , Remielinização/imunologia , Linfócitos T
7.
PLoS Pathog ; 15(8): e1007899, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31415679

RESUMO

West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.


Assuntos
Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Imunidade Inata/imunologia , Proteínas de Membrana/fisiologia , Replicação Viral , Febre do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/imunologia , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/virologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Carga Viral , Febre do Nilo Ocidental/metabolismo , Febre do Nilo Ocidental/virologia
8.
Nat Immunol ; 20(9): 1100-1109, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358997

RESUMO

Glioblastoma (GBM) is the deadliest form of brain cancer, with a median survival of less than 2 years despite surgical resection, radiation, and chemotherapy. GBM's rapid progression, resistance to therapy, and inexorable recurrence have been attributed to several factors, including its rapid growth rate, its molecular heterogeneity, its propensity to infiltrate vital brain structures, the regenerative capacity of treatment-resistant cancer stem cells, and challenges in achieving high concentrations of chemotherapeutic agents in the central nervous system. Escape from immunosurveillance is increasingly recognized as a landmark event in cancer biology. Translation of this framework to clinical oncology has positioned immunotherapy as a pillar of cancer treatment. Amid the bourgeoning successes of cancer immunotherapy, GBM has emerged as a model of resistance to immunotherapy. Here we review the mechanisms of immunotherapy resistance in GBM and discuss how insights into GBM-immune system interactions might inform the next generation of immunotherapeutics for GBM and other resistant pathologies.


Assuntos
Neoplasias Encefálicas/terapia , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/terapia , Imunoterapia/métodos , Evasão Tumoral/genética , Neoplasias Encefálicas/genética , Sistema Nervoso Central/imunologia , Glioblastoma/genética , Humanos
9.
J Immunol Res ; 2019: 4204512, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205957

RESUMO

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.


Assuntos
Sistema Nervoso Central/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Inflamação/imunologia , Nervo Óptico/patologia , Medula Espinal/patologia , Células Th2/imunologia , Animais , Autoimunidade , Citocinas/metabolismo , Humanos
10.
Cells ; 8(6)2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195710

RESUMO

Multiple Sclerosis (MS) is a chronic demyelinating autoimmune disease primarily affecting young adults. Despite an unclear causal factor, symptoms and pathology arise from the infiltration of peripheral immune cells across the blood brain barrier. Accounting for the largest fraction of this infiltrate, macrophages are functionally heterogeneous innate immune cells capable of adopting either a pro or an anti-inflammatory phenotype, a phenomenon dependent upon cytokine milieu in the CNS. This functional plasticity is of key relevance in MS, where the pro-inflammatory state dominates the early stage, instructing demyelination and axonal loss while the later anti-inflammatory state holds a key role in promoting tissue repair and regeneration in later remission. This review highlights a potential therapeutic benefit of modulating macrophage polarisation to harness the anti-inflammatory and reparative state in MS. Here, we outline the role of macrophages in MS and look at the role of current FDA approved therapeutics in macrophage polarisation. Moreover, we explore the potential of particulate carriers as a novel strategy to manipulate polarisation states in macrophages, whilst examining how optimising macrophage uptake via nanoparticle size and functionalisation could offer a novel therapeutic approach for MS.


Assuntos
Macrófagos/metabolismo , Esclerose Múltipla/patologia , Nanopartículas/química , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Portadores de Fármacos/química , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/uso terapêutico , Imunossupressores/química , Imunossupressores/uso terapêutico , Macrófagos/citologia , Macrófagos/imunologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia
11.
Neuroscience ; 410: 264-273, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31128159

RESUMO

Neurobrucellosis, which is the most morbid form of brucellosis disease, presents with inflammatory signs and symptoms. Recent experimental evidence clearly indicates that deregulation of astrocytes and microglia caused by Brucella infection creates a microenvironment in the central nervous system (CNS) in which secretion of pro-inflammatory mediators lead to destabilization of the glial structure, the damage of the blood brain barrier (BBB) and neuronal demise. This review of Brucella interactions with cells of the CNS and the BBB is intended to present recent immunological findings that can explain, at least in part, the basis for the inflammatory pathogenesis of the nervous system that takes place upon Brucella infection.


Assuntos
Barreira Hematoencefálica/imunologia , Brucelose/imunologia , Sistema Nervoso Central/imunologia , Imunidade Inata/fisiologia , Fatores Imunológicos/imunologia , Animais , Barreira Hematoencefálica/metabolismo , Brucelose/metabolismo , Sistema Nervoso Central/metabolismo , Humanos , Fatores Imunológicos/metabolismo
12.
J Neuroinflammation ; 16(1): 111, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138214

RESUMO

BACKGROUND: In a subgroup of patients suffering from progressive multiple sclerosis (MS), which is an inflammation-mediated neurodegenerative disease of the central nervous system (CNS), B cell aggregates were discovered within the meninges. Occurrence of these structures was associated with a more severe disease course and cortical histopathology. We have developed the B cell-dependent MP4-induced experimental autoimmune encephalomyelitis (EAE) as a mouse model to mimic this trait of the human disease. The aim of this study was to determine a potential role of lymphoid tissue inducer (LTi) and TH17 cells in the process of B cell aggregate formation in the MP4 model. METHODS: We performed flow cytometry of cerebellar and splenic tissue of MP4-immunized mice in the acute and chronic stage of the disease to analyze the presence of CD3-CD5-CD4+RORγt+ LTi and CD3+CD5+CD4+RORγt+ TH17 cells. Myelin oligodendrocyte glycoprotein (MOG):35-55-induced EAE was used as B cell-independent control model. We further determined the gene expression profile of B cell aggregates using laser capture microdissection, followed by RNA sequencing. RESULTS: While we were able to detect LTi cells in the embryonic spleen and adult intestine, which served as positive controls, there was no evidence for the existence of such a population in acute or chronic EAE in neither of the two models. Yet, we detected CD3-CD5-CD4-RORγt+ innate lymphoid cells (ILCs) and TH17 cells in the CNS, the latter especially in the chronic stage of MP4-induced EAE. Moreover, we observed a unique gene signature in CNS B cell aggregates compared to draining lymph nodes of MP4-immunized mice and to cerebellum as well as draining lymph nodes of mice with MOG:35-55-induced EAE. CONCLUSION: The absence of LTi cells in the cerebellum suggests that other cells might take over the function as an initiator of lymphoid tissue formation in the CNS. Overall, the development of ectopic lymphoid organs is a complex process based on an interplay between several molecules and signals. Here, we propose some potential candidates, which might be involved in the formation of B cell aggregates in the CNS of MP4-immunized mice.


Assuntos
Linfócitos B/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Tecido Linfoide/imunologia , Esclerose Múltipla/imunologia , Células Th17/imunologia , Animais , Linfócitos B/patologia , Agregação Celular/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Imunidade Inata/imunologia , Tecido Linfoide/patologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Gravidez , Células Th17/patologia
13.
EMBO J ; 38(10)2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30944096

RESUMO

Astrocytes are critical regulators of neuroinflammation in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Growing evidence indicates that ubiquitination of signaling molecules is an important cell-intrinsic mechanism governing astrocyte function during MS and EAE Here, we identified an upregulation of the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in astrocytes during MS and EAE Mice with astrocyte-specific OTUB1 ablation developed more severe EAE due to increased leukocyte accumulation, proinflammatory gene transcription, and demyelination in the spinal cord as compared to control mice. OTUB1-deficient astrocytes were hyperactivated in response to IFN-γ, a fingerprint cytokine of encephalitogenic T cells, and produced more proinflammatory cytokines and chemokines than control astrocytes. Mechanistically, OTUB1 inhibited IFN-γ-induced Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling by K48 deubiquitination and stabilization of the JAK2 inhibitor suppressor of cytokine signaling 1 (SOCS1). Thus, astrocyte-specific OTUB1 is a critical inhibitor of neuroinflammation in CNS autoimmunity.


Assuntos
Astrócitos/imunologia , Astrócitos/patologia , Autoimunidade/genética , Cisteína Endopeptidases/fisiologia , Interferon gama/fisiologia , Inflamação Neurogênica/genética , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Células Cultivadas , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Interferon gama/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inflamação Neurogênica/patologia , Neuroimunomodulação/genética
14.
Mol Immunol ; 111: 32-42, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959419

RESUMO

The peripheral activation of autoreactive T cells and subsequent central nervous system (CNS) immune cell infiltration are key events relevant for experimental autoimmune encephalomyelitis (EAE), a commonly employed multiple sclerosis (MS) model, influenced by TH1 and TH17 mediated immunity. The phosphoinositide-3-kinase (PI3K)-AKT kinase pathway modulates outcome during EAE, with direct actions of PI3K on adaptive immunity implicated in deleterious and effects on antigen presenting cells involved in beneficial responses during EAE. Here, by genetically deleting the regulatory subunit of Class Ia PI3K, p85α, in selective myeloid cells, we aimed to resolve the impact of PI3K in EAE. While genetically deleting PI3K in LysM expressing cells exerted unremarkable effects, attenuating PI3K function in CD11c+ dendritic cells (DCs), promoted secretion of pathogenic EAE promoting cytokines, particularly skewing TH1 and TH17 immunity, while notably, improving health in EAE. Neutralizing IFN-γ activity using blocking antibodies revealed a prolonged TH1 response was critical for the decreased disease of these animals. Thus, PI3K-AKT signaling in DCs acts in a paradoxical manner. While attenuating EAE associated TH1 and TH17 responses, it impairs health during autoimmune inflammation.


Assuntos
Doenças Autoimunes/imunologia , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Inflamação/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Sistema Nervoso Central/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Interferon gama/imunologia , Camundongos , Esclerose Múltipla/imunologia , Células Mieloides/imunologia , Células Th1/imunologia , Células Th17/imunologia
15.
Biotech Histochem ; 94(2): 75-83, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30957550

RESUMO

We investigated the effects of Oenothera biennis L. and Hypericum perforatum L. extracts on brain tissue histopathology, myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) in mice with experimental autoimmune encephalomyelitis (EAE). Forty-seven C57BL/6J mice were divided into the following groups: multiple sclerosis (MS), control (healthy mice), MS + H. perforatum treated (MS + HP), MS + O. biennis treated (MS + OB). All groups except the control group were immunized by EAE methods. Two weeks after the immunization, the mice in the MS + HP group were fed normal food containing 18 - 21 g/kg H. perforatum extract, the mice in MS + OB group were fed normal food containing 18 - 21 g/kg O. biennis extract, and the mice in control and MS groups were fed normal food for six weeks. Brain tissue samples were collected from all mice for histopathological and biochemical analysis. Clinical signs of the disease were scored using functional systems scores (FSS) daily. The H. perforatum and O. biennis extracts ameliorated the increased brain tissue MOG and MBP values for animals with MS. H. perforatum and O. biennis extract decreased the TOS and OSI values for brain tissue and increased TAS levels in brain tissue of animals with MS. In addition, H. perforatum and O. biennis extracts decreased the clinical signs at the end of the experiment compared to the beginning of extract administration. We found that myelin was lost in MS group vs. control group. H. perforatum and O. biennis extract treatments decreased the amount of myelin loss in the MS + HP and MS + OB groups. We also observed amyloid deposition on vascular walls, in the cytoplasm of the neurons and in the intercellular space in the MS group. O. biennis and H. perforatum treated groups exhibited neither abnormal amyloid deposition nor obvious cell infiltration. The beneficial effects of O. biennis and H. perforatum for attenuating myelin loss and amyloid deposition suggest their therapeutic utility for treatment of MS.


Assuntos
Sistema Nervoso Central/imunologia , Hypericum/imunologia , Bainha de Mielina/metabolismo , Oenothera biennis/imunologia , Estresse Oxidativo/imunologia , Animais , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurônios/imunologia
16.
Methods Mol Biol ; 1936: 295-310, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820906

RESUMO

Genetic mouse models facilitate investigation of mechanisms underpinning human diseases and aid the development of novel therapeutic treatments. To better understand the demyelination and remyelination processes in adult-onset demyelinating diseases like multiple sclerosis (MS), we have developed the DTA mouse model system that allows for the widespread ablation of the mature oligodendrocytes, resulting in demyelination throughout the central nervous system (CNS). Induction of oligodendrocyte death in young adult DTA mice causes extensive CNS demyelination that leads to a severe neurological disease, followed by a full recovery that is associated with extensive replenishment of oligodendrocytes and remyelination. Thus, the DTA mouse enables investigation of the mechanisms that promote remyelination in MS and other adult-onset demyelinating diseases. Approximately 30 weeks later, the recovered DTA mice develop a fatal secondary demyelinating disease that is mediated by autoimmune T cells. Therefore, the DTA mouse model is also ideal for elucidating the role of oligodendrocyte death in eliciting autoimmunity in MS. In this chapter we describe the methods we used to generate the DTA mouse model and to analyze both the primary and secondary demyelinating diseases in DTA mice.


Assuntos
Doenças Desmielinizantes/imunologia , Toxina Diftérica/genética , Modelos Animais de Doenças , Fragmentos de Peptídeos/genética , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/imunologia , Doenças Desmielinizantes/genética , Feminino , Humanos , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Oligodendroglia/citologia , Oligodendroglia/imunologia , Oligodendroglia/patologia , Remielinização
17.
Nat Immunol ; 20(4): 407-419, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30886419

RESUMO

Tissue macrophages have an embryonic origin and can be replenished in some tissues under steady-state conditions by blood monocytes. However, little is known about the residency and properties of infiltrating monocytes after an inflammatory challenge. The meninges of the central nervous system (CNS) are populated by a dense network of macrophages that act as resident immune sentinels. Here we show that, following lymphocytic choriomeningitis virus infection, resident meningeal macrophages (MMs) acquired viral antigen and interacted directly with infiltrating cytotoxic T lymphocytes, which led to macrophage depletion. Concurrently, the meninges were infiltrated by inflammatory monocytes that engrafted the meningeal niche and remained in situ for months after viral clearance. This engraftment led to interferon-γ-dependent functional changes in the pool of MMs, including loss of bacterial and immunoregulatory sensors. Collectively, these data indicate that peripheral monocytes can engraft the meninges after an inflammatory challenge, imprinting the compartment with long-term defects in immune function.


Assuntos
Sistema Nervoso Central/imunologia , Macrófagos/imunologia , Meningite Viral/imunologia , Monócitos/imunologia , Animais , Imunidade , Inflamação/imunologia , Interferon gama/fisiologia , Meninges/imunologia , Camundongos
19.
Front Immunol ; 10: 201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30800132

RESUMO

Our pathophysiological concept of the most common central nervous system demyelinating disease, multiple sclerosis, strikingly evolved by recent discoveries suggesting that B lymphocytes substantially contribute in its initiation and chronic propagation. In this regard, activated B cells are nowadays considered to act as important antigen-presenting cells for the activation of T cells and as essential source of pro-inflammatory cytokines. Hereby, they create a milieu in which other immune cells differentiate and join an orchestrated inflammatory infiltration of the CNS. Without a doubt, this scientific leap was critically pioneered by the empirical use of anti-CD20 antibodies in recent clinical MS trials, which revealed that the therapeutic removal of immature and mature B cells basically halted development of new inflammatory flares in otherwise relapsing MS patients. This stabilization occurred largely independent of any indirect effect on plasma cell-produced antibody levels. On the contrary, peripherally produced autoantibodies are probably the most important B cell component in two other CNS demyelinating diseases which are currently in the process of being delineated as separate disease entities. The first one is neuromyelitis optica in which an antibody response against aquaporin-4 targets and destroys astrocytes, the second, likely distinct entity embraces a group of patients containing antibodies against myelin oligodendrocyte glycoprotein. In this review, we will describe and summarize pro-inflammatory B cell properties in these three CNS demyelinating disorders; we will however also provide an overview on the emerging concept that B cells or B cell subsets may exert immunologically counterbalancing properties, which may be therapeutically desirable to maintain and foster in inflammatory CNS demyelination. In an outlook, we will discuss accordingly, how this potentially important aspect can be harnessed to advance future B cell-directed therapeutic approaches in multiple sclerosis and related diseases.


Assuntos
Autoanticorpos/imunologia , Linfócitos B Reguladores/imunologia , Esclerose Múltipla/imunologia , Neuromielite Óptica/imunologia , Plasmócitos/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Sistema Nervoso Central/citologia , Sistema Nervoso Central/imunologia , Citocinas/metabolismo , Humanos , Ativação Linfocitária , Camundongos , Linfócitos T Reguladores/imunologia
20.
Int Immunopharmacol ; 70: 187-200, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30807932

RESUMO

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a member of the scavenger receptor family, recognizes multiple ligands and participates in several inflammatory responses, but its function within the central nervous system (CNS) remains unclear. In this study, we discovered an increased LOX-1 expression in activated microglia in vivo and in vitro. Employing the specific inhibitors, we found that conditioned medium of necrotic neurons (Necrotic-CM) induced microglial LOX-1 expression through the MAPKs/NF-κB pathway. Silencing LOX-1 inhibited MAPK phosphorylation, NF-κB-p65 nuclear transportation, and pro-inflammatory factor production in microglia exposed to Necrotic-CM. Furthermore, utilizing the conditioned medium of activated microglia (MG-CM), we discovered microglial LOX-1 aggravated the neuroinflammation-induced neuronal apoptosis. Collectively, a LOX-1/MPAKs/NF-κB positive loop might promote microglia activation and drive the vicious cycle of neuroinflammation and neuronal injury.


Assuntos
Sistema Nervoso Central/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Microglia/fisiologia , NF-kappa B/metabolismo , Inflamação Neurogênica/metabolismo , Neurônios/patologia , Receptores Depuradores Classe E/metabolismo , Animais , Apoptose , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose , RNA Interferente Pequeno/genética , Receptores Depuradores Classe E/genética , Transdução de Sinais , Regulação para Cima
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