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1.
Brain Behav Immun ; 90: 208-215, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32827702

RESUMO

Although several studies demonstrate that stressful situations, such as sleep disturbances, negatively impact the innate and adaptive arms of the immune system, their influence on invariant Natural Killer T (iNKT) cells remains unclear. iNKT cells are CD1d-restricted innate T cells that recognize glycolipid antigens and rapidly produce polarizing cytokines being key players in several immune responses, and a potential target for immunotherapy. iNKT cells differ in several aspects from conventional T lymphocytes, including a unique dependence on CD1d-expressing double-positive (DP) thymocytes for intrathymic maturation. As a consequence of stress, DP thymocytes undergo glucocorticoid-induced apoptosis, which might compromise iNKT developmental pathway. Therefore, we used a paradoxical sleep deprivation (SD) model to determine the impact of sleep disturbance on iNKT cell biology. After 72 h of SD, C57Bl/6 mice exhibited a significant increase in systemic glucocorticoid levels and thymus atrophy. Despite marked decrease in the number of DP thymocytes, the ratio CD1d+/CD1d- was higher in SD mice, and the number of thymic iNKT cells remained unaltered, suggesting that SD did not compromise the iNKT developmental pathway. In contrast, SD reduced hepatic IFN-γ, but not, IL-4-producing iNKT cells, without further effect in the spleen. Despite this fact, SD did not affect stimulation of IFN-γ production by iNKT cells, or cytokine release, in response to α-galactosylceramide, a specific antigen. Furthermore, although SD impaired splenic NK cells activity against tumor cells, it did not affect iNKT cell-specific cytotoxicity. Thus, our study shows that SD-induced stress did not impair the iNKT cells' responses to a cognate antigen.


Assuntos
Células T Matadoras Naturais , Animais , Citocinas , Células Matadoras Naturais , Camundongos , Camundongos Endogâmicos C57BL , Sono REM , Baço
2.
J Immunol ; 196(2): 637-44, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26663782

RESUMO

Despite accumulating evidence indicating that neurotransmitters released by the sympathetic nervous system can modulate the activity of innate immune cells, we still know very little about how norepinephrine impacts signaling pathways in dendritic cells (DC) and the consequence of that in DC-driven T cell differentiation. In this article, we demonstrate that ß2-adrenergic receptor (ß2AR) activation in LPS-stimulated DC does not impair their ability to promote T cell proliferation; however, it diminishes IL-12p70 secretion, leading to a shift in the IL-12p70/IL-23 ratio. Although ß2AR stimulation in DC induces protein kinase A-dependent cAMP-responsive element-binding protein phosphorylation, the effect of changing the profile of cytokines produced upon LPS challenge occurs in a protein kinase A-independent manner and, rather, is associated with inhibition of the NF-κB and AP-1 signaling pathways. Moreover, as a consequence of the inverted IL-12p70/IL-23 ratio following ß2AR stimulation, LPS-stimulated DC promoted the generation of CD4(+) T cells that, upon TCR engagement, produced lower amounts of IFN-γ and higher levels of IL-17. These findings provide new insights into molecular and cellular mechanisms by which ß2AR stimulation in murine DC can influence the generation of adaptive immune responses and may explain some aspects of how sympathetic nervous system activity can modulate immune function.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Norepinefrina/imunologia , Receptores Adrenérgicos beta 2/imunologia , Transdução de Sinais/imunologia , Animais , Western Blotting , Diferenciação Celular/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição AP-1/imunologia
3.
Eur J Immunol ; 44(3): 794-806, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24271843

RESUMO

Leptin is an adipose-secreted hormone that plays an important role in both metabolism and immunity. Leptin has been shown to induce Th1-cell polarization and inhibit Th2-cell responses. Additionally, leptin induces Th17-cell responses, inhibits regulatory T (Treg) cells and modulates autoimmune diseases. Here, we investigated whether leptin mediates its activity on T cells by influencing dendritic cells (DCs) to promote Th17 and Treg-cell immune responses in mice. We observed that leptin deficiency (i) reduced the expression of DC maturation markers, (ii) decreased DC production of IL-12, TNF-α, and IL-6, (iii) increased DC production of TGF-ß, and (iv) limited the capacity of DCs to induce syngeneic CD4(+) T-cell proliferation. As a consequence of this unique phenotype, DCs generated under leptin-free conditions induced Treg or TH 17 cells more efficiently than DCs generated in the presence of leptin. These data indicate important roles for leptin in DC homeostasis and the initiation and maintenance of inflammatory and regulatory immune responses by DCs.


Assuntos
Diferenciação Celular/genética , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Leptina/deficiência , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Animais , Células Dendríticas/imunologia , Imunofenotipagem , Leptina/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Células Th17/citologia , Células Th17/imunologia
4.
Eur J Immunol ; 43(4): 1001-12, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23436577

RESUMO

Beta2-adrenergic receptor (B2AR) signaling is known to impair Th1-cell differentiation and function in a cAMP-dependent way, leading to inhibition of cell proliferation and decreased production of IL-2 and IFN-γ. CD4(+) Foxp3(+) Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self-tolerance. Nevertheless, very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function. Here we show that Foxp3(+) Treg cells express functional B2AR. B2AR activation in Treg cells leads to increased intracellular cAMP levels and to protein kinase A (PKA)-dependent CREB phosphorylation. We also found that signaling via B2AR enhances the in vitro suppressive activity of Treg cells. B2AR-mediated increase in Treg-cell suppressive function was associated with decreased IL-2 mRNA levels in responder CD4(+) T cells and improved Treg-cell-induced conversion of CD4(+) Foxp3(-) cells into Foxp3(+) induced Treg cells. Moreover, B2AR signaling increased CTLA-4 expression in Treg cells in a PKA-dependent way. Finally, we found that PKA inhibition totally prevented the B2AR-mediated increase in Treg-cell suppressive function. Our data suggest that sympathetic fibers are able to regulate Treg-cell suppressive activity in a positive manner through B2AR signaling.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Antígenos CD4/metabolismo , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Interleucina-2/biossíntese , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout
5.
Brain Behav Immun ; 37: 177-86, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24362236

RESUMO

Experimental autoimmune encephalomyelitis (EAE) has been widely employed as a model to study multiple sclerosis (MS) and indeed has allowed some important advances in our comprehension of MS pathogenesis. Several pieces of evidence suggest that infiltrating Th1 and Th17 lymphocytes are important players leading to CNS demyelination and lesion during the peak of murine EAE. Subsequently, effector T cell responses rapidly decline and the recovery phase of the disease strongly correlates with the expression of anti-inflammatory cytokines and the enrichment of Foxp3+ regulatory T (Treg) cells within the target organ. However, the mechanisms leading to the increased presence of Treg cells and to the remission phase of the disease are still poorly understood. Recent researches demonstrated that chemically induced amino-acid starvation response might suppress CNS immune activity. Here we verified an important participation of the general control nonrepressible 2 (GCN2), a key regulator kinase of the amino-acid starvation response, in the development of the remission phase of EAE in C57BL/6 mice. By immunizing wild type C57BL/6 (WT) and GCN2 knock-out mice (GCN2 KO) with myelin oligodendrocyte glycoprotein peptide (MOG35-55), it was noticed that GCN2 KO mice did not develop the remission phase of the disease and this was associated with higher levels of CNS inflammation and increased presence of effector T cells (Th1/Th17). These animals also showed lower frequency of Treg cells within the CNS as compared to WT animals. Higher expression of indoleamine 2,3-dioxygenase (IDO) and higher frequency of plasmacytoid dendritic cells (pDCs) were found at the peak of the disease in the CNS of WT animals. Our results suggest that the GCN2 kinase-dependent sensing of IDO activity represents an important trigger to the EAE remission phase. The IDO-mediated immunoregulatory events may include the arresting of effector T cell responses and the differentiation/expansion of Treg cells within the target organ.


Assuntos
Encefalomielite Autoimune Experimental/enzimologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Fatores de Transcrição Forkhead/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Remissão Espontânea , Medula Espinal/patologia , Células Th1/metabolismo , Células Th17/metabolismo
6.
Nature ; 453(7191): 65-71, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18362915

RESUMO

Regulatory T cells (T(reg)) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of T(reg) cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 (T(H)17). Although T(reg) cell dysfunction and/or T(H)17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of T(reg) and T(H)17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional T(reg) cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with T(reg) cell development, boosted T(H)17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both T(reg) and T(H)17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation.


Assuntos
Diferenciação Celular , Interleucina-17/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Animais , Carbazóis/metabolismo , Carbazóis/farmacologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Indóis/metabolismo , Indóis/farmacologia , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Dibenzodioxinas Policloradas/metabolismo , Dibenzodioxinas Policloradas/farmacologia , Receptores de Hidrocarboneto Arílico/genética , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta1/imunologia , Fator de Crescimento Transformador beta1/metabolismo
7.
Nat Med ; 12(6): 627-35, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16715091

RESUMO

A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+ CD25- LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-beta-dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/terapia , Peptídeos/imunologia , Receptores de Interleucina-2/imunologia , Subpopulações de Linfócitos T/imunologia , Administração Oral , Transferência Adotiva , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD4-Positivos/citologia , Cricetinae , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Peptídeos/genética , Receptores de Interleucina-2/genética , Subpopulações de Linfócitos T/citologia , Fator de Crescimento Transformador beta/imunologia
8.
Immunother Adv ; 2(1): ltac010, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36284839

RESUMO

Macrophages are immune cells that are widespread throughout the body and critical for maintaining tissue homeostasis. Their remarkable plasticity allows them to acquire different phenotypes, becoming able either to fight infection (M1-like, classically activated macrophages) or to promote tissue remodeling and repair (M2-like, alternatively activated macrophages). These phenotypes are induced by different cues present in the microenvironment. Among the factors that might regulate macrophage activation are mediators produced by different branches of the nervous system. The regulation exerted by the sympathetic nervous system (SNS) on macrophages (and the immune system in general) is becoming a subject of increasing interest, indeed a great number of articles have been published lately. Catecholamines (noradrenaline and adrenaline) activate α and ß adrenergic receptors expressed by macrophages and shape the effector functions of these cells in contexts as diverse as the small intestine, the lung, or the adipose tissue. Activation of different subsets of receptors seems to produce antagonistic effects, with α adrenergic receptors generally associated with pro-inflammatory functions and ß adrenergic receptors (particularly ß2) related to the resolution of inflammation and tissue remodeling. However, exceptions to this paradigm have been reported, and the factors contributing to these apparently contradictory observations are still far from being completely understood. Additionally, macrophages per se seem to be sources of catecholamines, which is also a subject of some debate. In this review, we discuss how activation of adrenergic receptors modulates macrophage effector functions and its implications for inflammatory responses and tissue homeostasis.

9.
J Clin Invest ; 118(4): 1532-43, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18340379

RESUMO

Axonal degeneration is an important determinant of progressive neurological disability in multiple sclerosis (MS). Thus, therapeutic approaches promoting neuroprotection could aid the treatment of progressive MS. Here, we used what we believe is a novel water-soluble fullerene derivative (ABS-75) attached to an NMDA receptor antagonist, which combines antioxidant and anti-excitotoxic properties, to block axonal damage and reduce disease progression in a chronic progressive EAE model. Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with myelin-oligodendrocyte glycoprotein (MOG). Reduced disease progression in ABS-75-treated mice was associated with reduced axonal loss and demyelination in the spinal cord. Fullerene ABS-75 halted oxidative injury, CD11b+ infiltration, and CCL2 expression in the spinal cord of mice without interfering with antigen-specific T cell responses. In vitro, fullerene ABS-75 protected neurons from oxidative and glutamate-induced injury and restored glutamine synthetase and glutamate transporter expression in astrocytes under inflammatory insult. Glutamine synthetase expression was also increased in the white matter of fullerene ABS-75-treated animals. Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases.


Assuntos
Axônios/patologia , Esclerose Múltipla/patologia , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Axônios/efeitos dos fármacos , Axônios/metabolismo , Linfócitos B/efeitos dos fármacos , Antígeno CD11b/metabolismo , Quimiocina CCL2/metabolismo , Doença Crônica , Modelos Animais de Doenças , Progressão da Doença , Fulerenos/química , Fulerenos/uso terapêutico , Ácido Glutâmico/farmacologia , Memória/efeitos dos fármacos , Camundongos , Estrutura Molecular , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos
10.
Proc Natl Acad Sci U S A ; 105(48): 18889-94, 2008 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-19028871

RESUMO

Multiple sclerosis (MS) is a chronic relapsing disease of the central nervous system (CNS) in which immune processes are believed to play a major role. To date, there is no reliable method by which to characterize the immune processes and their changes associated with different forms of MS and disease progression. We performed antigen microarray analysis to characterize patterns of antibody reactivity in MS serum against a panel of CNS protein and lipid autoantigens and heat shock proteins. Informatic analysis consisted of a training set that was validated on a blinded test set. The results were further validated on an independent cohort of relapsing-remitting (RRMS) samples. We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer's disease, adrenoleukodystropy, and lupus erythematosus. RRMS was characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. In addition, RRMS, SPMS, and PPMS were characterized by unique patterns of reactivity to CNS antigens. Furthermore, we examined sera from patients with different immunopathologic patterns of MS as determined by brain biopsy, and we identified unique antibody patterns to lipids and CNS-derived peptides that were linked to each type of pathology. The demonstration of unique serum immune signatures linked to different stages and pathologic processes in MS provides an avenue to monitor MS and to characterize immunopathogenic mechanisms and therapeutic targets in the disease.


Assuntos
Autoanticorpos , Análise em Microsséries/métodos , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Colesterol/química , Colesterol/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/classificação , Esclerose Múltipla/fisiopatologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Soro/imunologia
11.
Neuroimmunomodulation ; 16(1): 19-27, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19077442

RESUMO

BACKGROUND: Mice allergic to ovalbumin (OVA) avoid drinking a solution containing this antigen. This was interpreted as related to IgE-dependent mast cell degranulation and sensory C fiber activation. METHODS: We employed pharmacological manipulation to further investigate the mediators involved in immune-induced food aversion. RESULTS: While nonimmunized rats preferred a sweetened OVA solution, immunized rats avoided it. We also employed a paradigm in which rats are conditioned to drink water for two 10-min sessions a day. Tolerant rats presented lower IgE titers, and this manipulation abrogated food aversion. Dexamethasone (1.0 mg/kg) prevented the aversion of OVA-immunized rats to the antigen-containing solution. Combined blockade of H(1) and 5-hydroxytryptamine (5-HT)(2) receptors by promethazine (3.0 mg/kg) plus methysergide (5.0 mg/kg) was unable to alter food aversion. Blockade of 5-HT(3) receptors by ondansetron (1.0 mg/kg) caused a twofold increase in the ingestion of the sweetened OVA solution by immunized rats, suggesting the involvement of 5-HT(3) receptors in food aversion. Finally, we showed that dexamethasone or promethazine plus methysergide, but not ondansetron, effectively prevented the IgE-dependent mast-cell-degranulation-induced increase in vascular permeability in rats. CONCLUSION: We suggest that regardless of whether or not they cause edema, IgE-mediated mast cell degranulation and consequent 5-HT(3) signaling are involved in the process that triggers avoidance to the source of the allergen in allergic rats.


Assuntos
Comportamento Alimentar , Hipersensibilidade Alimentar/imunologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/imunologia , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Condicionamento Psicológico/fisiologia , Dexametasona/farmacologia , Modelos Animais de Doenças , Hipersensibilidade Alimentar/fisiopatologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunossupressores/farmacologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Metisergida/farmacologia , Ondansetron/farmacologia , Ovalbumina/imunologia , Ratos , Ratos Wistar , Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina , Antagonistas da Serotonina/farmacologia
12.
Cell Rep ; 28(12): 3120-3130.e5, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533035

RESUMO

Noradrenaline (NE), the main neurotransmitter released by sympathetic nerve terminals, is known to modulate the immune response. However, the role of the sympathetic nervous system (SNS) on the development of autoimmune diseases is still unclear. Here, we report that the SNS limits the generation of pathogenic T cells and disease development in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). ß2-Adrenergic receptor (Adrb2) signaling limits T cell autoimmunity in EAE through a mechanism mediated by the suppression of IL-2, IFN-γ, and GM-CSF production via inducible cAMP early repressor (ICER). Accordingly, the lack of Adrb2 signaling in immune cells is sufficient to abrogate the suppressive effects of SNS activity, resulting in increased pathogenic T cell responses and EAE development. Collectively, these results uncover a suppressive role for the SNS in CNS autoimmunity while they identify potential targets for therapeutic intervention.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Imunidade Celular , Esclerose Múltipla/imunologia , Receptores Adrenérgicos beta 2/imunologia , Transdução de Sinais/imunologia , Sistema Nervoso Simpático/imunologia , Linfócitos T/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Encefalomielite Autoimune Experimental/patologia , Camundongos , Camundongos Knockout , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Receptores Adrenérgicos beta 2/genética , Transdução de Sinais/genética , Sistema Nervoso Simpático/patologia , Linfócitos T/patologia
14.
Semin Immunopathol ; 39(2): 165-176, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27800584

RESUMO

Dendritic cells are of paramount importance bridging innate and adaptive immune responses. Depending on the context, after sensing environmental antigens, commensal microorganisms, pathogenic agents, or antigens from the diet, dendritic cells may drive either different effector adaptive immune responses or tolerance, avoiding tissue damage. Although the plasticity of the immune response and the capacity to regulate itself are considered essential to orchestrate appropriate physiological responses, it is known that the nervous system plays a relevant role controlling immune cell function. Dendritic cells present in the skin, the intestine, and lymphoid organs, besides expressing adrenergic receptors, can be reached by neurotransmitters released by sympathetic fibers innervating these tissues. These review focus on how neurotransmitters from the sympathetic nervous system can modulate dendritic cell function and how this may impact the immune response and immune-mediated disorders.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Sistema Imunitário/citologia , Sistema Imunitário/fisiologia , Neuroimunomodulação , Sistema Nervoso Simpático/fisiologia , Animais , Citocinas/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Intestinos/inervação , Tecido Linfoide/imunologia , Tecido Linfoide/inervação , Tecido Linfoide/metabolismo , Norepinefrina/metabolismo , Receptores Adrenérgicos/metabolismo , Transdução de Sinais , Pele/imunologia , Pele/inervação , Pele/metabolismo
15.
Nat Med ; 21(6): 638-46, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26005855

RESUMO

Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory T cell (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular ATP (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen-presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imunidade Celular , Inflamação/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Reguladores/metabolismo , Adulto , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Apirase/imunologia , Apirase/metabolismo , Diferenciação Celular/imunologia , Feminino , Hematopoese/imunologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Inflamação/metabolismo , Inflamação/patologia , Ativação Linfocitária/imunologia , Camundongos , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia , Linfócitos T Reguladores/imunologia
16.
Diabetes ; 61(10): 2534-45, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22688334

RESUMO

Adipose-derived mesenchymal stem cells (ADMSCs) display immunosuppressive properties, suggesting a promising therapeutic application in several autoimmune diseases, but their role in type 1 diabetes (T1D) remains largely unexplored. The aim of this study was to investigate the immune regulatory properties of allogeneic ADMSC therapy in T cell-mediated autoimmune diabetes in NOD mice. ADMSC treatment reversed the hyperglycemia of early-onset diabetes in 78% of diabetic NOD mice, and this effect was associated with higher serum insulin, amylin, and glucagon-like peptide 1 levels compared with untreated controls. This improved outcome was associated with downregulation of the CD4(+) Th1-biased immune response and expansion of regulatory T cells (Tregs) in the pancreatic lymph nodes. Within the pancreas, inflammatory cell infiltration and interferon-γ levels were reduced, while insulin, pancreatic duodenal homeobox-1, and active transforming growth factor-ß1 expression were increased. In vitro, ADMSCs induced the expansion/proliferation of Tregs in a cell contact-dependent manner mediated by programmed death ligand 1. In summary, ADMSC therapy efficiently ameliorates autoimmune diabetes pathogenesis in diabetic NOD mice by attenuating the Th1 immune response concomitant with the expansion/proliferation of Tregs, thereby contributing to the maintenance of functional ß-cells. Thus, this study may provide a new perspective for the development of ADMSC-based cellular therapies for T1D.


Assuntos
Adipócitos/transplante , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Hiperglicemia/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Adipócitos/imunologia , Animais , Proliferação de Células , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Peptídeo 1 Semelhante ao Glucagon/sangue , Hiperglicemia/sangue , Hiperglicemia/imunologia , Insulina/sangue , Polipeptídeo Amiloide das Ilhotas Pancreáticas/sangue , Camundongos , Camundongos Endogâmicos NOD , Linfócitos T Reguladores/imunologia
17.
J Neuroimmunol ; 227(1-2): 10-7, 2010 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-20580440

RESUMO

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory immune response directed against myelin antigens of the central nervous system. In its murine model, EAE, Th17 cells play an important role in disease pathogenesis. These cells can induce blood-brain barrier disruption and CNS immune cells activation, due to the capacity to secrete high levels of IL-17 and IL-22 in an IL-6+TGF-ß dependent manner. Thus, using the oral tolerance model, by which 200 µg of MOG 35-55 is given orally to C57BL/6 mice prior to immunization, we showed that the percentage of Th17 cells as well as IL-17 secretion is reduced both in the periphery and also in the CNS of orally tolerated animals. Altogether, our data corroborates with the pathogenic role of IL-17 and IFN-γ in EAE, as its reduction after oral tolerance, leads to an overall reduction of pro-inflammatory cytokines, such as IL-1α, IL-6, IL-9, IL-12p70 and the chemokines MIP-1ß, RANTES, Eotaxin and KC in the CNS. It is noteworthy that this was associated to an increase in IL-10 levels. Thus, our data clearly show that disease suppression after oral tolerance induction, correlates with reduction in target organ inflammation, that may be caused by a reduced Th1/Th17 response.


Assuntos
Alérgenos/administração & dosagem , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Tolerância Imunológica , Interleucina-17/antagonistas & inibidores , Depleção Linfocítica , Proteínas do Tecido Nervoso/administração & dosagem , Linfócitos T Auxiliares-Indutores/imunologia , Administração Oral , Alérgenos/imunologia , Sequência de Aminoácidos , Animais , Encefalomielite Autoimune Experimental/terapia , Glicoproteínas/administração & dosagem , Glicoproteínas/imunologia , Glicoproteínas/uso terapêutico , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Interleucina-17/metabolismo , Depleção Linfocítica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Glicoproteína Mielina-Oligodendrócito , Proteínas do Tecido Nervoso/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Linfócitos T Auxiliares-Indutores/patologia
18.
Cell Res ; 19(4): 399-411, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19255592

RESUMO

For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. The Th1/Th2 paradigm implied the existence of two different, mutually regulated, CD4(+) T helper subsets: Th1 cells, driving cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites; and Th2 cells that mediate IgE production and are particularly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4(+) T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells. The Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines. Interestingly, it has been reported that there is not only a cross-regulation among Th1, Th2 and Th17 effector cells but there is also a dichotomy in the generation of Th17 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-beta or TGF-beta plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.


Assuntos
Interleucina-17/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Regulação para Baixo , Interleucina-23/metabolismo , Interleucina-6/metabolismo , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Células Th2/imunologia , Transcrição Gênica , Fator de Crescimento Transformador beta/metabolismo
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