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1.
Br J Pharmacol ; 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31976546

RESUMO

BACKGROUND AND PURPOSE: Despite recent advances in understanding its pathophysiology, treatment of acute kidney injury (AKI) remains a major unmet medical need, and novel therapeutic strategies are needed. Cathelicidin-related antimicrobial peptide (CRAMP) with immunomodulatory properties has an emerging role in various disease contexts. Here, we aimed to investigate the role of CRAMP and its underlying mechanisms in AKI. EXPERIMENTAL APPROACH: The human homologue LL-37 and CRAMP were measured in blood samples of AKI patients and in experimental AKI mice respectively. Experimental AKI was induced in wild-type and CRAMP-deficient (Cnlp-/- ) mice by ischaemia/reperfusion (I/R). Therapeutic evaluation of CRAMP was performed with exogenous CRAMP (5 mg·kg-1 , i.p.) treatment. KEY RESULTS: Cathelicidin expression was inversely related to clinical signs in patients and down-regulated in renal I/R-induced injury in mice. Cnlp-/- mice exhibited exacerbated I/R-induced renal dysfunction, aggravated inflammatory responses and apoptosis. Moreover, over-activation of the NLRP3 inflammasome in Cnlp-/- mice was associated with I/R-induced renal injury. Exogenous CRAMP treatment markedly attenuated I/R-induced renal dysfunction, inflammatory response and apoptosis, correlated with modulation of immune cell infiltration and phenotype. Consistent with Cnlp-/- mouse data, CRAMP administration suppressed renal I/R-induced NLRP3 inflammasome activation, and its renal protective effects were mimicked by a specific NLRP3 inhibitor CY-09. The reno-protective and NLRP3 inhibitory effects of CRAMP required the EGF receptor. CONCLUSION AND IMPLICATIONS: Our results suggest that CRAMP acts as a novel immunomodulatory mediator of AKI and modulation of CRAMP may represent a potential therapeutic strategy.

2.
Cell Metab ; 28(4): 557-572.e6, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30017352

RESUMO

The gut microbiota is essential for the normal function of the gut immune system, and microbiota alterations are associated with autoimmune disorders. However, how the gut microbiota prevents autoimmunity in distant organs remains poorly defined. Here we reveal that gut microbiota conditioned innate lymphoid cells (ILCs) induce the expression of mouse ß-defensin 14 (mBD14) by pancreatic endocrine cells, preventing autoimmune diabetes in the non-obese diabetic (NOD) mice. MBD14 stimulates, via Toll-like receptor 2, interleukin-4 (IL-4)-secreting B cells that induce regulatory macrophages, which in turn induce protective regulatory T cells. The gut microbiota-derived molecules, aryl hydrocarbon receptor (AHR) ligands and butyrate, promote IL-22 secretion by pancreatic ILCs, which induce expression of mBD14 by endocrine cells. Dysbiotic microbiota and low-affinity AHR allele explain the defective pancreatic expression of mBD14 observed in NOD mice. Our study reveals a yet unidentified crosstalk between ILCs and endocrine cells in the pancreas that is essential for the prevention of autoimmune diabetes development.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Microbioma Gastrointestinal/imunologia , Células Secretoras de Insulina/metabolismo , Linfócitos/metabolismo , Células Secretoras de Polipeptídeo Pancreático/metabolismo , beta-Defensinas/metabolismo , Animais , Linfócitos B Reguladores/metabolismo , Feminino , Humanos , Imunidade Inata , Interleucinas/metabolismo , Ilhotas Pancreáticas/metabolismo , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Estatísticas não Paramétricas , Linfócitos T Reguladores/metabolismo , Receptor 2 Toll-Like/metabolismo
3.
Front Immunol ; 9: 751, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29719535

RESUMO

Acute pancreatitis (AP) is one common clinical acute abdominal disease, for which specific pharmacological or nutritional therapies remain elusive. Lactose, a macronutrient and an inducer of host innate immune responses, possesses immune modulatory functions. The current study aimed to investigate potential modulatory effects of lactose and the interplay between the nutrient and pancreatic immunity during experimentally induced AP in mice. We found that either prophylactic or therapeutic treatment of lactose time-dependently reduced the severity of AP, as evidenced by reduced pancreatic edema, serum amylase levels, and pancreatic myeloperoxidase activities, as well as by histological examination of pancreatic damage. Overall, lactose promoted a regulatory cytokine milieu in the pancreas and reduced infiltration of inflammatory neutrophils and macrophages. On acinar cells, lactose was able to suppress caerulein-induced inflammatory signaling pathways and to suppress chemoattractant tumor necrosis factor (TNF)-α and monocyte chemotactic protein-1 production. Additionally, lactose acted on pancreas-infiltrated macrophages, increasing interleukin-10 and decreasing tumor necrosis factor alpha production. Notably, lactose treatment reversed AP-associated infiltration of activated neutrophils. Last, the effect of lactose on neutrophil infiltration was mimicked by a galectin-3 antagonist, suggesting a potential endogenous target of lactose. Together, the current study demonstrates an immune regulatory effect of lactose to alleviate AP and suggests its potential as a convenient, value-added therapeutic macronutrient to control AP, and lower the risk of its systemic complications.


Assuntos
Fatores Imunológicos/uso terapêutico , Lactose/uso terapêutico , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Doença Aguda , Animais , Ceruletídeo , Citocinas/imunologia , Feminino , Fatores Imunológicos/farmacologia , Lactose/farmacologia , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/imunologia , Pancreatite/patologia , Fenótipo
4.
Front Immunol ; 8: 1345, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29097999

RESUMO

Recent evidence indicates that indigenous Clostridium species induce colonic regulatory T cells (Tregs), and gut lymphocytes are able to migrate to pancreatic islets in an inflammatory environment. Thus, we speculate that supplementation with the well-characterized probiotics Clostridium butyricum CGMCC0313.1 (CB0313.1) may induce pancreatic Tregs and consequently inhibit the diabetes incidence in non-obese diabetic (NOD) mice. CB0313.1 was administered daily to female NOD mice from 3 to 45 weeks of age. The control group received an equal volume of sterile water. Fasting glucose was measured twice a week. Pyrosequencing of the gut microbiota and flow cytometry of mesenteric lymph node (MLN), pancreatic lymph node (PLN), pancreatic and splenic immune cells were performed to investigate the effect of CB0313.1 treatment. Early oral administration of CB0313.1 mitigated insulitis, delayed the onset of diabetes, and improved energy metabolic dysfunction. Protection may involve increased Tregs, rebalanced Th1/Th2/Th17 cells and changes to a less proinflammatory immunological milieu in the gut, PLN, and pancreas. An increase of α4ß7+ (the gut homing receptor) Tregs in the PLN suggests that the mechanism may involve increased migration of gut-primed Tregs to the pancreas. Furthermore, 16S rRNA gene sequencing revealed that CB0313.1 enhanced the Firmicutes/Bacteroidetes ratio, enriched Clostridium-subgroups and butyrate-producing bacteria subgroups. Our results provide the basis for future clinical investigations in preventing type 1 diabetes by oral CB0313.1 administration.

5.
Mol Nutr Food Res ; 61(8)2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28218451

RESUMO

SCOPE: Dietary fibers capable of modifying gut barrier and microbiota homeostasis affect the progression of type 1 diabetes (T1D). Here, we aim to compare modulatory effects of inulin-type fructans (ITFs), natural soluble dietary fibers with different degrees of fermentability from chicory root, on T1D development in nonobese diabetic mice. METHODS AND RESULTS: Female nonobese diabetic mice were weaned to long- and short-chain ITFs [ITF(l) and ITF(s), 5%] supplemented diet up to 24 weeks. T1D incidence, pancreatic-gut immune responses, gut barrier function, and microbiota composition were analyzed. ITF(l) but not ITF(s) supplementation dampened the incidence of T1D. ITF(l) promoted modulatory T-cell responses, as evidenced by increased CD25+ Foxp3+ CD4+ regulatory T cells, decreased IL17A+ CD4+ Th17 cells, and modulated cytokine production profile in the pancreas, spleen, and colon. Furthermore, ITF(l) suppressed NOD like receptor protein 3 caspase-1-p20-IL-1ß inflammasome in the colon. Expression of barrier reinforcing tight junction proteins occludin and claudin-2, antimicrobial peptides ß-defensin-1, and cathelicidin-related antimicrobial peptide as well as short-chain fatty acid production were enhanced by ITF(l). Next-generation sequencing analysis revealed that ITF(l) enhanced Firmicutes/Bacteroidetes ratio to an antidiabetogenic balance and enriched modulatory Ruminococcaceae and Lactobacilli. CONCLUSION: Our data demonstrate that ITF(l) but not ITF(s) delays the development of T1D via modulation of gut-pancreatic immunity, barrier function, and microbiota homeostasis.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Fibras na Dieta/farmacologia , Frutanos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Colo/citologia , Colo/efeitos dos fármacos , Colo/imunologia , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/microbiologia , Feminino , Frutanos/química , Frutanos/imunologia , Inulina/química , Inulina/farmacologia , Camundongos Endogâmicos NOD , Pâncreas/citologia , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Células Th17/efeitos dos fármacos
6.
F1000Res ; 52016.
Artigo em Inglês | MEDLINE | ID: mdl-27158463

RESUMO

Research focusing on type 1 diabetes (T1D) autoantigens aims to explore our understanding of these beta cell proteins in order to design assays for monitoring the pathogenic autoimmune response, as well as safe and efficient therapies preventing or stopping it. In this review, we will discuss progress made in the last 5 years with respect to mechanistic understanding, diagnostic monitoring, and therapeutic modulation of the autoantigen-specific cellular immune response in T1D. Some technical progress in monitoring tools has been made; however, the potential of recent technologies for highly multiplexed exploration of human cellular immune responses remains to be exploited in T1D research, as it may be the key to the identification of surrogate markers of disease progression that are still wanting. Detailed analysis of autoantigen recognition by T cells suggests an important role of non-conventional antigen presentation and processing in beta cell-directed autoimmunity, but the impact of this in human T1D has been little explored. Finally, therapeutic administration of autoantigens to T1D patients has produced disappointing results. The application of novel modes of autoantigen administration, careful translation of mechanistic understanding obtained in preclinical studies and in vitro with human cells, and combination therapies including CD3 antibodies may help to make autoantigen-based immunotherapy for T1D a success story in the future.

7.
FASEB J ; 30(2): 884-94, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26527065

RESUMO

Cathelicidins are pleiotropic antimicrobial peptides largely described for innate antimicrobial defenses and, more recently, immunomodulation. They are shown to modulate a variety of immune or nonimmune host cell responses. However, how cathelicidins are expressed by ß cells and modulate ß-cell functions under steady-state or proinflammatory conditions are unknown. We find that cathelicidin-related antimicrobial peptide (CRAMP) is constitutively expressed by rat insulinoma ß-cell clone INS-1 832/13. CRAMP expression is inducible by butyrate or phenylbutyric acid and its secretion triggered upon inflammatory challenges by IL-1ß or LPS. CRAMP promotes ß-cell survival in vitro via the epidermal growth factor receptor (EGFR) and by modulating expression of antiapoptotic Bcl-2 family proteins: p-Bad, Bcl-2, and Bcl-xL. Also via EGFR, CRAMP stimulates glucose-stimulated insulin secretion ex vivo by rat islets. A similar effect is observed in diabetes-prone nonobese diabetic (NOD) mice. Additional investigation under inflammatory conditions reveals that CRAMP modulates inflammatory responses and ß-cell apoptosis, as measured by prostaglandin E2 production, cyclooxygenases (COXs), and caspase activation. Finally, CRAMP-deficient cnlp(-/-) mice exhibit defective insulin secretion, and administration of CRAMP to prediabetic NOD mice improves blood glucose clearance upon glucose challenge. Our finding suggests that cathelicidins positively regulate ß-cell functions and may be potentially used for intervening ß-cell dysfunction-associated diseases.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Células Secretoras de Insulina/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Apoptose/genética , Linhagem Celular Tumoral , Dinoprostona/genética , Dinoprostona/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Proteína de Morte Celular Associada a bcl/genética , Proteína de Morte Celular Associada a bcl/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
8.
Immunity ; 43(2): 304-17, 2015 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-26253786

RESUMO

Antimicrobial peptides (AMPs) expressed by epithelial and immune cells are largely described for the defense against invading microorganisms. Recently, their immunomodulatory functions have been highlighted in various contexts. However how AMPs expressed by non-immune cells might influence autoimmune responses in peripheral tissues, such as the pancreas, is unknown. Here, we found that insulin-secreting ß-cells produced the cathelicidin related antimicrobial peptide (CRAMP) and that this production was defective in non-obese diabetic (NOD) mice. CRAMP administrated to prediabetic NOD mice induced regulatory immune cells in the pancreatic islets, dampening the incidence of autoimmune diabetes. Additional investigation revealed that the production of CRAMP by ß-cells was controlled by short-chain fatty acids produced by the gut microbiota. Accordingly, gut microbiota manipulations in NOD mice modulated CRAMP production and inflammation in the pancreatic islets, revealing that the gut microbiota directly shape the pancreatic immune environment and autoimmune diabetes development.


Assuntos
Catelicidinas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/imunologia , Intestinos/imunologia , Microbiota/fisiologia , Pâncreas/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos , Catelicidinas/genética , Diabetes Mellitus Tipo 1/microbiologia , Ácidos Graxos Voláteis/imunologia , Feminino , Intestinos/microbiologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Pâncreas/microbiologia
9.
EMBO Mol Med ; 6(8): 1090-104, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24968718

RESUMO

Autoimmune type 1 diabetes (T1D) development results from the interaction between pancreatic ß-cells, and the innate and the adaptive immune systems culminating with the destruction of the insulin-secreting ß-cells by autoreactive T cells. This diabetogenic course starts during the first postnatal weeks by the infiltration of the pancreatic islets by innate immune cells and particularly neutrophils. Here, we aim to determine the cellular and molecular mechanism leading to the recruitment of this neutrophils in the pancreatic islets of non-obese diabetic (NOD) mice. Here, we show that neutrophil recruitment in the pancreatic islets is controlled by inflammatory macrophages and ß-cells themselves. Macrophages and ß-cells produce the chemokines CXCL1 and CXCL2, recruiting CXCR2-expressing neutrophils from the blood to the pancreatic islets. We further show that pancreatic macrophages secrete IL-1ß-inducing CXCR2 ligand production by the ß-cells. Finally, the blockade of neutrophil recruitment at early ages using CXCR2 antagonist dampens the diabetogenic T-cell response and the later development of autoimmune diabetes, supporting the therapeutic potential of this approach.


Assuntos
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina/imunologia , Macrófagos/imunologia , Infiltração de Neutrófilos , Pâncreas/patologia , Receptores de Interleucina-8B/metabolismo , Animais , Camundongos Endogâmicos NOD
10.
Eur J Immunol ; 44(5): 1454-66, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24481989

RESUMO

Invariant NKT (iNKT)-cell stimulation with exogenous specific ligands prevents the development of type 1 diabetes (T1D) in NOD mice. Studies based on anti-islet T-cell transfer showed that iNKT cells prevent the differentiation of these T cells into effector T cells in the pancreatic lymph nodes (PLNs). We hypothesize that this defective priming could be explained by the ability of iNKT cells to induce tolerogenic dendritic cells (DCs) in the PLNs. We evaluated the effect of iNKT-cell stimulation on T1D development by transferring naïve diabetogenic BDC2.5 T cells into proinsulin 2(-/-) NOD mice treated with a long-lasting α-galactosylceramide regimen. In this context, iNKT cells induce the conversion of BDC2.5 T cells into Foxp3(+) Treg cells in the PLNs accumulating in the pancreatic islets. Furthermore, tolerogenic plasmacytoid DCs (pDCs) characterized by low MHC class II molecule expression and TGF-ß production are critical in the PLNs for the recruitment of Treg cells into the pancreatic islets by inducing CXCR3 expression. Accordingly, pDC depletion in α-galactosylceramide-treated proinsulin 2(-/-) NOD mice abrogates the protection against T1D. These findings reveal that upon repetitive iNKT-cell stimulation, pDCs are critical for the recruitment of Treg cells in the pancreatic islets and the prevention of T1D development.


Assuntos
Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Células T Matadoras Naturais/imunologia , Plasmócitos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Dendríticas/patologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/prevenção & controle , Ilhotas Pancreáticas/patologia , Linfonodos/imunologia , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Células T Matadoras Naturais/patologia , Plasmócitos/patologia , Proinsulina/genética , Proinsulina/imunologia , Linfócitos T Reguladores/patologia
11.
J Immunol ; 191(5): 2335-43, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23926325

RESUMO

IgA plays ambivalent roles in the immune system. The balance between inhibitory and activating responses relies on the multimerization status of IgA and interaction with their cognate receptors. In mucosal sites, secretory IgA (SIgA) protects the host through immune-exclusion mechanisms, but its function in the bloodstream remains unknown. Using bone marrow-derived dendritic cells, we found that both human and mouse SIgA induce tolerogenic dendritic cells (DCs) following binding to specific ICAM-3 grabbing nonintegrin receptor 1. This interaction was dependent on Ca(2+) and mannose residues. SIgA-primed DCs (SIgA-DCs) are resistant to TLR-dependent maturation. Although SIgA-DCs fail to induce efficient proliferation and Th1 differentiation of naive responder T cells, they generate the expansion of regulatory T cells through IL-10 production. SIgA-DCs are highly potent in inhibiting autoimmune responses in mouse models of type 1 diabetes and multiple sclerosis. This discovery may offer new insights about mucosal-derived DC immunoregulation through SIgA opening new therapeutic approaches to autoimmune diseases.


Assuntos
Autoimunidade/imunologia , Moléculas de Adesão Celular/imunologia , Células Dendríticas/imunologia , Imunoglobulina A Secretora/imunologia , Lectinas Tipo C/imunologia , Receptores de Superfície Celular/imunologia , Animais , Células da Medula Óssea/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/citologia , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Humanos , Tolerância Imunológica/imunologia , Camundongos , Camundongos Endogâmicos C57BL
12.
Diabetes ; 62(11): 3785-96, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23894189

RESUMO

Invariant natural killer T (iNKT) cells belong to the innate immune system and exercise a dual role as potent regulators of autoimmunity and participate in responses against different pathogens. They have been shown to prevent type 1 diabetes development and to promote antiviral responses. Many studies in the implication of environmental factors on the etiology of type 1 diabetes have suggested a link between enteroviral infections and the development of this disease. This study of the pancreatropic enterovirus Coxsackievirus B4 (CVB4) shows that although infection accelerated type 1 diabetes development in a subset of proinsulin 2-deficient NOD mice, the activation of iNKT cells by a specific agonist, α-galactosylceramide, at the time of infection inhibited the disease. Diabetes development was associated with the infiltration of pancreatic islets by inflammatory macrophages, producing high levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α and activation of anti-islet T cells. On the contrary, macrophages infiltrating the islets after CVB4 infection and iNKT-cell stimulation expressed a number of suppressive enzymes, among which indoleamine 2,3-dioxygenase was sufficient to inhibit anti-islet T-cell response and to prevent diabetes. This study highlights the critical interaction between virus and the immune system in the acceleration or prevention of type 1 diabetes.


Assuntos
Ilhotas Pancreáticas/imunologia , Células T Matadoras Naturais/imunologia , Animais , Infecções por Coxsackievirus/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Feminino , Galactosilceramidas/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Interferon gama/fisiologia , Interleucina-13/fisiologia , Ilhotas Pancreáticas/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Células T Matadoras Naturais/efeitos dos fármacos
13.
Nat Med ; 19(1): 65-73, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23242473

RESUMO

Type 1 diabetes develops over many years and is characterized ultimately by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. Nonetheless, the role of innate cells in the initiation of this disease remains poorly understood. Here, we show that in young female nonobese diabetic mice, physiological beta cell death induces the recruitment and activation of B-1a cells, neutrophils and plasmacytoid dendritic cells (pDCs) to the pancreas. Activated B-1a cells secrete IgGs specific for double-stranded DNA. IgGs activate neutrophils to release DNA-binding cathelicidin-related antimicrobial peptide (CRAMP), which binds self DNA. Then, self DNA, DNA-specific IgG and CRAMP peptide activate pDCs through the Toll-like receptor 9-myeloid differentiation factor 88 pathway, leading to interferon-α production in pancreatic islets. We further demonstrate through the use of depleting treatments that B-1a cells, neutrophils and IFN-α-producing pDCs are required for the initiation of the diabetogenic T cell response and type 1 diabetes development. These findings reveal that an innate immune cell crosstalk takes place in the pancreas of young NOD mice and leads to the initiation of T1D.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Células Secretoras de Insulina/imunologia , Neutrófilos/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos , Linfócitos B/metabolismo , Catelicidinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células Dendríticas/metabolismo , Feminino , Imunoglobulina G/imunologia , Células Secretoras de Insulina/metabolismo , Interferon-alfa/biossíntese , Interferon-alfa/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Fator 88 de Diferenciação Mieloide/metabolismo , Neutrófilos/metabolismo , Pâncreas/imunologia , Receptor Toll-Like 9/metabolismo
14.
Cell Mol Life Sci ; 70(2): 239-55, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22766971

RESUMO

Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic ß-cells. Even though extensive scientific research has yielded important insights into the immune mechanisms involved in pancreatic ß-cell destruction, little is known about the events that trigger the autoimmune process. Recent epidemiological and experimental data suggest that environmental factors are involved in this process. In this review, we discuss the role of viruses as an environmental factor on the development of type 1 diabetes, and the immune mechanisms by which they can trigger or protect against this pathology.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/virologia , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Enterovirus/patogenicidade , Células Secretoras de Insulina/imunologia , Animais , Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/genética , Humanos , Hipótese da Higiene , Células Secretoras de Insulina/virologia , Camundongos , Fatores de Risco , Fatores Socioeconômicos , Linfócitos T/imunologia
15.
Discov Med ; 11(61): 513-20, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21712017

RESUMO

Type 1 diabetes (T1D) is a complex autoimmune disease that is untimely caused by the destruction of insulin-producing pancreatic ß-cells by autoreactive T cells. The development of the pathology involved several cell types of both the innate and adaptive immune systems. This disease is under the control of several genetic loci of susceptibility but it is also influenced by environmental factors such as infectious agents. Studies in animal models, such as the non-obese diabetic (NOD) mouse, reveal that during the development of T1D multiple interactions occur between macrophages, dendritic cells (DC), natural killer (NK) cells, NKT cells, and lymphocytes. As a consequence, the various components of the immune system can be of peculiar interest as therapeutic targets for disease prevention or cure. This review focuses on the involvement of innate immune cells in the development and the prevention of T1D.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Imunidade Inata/imunologia , Animais , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Humanos , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Camundongos
16.
J Exp Med ; 208(4): 729-45, 2011 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-21444661

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell-mediated destruction of insulin-producing ß cells, and viral infections can prevent the onset of disease. Invariant natural killer T cells (iNKT cells) exert a regulatory role in T1D by inhibiting autoimmune T cell responses. As iNKT cell-plasmacytoid dendritic cell (pDC) cooperation controls viral replication in the pancreatic islets, we investigated whether this cellular cross talk could interfere with T1D development during viral infection. Using both virus-induced and spontaneous mouse models of T1D, we show that upon viral infection, iNKT cells induce TGF-ß-producing pDCs in the pancreatic lymph nodes (LNs). These tolerogenic pDCs convert naive anti-islet T cells into Foxp3(+) CD4(+) regulatory T cells (T reg cells) in pancreatic LNs. T reg cells are then recruited into the pancreatic islets where they produce TGF-ß, which dampens the activity of viral- and islet-specific CD8(+) T cells, thereby preventing T1D development in both T1D models. These findings reveal a crucial cooperation between iNKT cells, pDCs, and T reg cells for prevention of T1D by viral infection.


Assuntos
Comunicação Celular , Células Dendríticas/fisiologia , Diabetes Mellitus Tipo 1/prevenção & controle , Células T Matadoras Naturais/fisiologia , Linfócitos T Reguladores/imunologia , Viroses/imunologia , Animais , Antígenos de Superfície/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Antígeno B7-1/fisiologia , Antígeno B7-H1 , Linfócitos T CD8-Positivos/imunologia , Interleucina-10/fisiologia , Ilhotas Pancreáticas/imunologia , Linfonodos/imunologia , Ativação Linfocitária , Glicoproteínas de Membrana/fisiologia , Camundongos , Peptídeos/fisiologia , Receptor de Morte Celular Programada 1 , Fator de Crescimento Transformador beta/biossíntese
17.
Methods Mol Biol ; 677: 193-206, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-20941612

RESUMO

NKT cells are innate-like αß T cells that are conserved between humans and mice. They are distinct from conventional T cells as they recognize lipid antigens presented by the CD1d molecule. Most NKT cells expressed a highly restricted TCR repertoire and can be activated by α-galactosylceramide (α-GalCer) and detected by α-GalCer-loaded-CD1d tetramers. Upon activation, NKT cells respond in few hours by producing cytokines and stimulating many other cells of the innate and adaptive immune system. Over the last decade, many studies have analyzed the regulatory role of NKT cells that can either suppress or exacerbate immune functions. This chapter describes the tools and techniques required to study in vivo and in vitro the regulatory role of NKT cells in mouse as well as from human blood.


Assuntos
Galactosilceramidas/farmacologia , Tolerância Imunológica/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/fisiologia , Animais , Apresentação do Antígeno/fisiologia , Antígenos CD1d/imunologia , Linfócitos B/imunologia , Células Cultivadas , Citocinas/imunologia , Células Dendríticas/imunologia , Humanos , Tolerância Imunológica/fisiologia , Células Matadoras Naturais/imunologia , Receptores de Lipopolissacarídeos/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Células T Matadoras Naturais/fisiologia , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia
18.
Nat Rev Immunol ; 10(7): 501-13, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20577267

RESUMO

The development of type 1 diabetes involves a complex interaction between pancreatic beta-cells and cells of both the innate and adaptive immune systems. Analyses of the interactions between natural killer (NK) cells, NKT cells, different dendritic cell populations and T cells have highlighted how these different cell populations can influence the onset of autoimmunity. There is evidence that infection can have either a potentiating or inhibitory role in the development of type 1 diabetes. Interactions between pathogens and cells of the innate immune system, and how this can influence whether T cell activation or tolerance occurs, have been under close scrutiny in recent years. This Review focuses on the nature of this crosstalk between the innate and the adaptive immune responses and how pathogens influence the process.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Animais , Autoimunidade , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/prevenção & controle , Humanos , Imunidade Inata , /imunologia , Células Secretoras de Insulina/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Linfócitos/imunologia , Camundongos , Modelos Imunológicos , Células T Matadoras Naturais/imunologia , Ratos
19.
Eur J Immunol ; 39(12): 3283-91, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19830742

RESUMO

NKT cells are innate-like T lymphocytes that are found in rodents and primates. They are non-conventional T cells restricted by the CD1d molecule that presents self and exogenous glycolipids. NKT cells are unique in their ability to promptly secrete copious amounts of cytokines such as IFN-gamma and IL-4. Once activated, NKT cells can provide maturation signals to downstream cells, including DC, NK cells, and lymphocytes, thereby contributing to both innate and acquired immunity. Accordingly, NKT cells can influence a wide array of immune responses, including tumor surveillance, maintenance of self-tolerance and anti-infectious defenses. Studies performed with NKT-cell-deficient mice have shown that these cells are critical for the clearance of various pathogens. During bacterial infections, NKT cells can be activated either indirectly by DC or directly by bacterial lipid antigens presented by CD1d. Although viruses do not contain lipid antigens, NKT cells have also been implicated in antiviral responses. The capacity of NKT cells to regulate viral immune-surveillance, either constitutively or post-activation, makes them an attractive clinical target. In this review, we summarize recent publications dealing with the functions and relevance of NKT cells in the context of viral infections, both in murine models and in humans.


Assuntos
Antígenos CD1d/imunologia , Células T Matadoras Naturais/imunologia , Transdução de Sinais/imunologia , Viroses/imunologia , Animais , Infecções Bacterianas/imunologia , Humanos , Camundongos , Modelos Imunológicos
20.
Immunity ; 30(2): 289-99, 2009 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-19217323

RESUMO

Invariant natural killer T (iNKT) cells promote immune responses to various pathogens, but exactly how iNKT cells control antiviral responses is unclear. Here, we showed that iNKT cells induced tissue-specific antiviral effects in mice infected by lymphocytic choriomeningitis virus (LCMV). Indeed, iNKT cells inhibited viral replication in the pancreas and liver but not in the spleen. In the pancreas, iNKT cells expressed the OX40 molecule and promoted type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) through OX40-OX40 ligand interaction. Subsequently, this iNKT cell-pDC cooperation attenuated the antiviral adaptive immune response in the pancreas but not in the spleen. The dampening of pancreatic anti-LCMV CD8(+) T cell response prevented tissue damage in transgenic mice expressing LCMV protein in islet beta cells. Thus, this study identifies pDCs as an essential partner of iNKT cells for mounting an efficient, nondeleterious antiviral response in peripheral tissue.


Assuntos
Células Dendríticas/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Células T Matadoras Naturais/imunologia , Receptores OX40/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/virologia , Fígado/imunologia , Fígado/virologia , Coriomeningite Linfocítica/complicações , Camundongos , Ligante OX40/imunologia , Especificidade de Órgãos/imunologia , Pâncreas/imunologia , Pâncreas/virologia , Transdução de Sinais/imunologia , Baço/imunologia , Baço/virologia , Replicação Viral
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