RESUMO
OBJECTIVES: Interleukin 9 (IL-9) is a mediator of tissue damage in several inflammatory diseases. In this study we aimed to evaluate the effects of in vivo IL-9 neutralisation in mice developing collagen induced arthritis (CIA). METHODS: DBA/1 were immunised with collagen in Freund's complete adjuvant (CFA) to induce arthritis. Anti-IL-9 mAb was injected in mice after the onset of arthritis (Group A) or on the same day as sensitisation and again on the day of the challenge (Group B). Histological analysis was performed in joints of mice and spleen cells were also analysed by flow cytometry. A geneset analysis was carried out on whole tarsal joint tissue transcriptomes. RESULTS: IL-9 was over-expressed in swollen joints of mice developing arthritis. Treatment with anti-IL-9 mAb after arthritis onset efficiently down-modulated the severity of joint inflammation. Similarly, anti-IL-9 mAb administered on the same day as sensitisation and on the day of challenge also delayed the onset of arthritis. Anti-IL-9 mAb injection after the onset of arthritis was associated with a decrease of CD4+ TNF-α+ cells and an increase of CD4+ FoxP3+ IL-10+ cells. Geneset analysis in CIA showed an up-regulation of GATA3 with no significant direct interactions between IL-9 and GATA3, which instead was mediated by IL-5 through STAT6. CONCLUSIONS: Our results suggest that IL-9 is involved in the immunopathogenesis of CIA. Further implications for the clinical translation of our findings are discussed.
Assuntos
Artrite Experimental , Animais , Camundongos , Artrite Experimental/patologia , Interleucina-9/uso terapêutico , Camundongos Endogâmicos DBA , Modelos Animais de Doenças , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
OBJECTIVE: The sound-induced flash illusion (SIFI) is a valid paradigm to study multisensorial perception. In the "fission" SIFI, multiple flashes are perceived when observing a single flash paired with two or more beeps. SIFI is largely dependent on visual and acoustic cortex excitability; in migraine, dysfunctional cortical excitability affects SIFI perception. Since estrogen peak occurring during ovulation can increase neuronal excitability, the present study aims to verify whether cortical excitability shifts linked to the menstrual cycle could influence SIFI. METHODS: In a comparative prospective study, we tested the effect of estrogens on crossmodal perception using the SIFI. We recruited 27 females in reproductive age, including 16 healthy and 11 menstrually related migraine females, testing their proneness to SIFI on day 14 (high estradiol) and day 27 (low estradiol) of menstrual cycle. RESULTS: Women on day 14 reported less flashes than on day 27 (p = 0.02) in the fission illusion, suggesting a pro-excitatory effect of estradiol on visual cortex excitability during ovulation. Moreover, we confirmed that migraine women perceived less flashes (p = 0.001) than controls, independently from cycle phase. Non-migraineurs women significantly reported more flashes on day 27 than on day 14 (p = 0.04). CONCLUSIONS: This study suggests that estradiol may influence the multisensory perception due to changes of visual cortex excitability, with high estradiol peak leading to increased visual cortical sensitivity during ovulation in non-migraineurs. Visual cortex hyperresponsiveness, here reflected by reduced SIFI, is not influenced by estradiol fluctuations in migraine women, as shown by reduced fission effects on day 14 and 27.
Assuntos
Ilusões , Transtornos de Enxaqueca , Humanos , Feminino , Estudos Prospectivos , Percepção Auditiva/fisiologia , Estimulação Acústica , Percepção Visual/fisiologia , Estimulação LuminosaRESUMO
Tick-transmitted pathogens cause infectious diseases in both humans and animals. Different types of adaptive immune mechanisms could be induced in hosts by these microorganisms, triggered either directly by pathogen antigens or indirectly through soluble factors, such as cytokines and/or chemokines, secreted by host cells as response. Adaptive immunity effectors, such as antibody secretion and cytotoxic and/or T helper cell responses, are mainly involved in the late and long-lasting protective immune response. Proteins and/or epitopes derived from pathogens and tick vectors have been isolated and characterized for the immune response induced in different hosts. This review was focused on the interactions between tick-borne pathogenic hemoparasites and different host effector mechanisms of T- and/or B cell-mediated adaptive immunity, describing the efforts to define immunodominant proteins or epitopes for vaccine development and/or immunotherapeutic purposes. A better understanding of these mechanisms of host immunity could lead to the assessment of possible new immunotherapies for these pathogens as well as to the prediction of possible new candidate vaccine antigens.
Assuntos
Imunidade Adaptativa , Antígenos/imunologia , Interações entre Hospedeiro e Microrganismos , Doenças Transmitidas por Carrapatos , Animais , Humanos , Doenças Transmitidas por Carrapatos/imunologia , Doenças Transmitidas por Carrapatos/prevenção & controle , Vacinas/imunologiaRESUMO
Many pathogens are transmitted by tick bites, including Anaplasma spp., Ehrlichia spp., Rickettsia spp., Babesia and Theileria sensu stricto species. These pathogens cause infectious diseases both in animals and humans. Different types of immune effector mechanisms could be induced in hosts by these microorganisms, triggered either directly by pathogen-derived antigens or indirectly by molecules released by host cells binding to these antigens. The components of innate immunity, such as natural killer cells, complement proteins, macrophages, dendritic cells and tumor necrosis factor alpha, cause a rapid and intense protection for the acute phase of infectious diseases. Moreover, the onset of a pro-inflammatory state occurs upon the activation of the inflammasome, a protein scaffold with a key-role in host defense mechanism, regulating the action of caspase-1 and the maturation of interleukin-1ß and IL-18 into bioactive molecules. During the infection caused by different microbial agents, very similar profiles of the human innate immune response are observed including secretion of IL-1α, IL-8, and IFN-α, and suppression of superoxide dismutase, IL-1Ra and IL-17A release. Innate immunity is activated immediately after the infection and inflammasome-mediated changes in the pro-inflammatory cytokines at systemic and intracellular levels can be detected as early as on days 2-5 after tick bite. The ongoing research field of "inflammasome biology" focuses on the interactions among molecules and cells of innate immune response that could be responsible for triggering a protective adaptive immunity. The knowledge of the innate immunity mechanisms, as well as the new targets of investigation arising by bioinformatics analysis, could lead to the development of new methods of emergency diagnosis and prevention of tick-borne infections.
Assuntos
Imunidade Inata , Insetos Vetores/imunologia , Doenças Transmitidas por Carrapatos/imunologia , Carrapatos/patogenicidade , Anaplasma/patogenicidade , Animais , Babesia/patogenicidade , Ehrlichia/patogenicidade , Humanos , Insetos Vetores/patogenicidade , Rickettsia/patogenicidade , Theileria/patogenicidade , Doenças Transmitidas por Carrapatos/transmissão , Carrapatos/microbiologiaRESUMO
OBJECTIVES: Hyperbaric oxygen therapy (HBOT) has been used as treatment for different clinical conditions, including fibromyalgia (FM). HBOT modulates brain activity, ameliorates chronic pain and modifies the ratio of immune cells. Clinical studies have provided evidence that FM is associated with immune system dysregulation. In the present study we aimed to evaluate the effect of HBOT on immune system and on the quality of life-style of FM patients. METHODS: Patients with primary FM and controls were treated with HBOT. Physical, emotional and social assessment, quality of sleep, tender points, intensity score, WPI and symptom severity were evaluated before and after HBOT. Furthermore, a characterisation of CD4 T lymphocytes and their cytokine production was performed by flow cytometry. The expression of TNF-α, IFN-γ, IL-17, IL-9 and IL-22 was also assessed by RT-PCR. Finally, the serum levels of serotonin were evaluated by ELISA. RESULTS: Our results confirm the participation of immune system in the pathogenesis of FM and highlight the impact of HBOT treatment, with particular regard to the changes on proinflammatory cytokines production by CD4 T cells subsets. CONCLUSIONS: FM patients show a Th1 signature and the activation of this subset is modulated by HBOT.
Assuntos
Citocinas/metabolismo , Fibromialgia/imunologia , Oxigenoterapia Hiperbárica , Qualidade de Vida , Contagem de Linfócito CD4 , Fadiga , Fibromialgia/terapia , Humanos , Sono , Células Th1/imunologiaRESUMO
OBJECTIVES: Vitamin D status influences the risk to develop autoimmune diseases affecting the percentage and/or functions of regulatory T cells (Tregs). Since low levels of 25 (OH) D have been decreased in patients with systemic sclerosis (SSc), we aimed to study the effect of Vitamin D3 (cholecalciferol) supplementation on Tregs frequencies and functions. METHODS: Peripheral blood and sera samples were obtained from 45 SSc patients and controls (HC). A number of eighteen SSc patients had consumed Cholecalciferol (orally) at the dose of 25.000 UI/month for 6 months at the time of enrollment. 25(OH)D serum levels were measured and VDR polymorphisms, were genotyped by polymerase chain reaction (PCR). Tregs isolated from peripheral blood mononuclear cells were in vitro expanded and a suppression assay was performed. Flow cytometry analysis was then carried out. Finally, IL-10 production was assayed by ELISA. RESULTS: Low serum levels of 25(OH)D were detected in SSc patients. The percentage of Tregs in SSc patients was similar to controls, but, among SSc patients, it was higher in those patients taking cholecalciferol. Tregs capability to suppress T cell proliferation was impaired in SSc patients and not restored after in vitro pre-treatment with the active form of Vitamin D (1,25(OH)2D3); but at the same time the production of IL-10 was increased in treated samples obtained from patients. The lack of response of Tregs from SSc patients to 1,25(OH)2D3 treatment in vitro was not due to altered Vitamin D/VDR signalling. CONCLUSIONS: Altogether, our results indicate that the increased production of IL-10 by 1,25(OH)2D3 -treated Tregs could provide a "suppressive" cytokine milieu able to modulate immune response but it is not sufficient to restore the immune suppressive functions of Tregs.
Assuntos
Interleucina-10/biossíntese , Escleroderma Sistêmico , Linfócitos T Reguladores/efeitos dos fármacos , Vitamina D , Estudos de Casos e Controles , Suplementos Nutricionais , Feminino , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/metabolismo , Vitamina D/farmacologiaRESUMO
Primary Sjogren syndrome (pSS) is a complex autoimmune disease mainly affecting salivary and lacrimal glands. Several factors contribute to pSS pathogenesis; in particular, innate immunity seems to play a key role in disease etiology. Invariant natural killer (NK) T cells (iNKT) are a T-cell subset able to recognize glycolipid antigens. Their function remains unclear, but studies have pointed out their ability to modulate the immune system through the promotion of specific cytokine milieu. In this review, we discussed the possible role of iNKT in pSS development, as well as their implications as future markers of disease activity.
Assuntos
Imunidade Inata/imunologia , Aparelho Lacrimal/imunologia , Células T Matadoras Naturais/imunologia , Doenças Reumáticas/imunologia , Glândulas Salivares/imunologia , Síndrome de Sjogren/imunologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Glicolipídeos/imunologia , Glicolipídeos/metabolismo , HumanosRESUMO
Natural killer T cells (NKT) are a subset of T lymphocytes bridging innate and adaptive immunity. These cells recognize self and microbial glycolipids bound to non-polymorphic and highly conserved CD1d molecules. Three NKT cell subsets, type I, II, and NKT-like expressing different antigen receptors (TCR) were described and TCR activation promotes intracellular events leading to specific functional activities. NKT can exhibit different functions depending on the secretion of soluble molecules and the interaction with other cell types. NKT cells act as regulatory cells in the defense against infections but, on the other hand, their effector functions can be involved in the pathogenesis of several inflammatory disorders due to their exposure to different microbial or self-antigens, respectively. A deep understanding of the biology and functions of type I, II, and NKT-like cells as well as their interplay with cell types acting in innate (neuthrophils, innate lymphoid cells, machrophages, and dendritic cells) and adaptive immunity (CD4âº,CD8âº, and double negative T cells) should be important to design potential immunotherapies for infectious and autoimmune diseases.
Assuntos
Autoimunidade/imunologia , Doenças Transmissíveis/imunologia , Células T Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Imunidade Adaptativa/imunologia , Animais , Doenças Transmissíveis/microbiologia , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Modelos Imunológicos , Células T Matadoras Naturais/classificação , Células T Matadoras Naturais/metabolismo , Subpopulações de Linfócitos T/metabolismoRESUMO
OBJECTIVES: Invariant NKT (iNKT) cells play a role in regulating the function of autoreactive B cells before their entry into germinal centres. Absence and/or reduction of iNKT cells have been demonstrated in patients with systemic lupus erythematosus (SLE) together with an increase of autoreactive B cell activity. Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease in which lymphocyte infiltration and organisation in lymphoid structures of inflamed salivary glands occurs. The aim of the study was to investigate the percentage and function of iNKT in the salivary glands and peripheral blood of patients with pSS. METHODS: Minor salivary gland biopsies were obtained from patients with pSS and with non-specific chronic sialoadenitis (nSS). Flow cytometry analysis of CD1d/α-GalactosylCeramide (α-GalCer) tetramer positive cells, producing IFN-γ and IL-17, and quantitative gene expression analysis by TaqMan real-time PCR for Vα24 were performed on salivary glands biopsies and peripheral blood samples obtained from patients and controls. Flow cytometry and immunofluorescence analysis for autoreactive B lymphocytes and ELISA for anti-SSA antibodies (Ab) detection were also performed. RESULTS: An increase of iNKT was detected ex vivo in peripheral blood of pSS patients; after α-GalCer stimulation this subset produce IL-17 and IFN-iNKT were undetectable in the salivary glands of pSS patients and anti-SSA specific B cells were found in target tissue. Invariant NKT cells were able to inhibit autoantibody production by B cells obtained from salivary glands of pSS. CONCLUSIONS: Impaired iNKT migration to inflamed sites might induce the activation of autoreactive B cells specific for SSA-antigen in salivary glands of pSS patients.
Assuntos
Proliferação de Células , Ativação Linfocitária , Células T Matadoras Naturais/imunologia , Glândulas Salivares/imunologia , Síndrome de Sjogren/imunologia , Anticorpos Antinucleares/biossíntese , Anticorpos Antinucleares/imunologia , Formação de Anticorpos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biópsia , Estudos de Casos e Controles , Comunicação Celular , Células Cultivadas , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Contagem de Linfócitos , Células T Matadoras Naturais/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Síndrome de Sjogren/sangue , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/genéticaRESUMO
BACKGROUND: The aim of the study was to better characterise the immunological origin and the behaviour of interleukin (IL)-23-responsive innate lymphoid cells (ILCs) in the gut, synovial fluid (SF) and bone marrow (BM) of patients with ankylosing spondylitis (AS). METHODS: ILC1, ILC2 and ILC3 cells were determined and characterised by confocal microscopy and flow cytometry in ileal and BM biopsies, in peripheral blood (PB) and SF mononuclear cells obtained from patients with AS and controls. Mucosal vascular addressin cell adhesion molecule 1 (MADCAM-1), IL-7, IL-15 and aggregates of lymphoid tissue inducer cells (LTi) were evaluated by immunohistochemistry. The in vitro ability of epithelial cells in driving the differentiation of ILC3 and the effect of tumour necrosis factor inhibitors (TNFi) on the frequency of ILC3 and the expression of MADCAM1 were also assessed. RESULTS: ILC3 characterised as Lyn(-)RORc(-)Tbet(+) NKp44(+) cells were significantly expanded in the gut, SF and BM of patients with AS compared with controls, produced high levels of IL-17 and IL-22 and expressed α4ß7. MADcAM1 was overexpressed in BM and ileal high endothelial venules. IL-7 was significantly increased in AS gut, especially in the context of Paneth cells, and accompanied by the presence of aggregates of c-kit/IL-7R(+) cells (LTi). In in vitro experiments, epithelial cells from patients with AS actively induced differentiation of ILC3 from LTi. TNFi efficacy was accompanied by a significant decrease in the percentage of intestinal and circulating ILC3 and in the expression of MADCAM1. CONCLUSIONS: Gut-derived IL-17(+) and IL-22(+)ILC3 are expanded in the peripheral blood, SF and inflamed BM of patients with AS, suggesting the presence of an active homing axis between the gut and the inflamed sacroiliac joints.
Assuntos
Medula Óssea/imunologia , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Espondilite Anquilosante/imunologia , Líquido Sinovial/imunologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Moléculas de Adesão Celular , Feminino , Humanos , Íleo/imunologia , Íleo/patologia , Imunoglobulinas/metabolismo , Interleucina-15/imunologia , Interleucina-17/imunologia , Interleucina-7/imunologia , Interleucinas/imunologia , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Mucoproteínas/metabolismo , Receptor 2 Desencadeador da Citotoxicidade Natural , Adulto Jovem , Interleucina 22RESUMO
OBJECTIVE: IL-9 has been shown to be upregulated before the clinical onset of articular disease in RA. The exact role of IL-9 and Th9 cells in RA, however, has not yet been adequately studied. The aim of this study was to evaluate the expression of IL-9 and IL-9-expressing cells in RA patients. METHODS: IL-9, IL-9R, PU.1, IL-9, thymic stromal lymphopoietin (TSLP), IL-4 and TGF-ß expression was assessed by real-time-PCR in the synovial tissues of RA and OA patients. IL-9, IL-9R, IL-4, TSLP and TGF-ß were also investigated by immunohistochemistry. Peripheral CD4(+) T cell subsets were studied by flow cytometry analysis before and after incubation with citrullinated peptides. RESULTS: IL-9 was overexpressed in RA synovial tissues and correlated with the degree of histological organization of B and T cells in ectopic lymphoid structures. The majority of IL-9-producing cells were identified as CD3(+) cells. Increased mRNA and protein expression of IL-9R, IL-4, TSLP and TGF-ß was also observed in RA synovial tissue. Blood peripheral Th9 cells were expanded by citrullinated peptides. CONCLUSION: These results indicate that Th9 cells and IL-9 were frequently detected in peripheral blood mononuclear cells and synovia of RA patients. A possible pathogenic role for Th9 in RA is discussed.
Assuntos
Artrite Reumatoide/imunologia , Interleucina-9/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Citocinas/biossíntese , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-4/biossíntese , Interleucina-9/biossíntese , Interleucina-9/genética , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Membrana Sinovial/imunologia , Fator de Crescimento Transformador beta/biossíntese , Adulto Jovem , Linfopoietina do Estroma do TimoRESUMO
OBJECTIVE: Long-term evolution of subclinical gut inflammation to overt Crohn's disease (CD) has been described in AS patients. The aim of this study was to evaluate macrophage polarization occurring in the inflamed gut of patients with AS. METHODS: Twenty-seven HLA-B27(+) AS patients, 20 CD patients and 17 normal controls were consecutively enrolled. Classic M1 (iNOS(+)IL-10(-)), resolution phase (iNOS(+)IL-10(+)), M2 and CD14(+) macrophages were characterized by immunohistochemistry and flow cytometry. Quantitative gene expression analysis of IFN-γ, IL-4, IL-5, IL-33 and STAT6 was performed by real time PCR. RESULTS: Classic M1 macrophages were expanded in CD and AS, where resolution phase macrophages predominate. A large increase in CD163(+) (M2) macrophages was observed in AS strictly correlated with the expression of IL-33, a Th2 cytokine involved in M2 polarization. Unlike in CD, CD14(+) macrophages were virtually absent in the gut of AS patients and controls. CONCLUSION: The absence of CD14(+) macrophages together with the expansion of resolution phase and M2 macrophages is the immunological signature of subclinical ileal inflammation in AS.
Assuntos
Citocinas/genética , DNA/genética , Regulação da Expressão Gênica , Ileíte/etiologia , Macrófagos/imunologia , Espondilite Anquilosante/genética , Adulto , Idoso , Biópsia , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Ileíte/genética , Ileíte/metabolismo , Íleo/imunologia , Íleo/metabolismo , Íleo/patologia , Imuno-Histoquímica , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Espondilite Anquilosante/complicações , Espondilite Anquilosante/imunologia , Adulto JovemRESUMO
OBJECTIVES: To investigate the in vitro and ex-vivo effect of IL-6 inhibition on the balance between Th1, Th2, Th17 and Treg cells. METHODS: Ten consecutive adult patients with active early rheumatoid arthritis (ERA) and ten healthy volunteers were included in the study. The percentages of Th1, Th2, Th17 and Treg cells were analysed by flow cytometry in the peripheral blood mononuclear cells obtained from controls and from RA patients at the time of first evaluation and just before the third TCZ infusion. The in vitro effect of TCZ on the different subsets of CD4+ T cells and the expression levels of Th1, Th2, Th17 and Treg-related cytokines was also assessed. RESULTS: Treatment with TCZ, both ex vivo and in vitro, resulted in a significant reduction of the percentage of Th1, Th17 and Treg cells with a concomitant significant increase of Th2 cell subsets. The reduction of the different subsets of T lymphocytes was associated with an intense staining with Annexin V, suggesting an apoptotic-related cell reduction. A significant decrease of Th1, Th17 and Treg cytokines and a concomitant increase of IL-4 was also observed after TCZ treatment in PBMC isolated from RA patients. CONCLUSIONS: TCZ could modify the immune imbalance in RA inducing apoptosis of Th1, Th17 and Treg cells and promoting the appearance of a Th2 response.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Adulto , Apoptose/efeitos dos fármacos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Células Cultivadas , Feminino , Citometria de Fluxo , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate the expression of IL-34 in labial salivary glands (LSGs) of patients with primary SS (p-SS) and its role in inducing a pro-inflammatory monocyte phenotype. METHODS: LSG biopsies were obtained from 20 patients with p-SS and 10 patients with non-Sjögren's sicca syndrome (n-SS). The expression of IL-34, IL-1ß, TNF-α, IL-17 and IL-23 was assessed by real-time PCR. IL-34 expression was also investigated in LSGs by immunohistochemistry. The frequencies of subpopulations of CD14(+) monocytes were evaluated by flow cytometry among isolated mononuclear cells from peripheral blood and salivary glands from both patients and controls. The role of recombinant IL-34 on isolated peripheral blood mononuclear cells was also evaluated. RESULTS: IL-34 m-RNA was overexpressed in the inflamed salivary glands of p-SS and associated with increased expression of TNF-α, IL-1ß, IL-17 and IL-23p19. The increased expression of IL-34 was confirmed by immunohistochemistry in paraffin-embedded salivary glands from p-SS patients. IL-34 expression was accompanied by the expansion of pro-inflammatory CD14(bright)CD16(+) monocytes in the salivary glands. In vitro stimulation of peripheral blood mononuclear cells with IL-34 induced the expansion of both CD14(+)CD16(-) cells and CD14(bright)CD16(+) cells in p-SS and non-SS subjects. CONCLUSION: IL-34 seems to be involved in the pathogenesis of salivary gland inflammation in p-SS.
Assuntos
Interleucinas/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Monócitos/metabolismo , Receptores de IgG/metabolismo , Glândulas Salivares/metabolismo , Síndrome de Sjogren/metabolismo , Adulto , Idoso , Feminino , Citometria de Fluxo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Glândulas Salivares/patologia , Síndrome de Sjogren/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In healthy adults, the major peripheral blood γδ T-cell subset expresses the Vγ9Vδ2 TCR and displays pleiotropic features. Here we report that coculture of naive Vγ9Vδ2 T cells with phosphoantigens and a cocktail of cytokines (IL-1-ß, TGF-ß, IL-6, and IL-23), leads to selective expression of the transcription factor RORγt and polarization toward IL-17 production. IL-17(+) Vγ9Vδ2 T cells express the chemokine receptor CCR6 and produce IL-17 but neither IL-22 nor IFN-γ; they have a predominant terminally differentiated (CD27(-)CD45RA(+)) phenotype and express granzyme B, TRAIL, FasL, and CD161. On antigen activation, IL-17(+) Vγ9Vδ2 T cells rapidly induce CXCL8-mediated migration and phagocytosis of neutrophils and IL-17-dependent production of ß-defensin by epithelial cells, indicating that they may be involved in host immune responses against infectious microorganisms. Accordingly, an increased percentage of IL-17(+) Vγ9Vδ2 lymphocytes is detected in the peripheral blood and at the site of disease in children with bacterial meningitis, and this pattern was reversed after successful antibacterial therapy. Most notably, the phenotype of IL-17(+) Vγ9Vδ2 T cells in children with meningitis matches that of in vitro differentiated IL-17(+) Vγ9Vδ2 T cells. Our findings delineate a previously unknown subset of human IL-17(+) Vγ9Vδ2 T lymphocytes implicated in the pathophysiology of inflammatory responses during bacterial infections.
Assuntos
Interleucina-17/metabolismo , Meningites Bacterianas/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Adolescente , Adulto , Antígenos de Bactérias/imunologia , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Células Cultivadas , Criança , Pré-Escolar , Técnicas de Cocultura , Feminino , Humanos , Imunofenotipagem , Interleucina-17/imunologia , Interleucina-8/imunologia , Interleucina-8/metabolismo , Masculino , Meningites Bacterianas/fisiopatologia , Neutrófilos/citologia , Neutrófilos/imunologia , Fagocitose/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Células Th17/microbiologia , beta-Defensinas/imunologia , beta-Defensinas/metabolismoRESUMO
Gammadelta T cells and dendritic cells (DCs) participate in early phases of immune response against Mycobacterium tuberculosis. We investigated whether a close functional relationship exists between these two cell populations using an in vitro coculture in a human system. Vgamma9Vdelta2 T cells induce full maturation of M. tuberculosis-infected immature DCs, as demonstrated by upregulation of the costimulatory CD80, CD86, CD40, and HLA-DR molecules on infected DCs after 24 h of coculture. Reciprocally, infected DCs induced substantial activation of Vgamma9Vdelta2 T cells upon coculture, which was cell-to-cell contact and TCR dependent, as demonstrated in transwell experiments. However, infected DCs selectively induced proliferative, but not cytokine or cytolytic, responses of Vgamma9Vdelta2 T cells, and this was associated with the expansion of phenotypically immature, central memory-type Vgamma9Vdelta2 T cells. Importantly, expansion of central memory Vgamma9Vdelta2 T cells and reduction of the pool of Vgamma9Vdelta2 T cells with immediate effector functions (effector memory and terminally differentiated cells) were also detected in vivo in the peripheral blood of patients with active tuberculosis, which reversed after antimycobacterial therapy. M. tuberculosis-infected DCs produced many different cytokines, but not IL-15, and addition of IL-15 to cocultures of infected DCs and Vgamma9Vdelta2 T cells caused efficient differentiation of these latter with generation of effector memory and terminally differentiated cells, which were capable of reducing the viability of intracellular M. tuberculosis. Overall, this study provides a further piece of information on the complex relationship between important players of innate immunity during mycobacterial infection.
Assuntos
Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Ativação Linfocitária/imunologia , Mycobacterium tuberculosis/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/imunologia , Adulto , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Testes Imunológicos de Citotoxicidade , Células Dendríticas/metabolismo , Feminino , Humanos , Memória Imunológica , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T gama-delta/biossíntese , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/microbiologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/microbiologiaRESUMO
In this paper we focus our attention on the role of two families of receptors, Toll-like receptors (TLR) and decoy receptors (DcR) involved in the generation of systemic lupus erythematosus (SLE) and lupus-like syndromes in human and mouse models. To date, these molecules were described in several autoimmune disorders such as rheumatoid arthritis, antiphospholipids syndrome, bowel inflammation, and SLE. Here, we summarize the findings of recent investigations on TLR and DcR and their role in the immunopathogenesis of the SLE.
Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Receptores Toll-Like/imunologia , Receptores Chamariz do Fator de Necrose Tumoral/imunologia , Animais , Autoantígenos/imunologia , Autoimunidade , Comunicação Celular , Quimiocinas/imunologia , Modelos Animais de Doenças , Humanos , Imunidade Inata , Camundongos , Transdução de SinaisRESUMO
Zoonoses include a broad range of diseases, that are becoming of great interest, due to the climate changing, that cause the adaptation of vectors to new niches and environments. Host immune responses play a crucial role in determining the outcome of infections, as documented by expansion of antigen-specific T cells during several zoonotic infections. Thus, understanding of the contribution of antigen-specific T-cell subsets in the host immune response is a powerful tool to evaluate the different immunological mechanisms involved in zoonotic infections and for the development of effective vaccines. In this paper we discuss the role of T cells in some eukaryotic and prokaryotic infectious models.