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Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.
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Linfo-Histiocitose Hemofagocítica/genética , Proteínas de Ligação a RNA/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Animais , Códon sem Sentido , Consanguinidade , Ciclosporina/uso terapêutico , Eosinofilia/genética , Eosinofilia/imunologia , Homozigoto , Humanos , Imunofenotipagem , Imunossupressores/uso terapêutico , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Camundongos , Monócitos/imunologia , Receptores OX40/genética , Receptores OX40/imunologia , Receptores OX40/metabolismo , Recidiva , Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Ubiquitina-Proteína Ligases/imunologiaRESUMO
Persistent activation of the transcription factor Nuclear factor-κB (NF-κB) is central to the pathogenesis of many inflammatory disorders, including those of the lung such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD). Despite recent advances in treatment, management of the inflammatory component of these diseases still remains suboptimal. A20 is an endogenous negative regulator of NF-κB signaling, which has been widely described in several autoimmune and inflammatory disorders and more recently in terms of chronic lung disorders. However, the underlying mechanism for the apparent lack of A20 in CF, COPD, and asthma has not been investigated. Transcriptional regulation of A20 is complex and requires coordination of different transcription factors. In this review we examine the existing body of research evidence on the regulation of A20, concentrating on pulmonary inflammation. Special focus is given to the repressor downstream regulatory element antagonist modulator (DREAM) and its nuclear and cytosolic action to regulate inflammation. We provide evidence that would suggest the A20-DREAM axis to be an important player in (airway) inflammatory responses and point to DREAM as a potential future therapeutic target for the modification of phenotypic changes in airway inflammatory disorders. A schematic summary describing the role of DREAM in inflammation with a focus on chronic lung diseases as well as the possible consequences of altered DREAM expression on immune responses is provided.
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Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Pneumopatias/tratamento farmacológico , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/efeitos dos fármacos , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Animais , Doença Crônica/tratamento farmacológico , Humanos , Inflamação/metabolismo , FenótipoRESUMO
The airway epithelium regulates responses to aeroallergens, acting as a physical and immunological barrier. In asthma, epithelial barrier function and the expression of adherens junction protein E-cadherin is compromised, but it is unknown whether this is cause or consequence of the disease. We hypothesized that airway epithelial loss of E-cadherin is a critical step in the development of manifestations of asthma. We generated a transgenic mouse model with conditional loss of E-cadherin in lung epithelial cells at birth and onwards. We observed normal lung development at the time of birth in mice lacking E-cadherin in the lung epithelium. However, E-cadherin deficiency led to progressive epithelial damage in mice growing into adulthood, as evidenced by airway epithelial denudation, decreased zonula occludens (ZO)-1 expression, loss of ciliated cells, and enlarged alveolar spaces. In addition, spontaneous goblet cell metaplasia with mucus production was observed. These epithelial changes were accompanied by elevated levels of the epithelial-derived chemokine CCL17, infiltration of eosinophils and dendritic cells, and mucus production. In conclusion, loss of E-cadherin induces features in the lung reminiscent of those observed in asthma, indicating that the disruption of E-cadherin-mediated cell-cell contacts may play a key role in the development of asthma manifestations.
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Caderinas/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Junções Aderentes/metabolismo , Animais , Asma/metabolismo , Caderinas/genética , Caderinas/fisiologia , Quimiocina CCL17/metabolismo , Células Dendríticas/imunologia , Modelos Animais de Doenças , Eosinófilos/metabolismo , Células Epiteliais/metabolismo , Epitélio/metabolismo , Células Caliciformes/metabolismo , Pulmão/patologia , Metaplasia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Junções Íntimas/metabolismo , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
BACKGROUND: In humans, both basophils and dendritic cells (DCs) express the high-affinity IgE receptor (FcεRI). OBJECTIVE: To gain more insight into the relation between serum IgE levels and FcεRI expression and IgE binding by DCs and basophils in house dust mite (HDM) allergy and during subcutaneous immunotherapy (SCIT). METHODS: We measured FcεRI, IgE and HDM allergen on DCs (conventional type 2 DCs, cDC2s; plasmacytoid dendritic cells, pDCs) and basophils by flow cytometry in 22 non-allergic vs 52 allergic subjects and upon HDM SCIT in 28 allergic subjects. IgE levels were measured in serum. RESULTS: Serum IgE correlated differentially with FcεRI expression and IgE binding depending on cell type and allergic status. In non-allergic subjects, FcεRI/IgE surface densities increased with serum IgE to a significantly stronger degree on basophils compared to cDC2s. By contrast, in allergic subjects FcεRI/IgE surface densities increased with serum IgE to a slightly stronger degree on cDC2s compared to basophils. In addition, the data set suggests sequential loading of IgE onto FcεRI expressed by these cells (basophils>cDC2s>pDCs). Finally, HDM SCIT induced a temporary increase in serum IgE, which was paralleled by a peak in FcεRI and IgE on DCs, but not on basophils. CONCLUSIONS & CLINICAL RELEVANCE: This study provides a comprehensive insight into the relation between serum IgE and FcεRI/IgE on basophils and DC subsets. The novel finding that HDM SCIT induces a temporary increase in FcεRI expression on DCs, but not on basophils, can be an incentive for future research on the potential tolerogenic role of IgE/FcεRI signalling in DCs in the setting of allergen immunotherapy.
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Basófilos/imunologia , Basófilos/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunoglobulina E/imunologia , Receptores de IgE/genética , Rinite Alérgica/etiologia , Rinite Alérgica/metabolismo , Adolescente , Adulto , Animais , Antígenos de Dermatophagoides/imunologia , Biomarcadores , Dessensibilização Imunológica , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Ligação Proteica , Pyroglyphidae/imunologia , Receptores de IgE/metabolismo , Rinite Alérgica/terapia , Adulto JovemRESUMO
Due to their capacity to skew T cell responses towards Th1 oriented immunity, oligonucleotides containing unmethylated CpG motifs (CpG) have emerged as interesting adjuvants for vaccination. Whereas the signalling pathways in response to CpG mediated TLR9 activation have been extensively documented at the level of the individual cell, little is however known on the precise identity of the innate immune cells that govern T cell priming and polarisation to CpG adjuvanted protein antigens in vivo. In this study, we demonstrate that optimal induction of Th1 oriented immunity to CpG adjuvanted protein vaccines requires the coordinated actions of conventional DCs and of monocytes. Whilst conventional DCs were required for antigen presentation and initial T cell priming, monocytes constitute the main source of the Th1 polarising cytokine IL-12.
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Adjuvantes Imunológicos/farmacologia , Imunidade Celular , Inflamação/patologia , Interleucina-12/biossíntese , Monócitos/patologia , Oligodesoxirribonucleotídeos/farmacologia , Células Th1/imunologia , Vacinas/imunologia , Animais , Apresentação de Antígeno/efeitos dos fármacos , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/metabolismo , Antígenos/metabolismo , Antígenos Ly/metabolismo , Movimento Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Imunidade Celular/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fenótipo , Receptores CCR2/metabolismo , VacinaçãoAssuntos
Bacillus/fisiologia , Roupas de Cama, Mesa e Banho , Probióticos/administração & dosagem , Pyroglyphidae/imunologia , Rinite Alérgica/terapia , Têxteis , Adolescente , Adulto , Idoso , Animais , Roupas de Cama, Mesa e Banho/efeitos adversos , Bélgica , Método Duplo-Cego , Feminino , Humanos , Testes Intradérmicos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Probióticos/efeitos adversos , Qualidade de Vida , Rinite Alérgica/diagnóstico , Rinite Alérgica/imunologia , Têxteis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Our understanding of conventional dendritic cell (cDC) development and the functional specializations of distinct subsets in the peripheral tissues has increased greatly in recent years. Here, we review cDC development from the distinct progenitors in the bone marrow through to the distinct cDC subsets found in barrier tissues, providing an overview of the different subsets described in each location. In addition, we detail the transcription factors and local signals that have been proposed to control this developmental process. Importantly, despite these significant advances, numerous questions remain to be answered regarding cDC development. For example, it remains unclear whether the different subsets described, such as the CD103+CD11b+ and CD103-CD11b+ cDCs in the intestines, truly represent different populations or rather distinct developmental or activation stages. Furthermore, whether distinct progenitors exist for these cDC subsets remains to be determined. Thus in the last part of this review we discuss what we believe will be the main questions facing the field for the coming years.
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Células da Medula Óssea/fisiologia , Células Dendríticas/fisiologia , Animais , Antígenos CD/metabolismo , Antígeno CD11b/metabolismo , Diferenciação Celular , Humanos , Cadeias alfa de Integrinas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The expression of allergen genes in house dust mites is influenced by temperature and relative humidity, but little is known of the impacts of other environmental factors that may alter the repertoire of allergens released by mites in home microhabitats. Bioassays were conducted in concave microscope slides in combination with real-time quantitative polymerase chain reaction (RT-qPCR) to analyse gene expression of 17 allergens of Dermatophagoides pteronyssinus (Acariformes: Pyroglyphidae) exposed to three chemical stressors that can be present in domestic environments. Short-term exposure (5-12 days) to diesel exhaust particles (DEPs) (1 µg/cm2 ), bacterial lipopolysaccharide endotoxin (0.1 µg/cm2 ) and benzyl benzoate (3.2 µg/cm2 ), at concentrations exceeding those expected in homes, had no significant effect on allergen transcription. A significant increase in the transcription of allergens Der p 3, Der p 8 and Der p 21 was observed only after exposing mites to a higher concentration of DEPs (10 µg/cm2 ) over a whole generation. In combination, the present results suggest that the analysed factors have low impact on allergen production. The methodology described here offers a sound and rapid approach to the broad-spectrum study of factors affecting allergen-related mite physiology, and allows the simultaneous screening of different factors in a relatively short period with consideration of the full spectrum of allergen genes.
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Poluentes Atmosféricos/análise , Alérgenos/genética , Dermatophagoides pteronyssinus/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Inseticidas/análise , Lipopolissacarídeos/fisiologia , Alérgenos/metabolismo , Animais , Benzoatos/análise , Dermatophagoides pteronyssinus/genética , Dermatophagoides pteronyssinus/metabolismo , Material Particulado/análise , Emissões de Veículos/análiseRESUMO
MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.
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Hipersensibilidade/diagnóstico , Hipersensibilidade/terapia , Medicina de Precisão/métodos , Biologia de Sistemas/métodos , Gerenciamento Clínico , União Europeia , Política de Saúde , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/prevenção & controle , Imunização , Imunoglobulina E/imunologia , Invenções , Prognóstico , Organização Mundial da SaúdeRESUMO
Immunity to Influenza A virus (IAV) is controlled by conventional TCRαß(+) CD4(+) and CD8(+) T lymphocytes, which mediate protection or cause immunopathology. Here, we addressed the kinetics, differentiation, and antigen specificity of CD4(-)CD8(-) double-negative (DN) T cells. DNT cells expressed intermediate levels of TCR/CD3 and could be further divided in γδ T cells, CD1d-reactive type I NKT cells, NK1.1(+) NKT-like cells, and NK1.1(-) DNT cells. NK1.1(-) DNT cells had a separate antigen-specific repertoire in the steady-state lung, and expanded rapidly in response to IAV infection, irrespectively of the severity of infection. Up to 10% of DNT cells reacted to viral nucleoprotein. Reinfection experiments with heterosubtypic IAV revealed that viral replication was a major trigger for recruitment. Unlike conventional T cells, the NK1.1(-) DNT cells were in a preactivated state, expressing memory markers CD44, CD11a, CD103, and the cytotoxic effector molecule FasL. DNT cells resided in the lung parenchyma, protected from intravascular labeling with CD45 antibody. The recruitment and maintenance of CCR2(+) CCR5(+) CXCR3(+) NK1.1(-) DNT cells depended on CD11c(hi) dendritic cells (DCs). Functionally, DNT cells controlled the lung DC subset balance, suggesting they might act as immunoregulatory cells. In conclusion, we identify activation of resident memory NK1.1(-) DNT cells as an integral component of the mucosal immune response to IAV infection.
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Células Dendríticas/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Pulmão/imunologia , Células T Matadoras Naturais/imunologia , Infecções por Orthomyxoviridae/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Antígenos Virais/imunologia , Antígeno CD11c/metabolismo , Diferenciação Celular , Movimento Celular , Células Cultivadas , Imunidade nas Mucosas , Memória Imunológica , Pulmão/patologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
BACKGROUND: Asthma, rhinitis and eczema often co-occur in children, but their interrelationships at the population level have been poorly addressed. We assessed co-occurrence of childhood asthma, rhinitis and eczema using unsupervised statistical techniques. METHODS: We included 17 209 children at 4 years and 14 585 at 8 years from seven European population-based birth cohorts (MeDALL project). At each age period, children were grouped, using partitioning cluster analysis, according to the distribution of 23 variables covering symptoms 'ever' and 'in the last 12 months', doctor diagnosis, age of onset and treatments of asthma, rhinitis and eczema; immunoglobulin E sensitization; weight; and height. We tested the sensitivity of our estimates to subject and variable selections, and to different statistical approaches, including latent class analysis and self-organizing maps. RESULTS: Two groups were identified as the optimal way to cluster the data at both age periods and in all sensitivity analyses. The first (reference) group at 4 and 8 years (including 70% and 79% of children, respectively) was characterized by a low prevalence of symptoms and sensitization, whereas the second (symptomatic) group exhibited more frequent symptoms and sensitization. Ninety-nine percentage of children with comorbidities (co-occurrence of asthma, rhinitis and/or eczema) were included in the symptomatic group at both ages. The children's characteristics in both groups were consistent in all sensitivity analyses. CONCLUSION: At 4 and 8 years, at the population level, asthma, rhinitis and eczema can be classified together as an allergic comorbidity cluster. Future research including time-repeated assessments and biological data will help understanding the interrelationships between these diseases.
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Asma/epidemiologia , Asma/imunologia , Eczema/epidemiologia , Eczema/imunologia , Rinite Alérgica/epidemiologia , Rinite Alérgica/imunologia , Distribuição por Idade , Asma/genética , Criança , Pré-Escolar , Análise por Conglomerados , Estudos de Coortes , Comorbidade , Estudos Transversais , Eczema/genética , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Internacionalidade , Masculino , Fenótipo , Prevalência , Rinite Alérgica/genética , Índice de Gravidade de Doença , Distribuição por SexoRESUMO
Calcineurin inhibitors (CNI), used frequently in solid organ transplant patients, are known to inhibit T cell proliferation, but their effect on humoral immunity is far less studied. Total and naive B cells from healthy adult donors were cultured in immunoglobulin (Ig)A- or IgG/IgE-promoting conditions with increasing doses of cyclosporin, tacrolimus, rapamycin or methylprednisolone. The effect on cell number, cell division, plasmablast differentiation and class-switching was tested. To examine the effect on T follicular helper (Tfh) cell differentiation, naive CD4(+) T cells were cultured with interleukin (IL)-12 and titrated immunosuppressive drug (IS) concentrations. Total B cell function was not affected by CNI. However, naive B cell proliferation was inhibited by cyclosporin and both CNI decreased plasmablast differentiation. Both CNI suppressed IgA, whereas only cyclosporin inhibited IgE class-switching. Rapamycin had a strong inhibitory effect on B cell function. Strikingly, methylprednisolone, increased plasmablast differentiation and IgE class-switching from naive B cells. Differentiation of Tfh cells decreased with increasing IS doses. CNI affected humoral immunity directly by suppressing naive B cells. CNI, as well as rapamycin and methylprednisolone, inhibited the in-vitro differentiation of Tfh from naive CD4(+) T cells. In view of its potent suppressive effect on B cell function and Tfh cell differentiation, rapamycin might be an interesting candidate in the management of B cell mediated complications post solid organ transplantation.
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Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Inibidores de Calcineurina/farmacologia , Imunidade Humoral/efeitos dos fármacos , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Switching de Imunoglobulina/efeitos dos fármacos , Switching de Imunoglobulina/imunologia , Imunossupressores/farmacologia , Interleucinas/metabolismo , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Plasmócitos/citologia , Plasmócitos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
BACKGROUND: Post-transplant food allergy (LTFA) is increasingly observed after paediatric liver transplantation (LT). Although the immunopathology of LTFA remains unclear, immunoglobulin (Ig) E seems to be implicated. OBJECTIVE: To study humoral and cellular immunity in paediatric LT patients in search for factors associated with LTFA, and compare with healthy controls (HC) and non-transplant food-allergic children (FA). METHODS: We studied serum Ig levels in 29 LTFA, 43 non-food-allergic LT patients (LTnoFA), 21 FA patients and 36 HC. Serum-specific IgA and IgE against common food allergens in LTFA, IgA1 , IgA2 and joining-chain-containing polymeric IgA (pIgA) were measured. Peripheral blood mononuclear cells were analysed by flow cytometry for B and T cell populations of interest. RESULTS: Serum IgA and specific IgA were higher in LTFA compared to LTnoFA. LTFA patients had the highest proportion of circulating T follicular helper cells (cTfh). The percentage of cTfh correlated positively with serum IgA. Unique in LTFA was also the significant increase in serum markers of mucosal IgA and the decrease in the Th17 subset of CXCR5(-) CD4(+) cells compared to HC. Both LT patients exhibited a rise in IgA(+) memory B cells and plasmablasts compared to HC and FA. CONCLUSIONS: LT has an impact on humoral immunity, remarkably in those patients developing FA. The increase in serum markers of mucosal IgA, food allergen-specific IgA and cTfh cells observed in LTFA, point towards a disturbance in intestinal immune homoeostasis in this patient group.
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Hipersensibilidade Alimentar/sangue , Hipersensibilidade Alimentar/imunologia , Imunoglobulina A/imunologia , Transplante de Fígado , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Fatores Etários , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Feminino , Hipersensibilidade Alimentar/diagnóstico , Humanos , Imunoglobulina A/sangue , Imunoglobulina A Secretora/imunologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Memória Imunológica , Imunofenotipagem , Lactente , Transplante de Fígado/efeitos adversos , Masculino , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
The identification of intestinal macrophages (mφs) and dendritic cells (DCs) is a matter of intense debate. Although CD103(+) mononuclear phagocytes (MPs) appear to be genuine DCs, the nature and origins of CD103(-) MPs remain controversial. We show here that intestinal CD103(-)CD11b(+) MPs can be separated clearly into DCs and mφs based on phenotype, gene profile, and kinetics. CD64(-)CD103(-)CD11b(+) MPs are classical DCs, being derived from Flt3 ligand-dependent, DC-committed precursors, not Ly6C(hi) monocytes. Surprisingly, a significant proportion of these CD103(-)CD11b(+) DCs express CCR2 and there is a selective decrease in CD103(-)CD11b(+) DCs in mice lacking this chemokine receptor. CCR2(+)CD103(-) DCs are present in both the murine and human intestine, drive interleukin (IL)-17a production by T cells in vitro, and show constitutive expression of IL-12/IL-23p40. These data highlight the heterogeneity of intestinal DCs and reveal a bona fide population of CCR2(+) DCs that is involved in priming mucosal T helper type 17 (Th17) responses.
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Diferenciação Celular , Células Dendríticas/citologia , Células Dendríticas/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th17/metabolismo , Animais , Antígenos CD/metabolismo , Células Dendríticas/metabolismo , Humanos , Imunofenotipagem , Cadeias alfa de Integrinas/metabolismo , Fatores Reguladores de Interferon/metabolismo , Interleucina-12/metabolismo , Interleucina-17/biossíntese , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/metabolismo , Fagócitos/imunologia , Fagócitos/metabolismo , Fenótipo , Receptores CCR2/metabolismo , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologiaRESUMO
The lung is highly exposed to the external environment. For this reason, the lung needs to handle a number of potential threats present in inhaled air such as viruses or bacteria. Dendritic cells (DCs) and macrophages (MFs) play an important role in orchestrating the immune responses to these challenges. The severe lung inflammation caused by some pathogens poses a unique challenge to the immune system: the potential insult must be eliminated rapidly whereas tissue inflammation must be controlled in order to avoid collateral damages that can lead to acute respiratory failure. Immune responses to infectious agents are initiated and controlled by various populations of antigen-presenting cells with specialized functions, which include conventional DCs (cDCs), monocyte-derived DCs (moDCs), plasmacytoid DCs (pDCs), and alveolar MFs (AMFs). This review will discuss the role of these different cells in responses to pulmonary infections, with a focus on influenza virus and Mycobacterium tuberculosis.
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Células Dendríticas/imunologia , Macrófagos Alveolares/imunologia , Mycobacterium tuberculosis/imunologia , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/imunologia , Infecções Respiratórias/imunologia , Tuberculose Pulmonar/imunologia , Animais , Apresentação de Antígeno , Humanos , Imunidade Celular , Pulmão/patologiaRESUMO
BACKGROUND: Sphingosine-1-phosphate (S1P) plays a crucial role in homeostasis of the immune system by regulating lymphocyte recirculation and inflammatory cell recruitment. The levels of S1P are tightly controlled through regulated production and controlled breakdown by sphingosine-lyase (SL). The S1P analogue FTY720 has been developed as an immunosuppressant in transplantation and tested as a treatment for various inflammatory diseases. FTY720 exploits S1P biology by acting as a S1P1 and S1P 3 agonist and by inhibiting S1P breakdown by SL. OBJECTIVE: Here, we investigate interfering S1P in allergic rhinitis (AR) and its way of action. METHODS: Allergic rhinitis was induced by sensitizing mice to ovalbumin (OVA) and challenging the nose with OVA allergen. At the time of allergen challenge, mice received topical intranasal treatment with FTY720. To address the relative contribution of SL inhibition in mediating its effects, some mice were treated with the SL inhibitor 2-acetyl-4-tetrahydroxybutyl (THI). RESULTS: FTY720 treatment resulted in significantly fewer eosinophils, mast cells and dendritic cells in the nasal mucosa of AR animals, compared with diluent treatment. Levels of IL-4, IL-5, IL-10 and IL-13 produced by lymph node cells fell significantly in FTY720-treated animals. Moreover, FTY720 proved potent enough to suppress inflammation in a model of persistent AR. In vitro and in vivo experiments indicate that FTY720 impaired Th2 differentiation and proliferation important in driving eosinophilia and induced apoptosis in mast cells. CONCLUSION: Our results indicate that interfering with S1P metabolism is a powerful and feasible strategy to develop new topical agents that suppress AR.
Assuntos
Imunossupressores/farmacologia , Lisofosfolipídeos/farmacologia , Propilenoglicóis/farmacologia , Rinite Alérgica Perene/tratamento farmacológico , Esfingosina/análogos & derivados , Administração Tópica , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Cloridrato de Fingolimode , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos , Ovalbumina/farmacologia , Distribuição Aleatória , Rinite Alérgica , Rinite Alérgica Perene/imunologia , Rinite Alérgica Perene/fisiopatologia , Sensibilidade e Especificidade , Esfingosina/farmacologia , Células Th2/efeitos dos fármacos , Células Th2/fisiologiaRESUMO
Airway epithelial cells are the first to encounter aeroallergens and therefore have recently become an interesting target of many studies investigating their involvement in the modulation of allergic inflammatory responses. Disruption of a passive structural barrier composed of epithelial cells by intrinsic proteolytic activity of allergens may facilitate allergen penetration into local tissues and additionally affect chronic and ongoing inflammatory processes in respiratory tissues. Furthermore, the ability of rhinoviruses to disrupt and interfere with epithelial tight junctions may alter the barrier integrity and enable a passive passage of inhaled allergens through the airway epithelium. On the other hand, epithelial cells are no longer considered to act only as a physical barrier toward inhaled allergens, but also to actively contribute to airway inflammation by detecting and responding to environmental factors. Epithelial cells can produce mediators, which may affect the recruitment and activation of more specialized immune cells to the local tissue and also create a microenvironment in which these activated immune cells may function and propagate the inflammatory processes. This review presents the dual role of epithelium acting as a passive and active barrier when encountering an inhaled allergen and how this double role contributes to the start of local immune responses.
Assuntos
Alérgenos/imunologia , Exposição Ambiental/efeitos adversos , Imunidade Inata/imunologia , Mediadores da Inflamação/imunologia , Mucosa Respiratória/imunologia , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/imunologia , Alérgenos/efeitos adversos , Animais , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Epiteliais/citologia , Células Epiteliais/imunologia , Humanos , Países Baixos , Mucosa Respiratória/fisiopatologia , Sistema Respiratório/imunologia , Sistema Respiratório/fisiopatologia , Fatores de Risco , Papel (figurativo)RESUMO
Influenza is a global health concern. Licensed influenza vaccines induce strain-specific virus-neutralizing antibodies but hamper the induction of possibly cross-protective T-cell responses upon subsequent infection.(1) In this study, we compared protection induced by a vaccine based on the conserved extracellular domain of matrix 2 protein (M2e) with that of a conventional whole inactivated virus (WIV) vaccine using single as well as consecutive homo- and heterosubtypic challenges. Both vaccines protected against a primary homologous (with respect to hemagglutinin and neuraminidase in WIV) challenge. Functional T-cell responses were induced after primary challenge of M2e-immune mice but were absent in WIV-vaccinated mice. M2e-immune mice displayed limited inducible bronchus-associated lymphoid tissue, which was absent in WIV-immune animals. Importantly, M2e- but not WIV-immune mice were protected from a primary as well as a secondary, severe heterosubtypic challenge, including challenge with pandemic H1N1 2009 virus. Our findings advocate the use of infection-permissive influenza vaccines, such as those based on M2e, in immunologically naive individuals. The combined immune response induced by M2e-vaccine and by clinically controlled influenza virus replication results in strong and broad protection against pandemic influenza. We conclude that the challenge of the M2e-immune host induces strong and broadly reactive immunity against influenza virus infection.
Assuntos
Imunidade Celular , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Proteínas da Matriz Viral/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Reações Cruzadas/imunologia , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno/imunologia , Pulmão/imunologia , Pulmão/virologia , Camundongos , Infecções por Orthomyxoviridae/virologiaRESUMO
BACKGROUND: Ursodeoxycholic acid (UDCA) is the only known beneficial bile acid with immunomodulatory properties. Ursodeoxycholic acid prevents eosinophilic degranulation and reduces eosinophil counts in primary biliary cirrhosis. It is unknown whether UDCA would also modulate eosinophilic inflammation outside the gastrointestinal (GI) tract, such as eosinophilic airway inflammation seen in asthma. The working mechanism for its immunomodulatory effect is unknown. METHODS: The immunosuppressive features of UDCA were studied in vivo, in mice, in an ovalbumin (OVA)-driven eosinophilic airway inflammation model. To study the mechanism of action of UDCA, we analyzed the effect of UDCA on eosinophils, T cells, and dendritic cell (DCs). DC function was studied in greater detail, focussing on migration and T-cell stimulatory strength in vivo and interaction with T cells in vitro as measured by time-lapse image analysis. Finally, we studied the capacity of UDCA to influence DC/T cell interaction. RESULTS: Ursodeoxycholic acid treatment of OVA-sensitized mice prior to OVA aerosol challenge significantly reduced eosinophilic airway inflammation compared with control animals. DCs expressed the farnesoid X receptor for UDCA. Ursodeoxycholic acid strongly promoted interleukin (IL)-12 production and enhanced the migration in DCs. The time of interaction between DCs and T cells was sharply reduced in vitro by UDCA treatment of the DCs resulting in a remarkable T-cell cytokine production. Ursodeoxycholic acid-treated DCs have less capacity than saline-treated DCs to induce eosinophilic inflammation in vivo in Balb/c mice. CONCLUSION: Ursodeoxycholic acid has the potency to suppress eosinophilic inflammation outside the GI tract. This potential comprises to alter critical function of DCs, in essence, the effect of UDCA on DCs through the modulation of the DC/T cell interaction.