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1.
Arthritis Rheumatol ; 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249544

RESUMO

OBJECTIVES: Transforming growth factor beta (TGFß) inhibitor Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor (BAMBI) has been shown to control CD4+ T lymphocytes differentiation into either tolerogenic regulatory T (Tregs) or pathogenic TH 17 cells through the regulation of TGFß and IL-2 signaling strength. In the present study, we explore the potential beneficial effects of its pharmacological inhibition with new anti-BAMBI monoclonal antibodies (mAbs) in different skin and joint experimental chronic-inflammatory/autoimmune diseases. METHODS: Development of saccharomyces cerevisiae mannan-induced psoriatic arthritis (MIP) (n= 18-30 mice/group), imiquimod-induced skin psoriasis (n= 20-30 mice/group) or collagen type II-induced arthritis (CIA) (n= 13-16 mice/group) was analyzed in a total number of 2-5 different experiments with B10.RIII wild type (WT) or BAMBI-deficient mice treated or not with B101.37 (mouse IgG1 anti-BAMBI), mouse IgG1 anti-TNP isotype control, anti-CD25 or anti-TGFß mAbs. RESULTS: Treatment of normal mice with an IgG1 anti-BAMBI mAb, clone B101.37, expands Tregs in vivo and has both preventive and therapeutic effects in the murine model of MIP (p<0.05 in both cases). Disease protection is mediated by Tregs, which control the activation and expansion of pathogenic IL-17-producing cells, and is dependent on TGFß. Furthermore, B101.37 treatment blocks the development of skin psoriasis induced by imiquimod and of CIA (p<0.05 in both cases). Finally, the pharmacological inhibition of BAMBI with the IgM anti-BAMBI B143.14 mAb also potentiates the suppressive activity of Tregs in vitro (p<0.001). CONCLUSIONS: We identify BAMBI as a promising new therapeutic target for chronic-inflammatory diseases and other pathological conditions modulated by Tregs.

2.
J Immunother Cancer ; 8(1)2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32217757

RESUMO

BACKGROUND: CD6 is a lymphocyte surface co-receptor physically associated with the T-cell receptor (TCR)/CD3 complex at the center of the immunological synapse. There, CD6 assists in cell-to-cell contact stabilization and modulation of activation/differentiation events through interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), its main reported ligand. While accumulating evidence is attracting new interest on targeting CD6 for therapeutic purposes in autoimmune disorders, little is known on its potential in cancer. In an attempt to elucidate the in vivo relevance of blocking CD6-mediated interactions in health and disease, we explored the consequences of expressing high circulating levels of a soluble form CD6 (sCD6) as a decoy receptor. METHODS: High sCD6 serum levels were achieved by using transgenic C57BL/6 mice expressing human sCD6 under the control of lymphoid-specific transcriptional elements (shCD6LckEµTg) or wild type either transduced with hepatotropic adeno-associated virus coding for mouse sCD6 or undergoing repeated infusions of recombinant human sCD6 protein. Characterization of sCD6-induced changes was performed by ex vivo flow cytometry and functional analyses of mouse lymphoid organ cells. The in vivo relevance of those changes was explored by challenging mice with subcutaneous or metastatic tumors induced by syngeneic cancer cells of different lineage origins. RESULTS: Through a combination of in vitro and in vivo studies, we show that circulating sCD6 expression induces defective regulatory T cell (Treg) generation and function, decreased CD166/ALCAM-mediated tumor cell proliferation/migration and impaired galectin-induced T-cell apoptosis, supporting the fact that sCD6 modulates antitumor lymphocyte effector function and tumorigenesis. Accordingly, sCD6 expression in vivo resulted in delayed subcutaneous tumor growth and/or reduced metastasis on challenge of mice with syngeneic cancer cells. CONCLUSIONS: Evidence is provided for the disruption of CD6 receptor-ligand interactions as a feasible immunomodulatory approach in cancer.

3.
Biol Res Nurs ; 20(4): 452-461, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29724113

RESUMO

BACKGROUND: Obstructive sleep apnea (OSA) is a chronic illness that increases in prevalence with age. Treatment includes continuous positive airway pressure (CPAP) devices. Studies about the use of CPAP in the elderly are scarce. The main objective of this study is to determine whether CPAP contributes to improvement in health-related quality of life (HRQL) in elderly patients with OSA. METHOD: This was a prospective, pre-/postintervention assessment of a cohort of patients ≥65 years of age with OSA diagnosis by polysomnography who were being treated with CPAP and were physically independent and had good cognitive status. We determined HRQL before and after 3 months of CPAP treatment using the Short Form-36 Health Survey (SF-36, a 36-item, patient-reported survey) and Sleep Apnea Quality of Life Index (SAQLI). The effect of CPAP on daytime sleepiness was assessed with the Epworth Sleepiness Scale (ESS). RESULTS: Of the 103 participants with a mean age of 71.5 ± 4.19 years, 66% were male. After 3 months of therapy, the mean CPAP usage was 6.3 ± 1.41 hr/day. The effectiveness of CPAP in controlling the OSA was demonstrated (mean difference pre- and posttherapy: 34.30 ± 18.52 events/hr, p < .001). Postintervention, the categories of the SF-36 improved meaningfully ( p < .001). Moreover, all categories of SAQLI improved ( p < .001) with the exception of "symptoms" ( p = .073). ESS scores also improved significantly (difference = 5.2 ± 4.47, p < .001) postintervention. CONCLUSION: Therapy with CPAP in elderly patients with OSA helps improve their HRQL and reduces daytime sleepiness.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/métodos , Pressão Positiva Contínua nas Vias Aéreas/psicologia , Qualidade de Vida/psicologia , Apneia Obstrutiva do Sono/psicologia , Apneia Obstrutiva do Sono/terapia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Polissonografia , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento
4.
Brain Behav Immun ; 73: 235-251, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29758264

RESUMO

Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., ß-amyloid (Aß) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than Aß plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble Aß species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, Aß peptide expression and neuroinflammation). Administration of anti-IL17 for 5 months, starting at the age of 7 months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and Aß1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics.


Assuntos
Síndrome de Down/imunologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Síndrome de Down/terapia , Feminino , Hipocampo/fisiologia , Interleucina-17/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Neurogênese , Neuroimunomodulação/fisiologia , Estresse Oxidativo , Fenótipo , Placa Amiloide/metabolismo
6.
PLoS One ; 11(7): e0159714, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27433938

RESUMO

The inhibition of apoptotic cell death in T cells through the dysregulated expression of BCL2 family members has been associated with the protection against the development of different autoimmune diseases. However, multiple mechanisms were proposed to be responsible for such protective effect. The purpose of this study was to explore the effect of the T-cell overexpression of BCL2A1, an anti-apoptotic BCL2 family member without an effect on cell cycle progression, in the development of collagen-induced arthritis. Our results demonstrated an attenuated development of arthritis in these transgenic mice. The protective effect was unrelated to the suppressive activity of regulatory T cells but it was associated with a defective activation of p38 mitogen-activated protein kinase in CD4+ cells after in vitro TCR stimulation. In addition, the in vitro and in vivo TH17 differentiation were impaired in BCL2A1 transgenic mice. Taken together, we demonstrated here a previously unknown role for BCL2A1 controlling the activation of CD4+ cells and their differentiation into pathogenic proinflammatory TH17 cells and identified BCL2A1 as a potential target in the control of autoimmune/inflammatory diseases.


Assuntos
Artrite Experimental/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Células Th17/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Animais , Apoptose/genética , Apoptose/imunologia , Artrite Experimental/genética , Artrite Experimental/patologia , Autoimunidade , Antígenos CD4/genética , Antígenos CD4/imunologia , Diferenciação Celular , Citocinas/genética , Citocinas/imunologia , Regulação da Expressão Gênica , Ativação Linfocitária , Camundongos , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor/genética , Fatores de Proteção , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética
7.
J Exp Med ; 213(8): 1387-97, 2016 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-27377588

RESUMO

The CD6 glycoprotein is a lymphocyte surface receptor putatively involved in T cell development and activation. CD6 facilitates adhesion between T cells and antigen-presenting cells through its interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), and physically associates with the T cell receptor (TCR) at the center of the immunological synapse. However, its precise role during thymocyte development and peripheral T cell immune responses remains to be defined. Here, we analyze the in vivo consequences of CD6 deficiency. CD6(-/-) thymi showed a reduction in both CD4(+) and CD8(+) single-positive subsets, and double-positive thymocytes exhibited increased Ca(2+) mobilization to TCR cross-linking in vitro. Bone marrow chimera experiments revealed a T cell-autonomous selective disadvantage of CD6(-/-) T cells during development. The analysis of TCR-transgenic mice (OT-I and Marilyn) confirmed that abnormal T cell selection events occur in the absence of CD6. CD6(-/-) mice displayed increased frequencies of antigen-experienced peripheral T cells generated under certain levels of TCR signal strength or co-stimulation, such as effector/memory (CD4(+)TEM and CD8(+)TCM) and regulatory (T reg) T cells. The suppressive activity of CD6(-/-) T reg cells was diminished, and CD6(-/-) mice presented an exacerbated autoimmune response to collagen. Collectively, these data indicate that CD6 modulates the threshold for thymocyte selection and the generation and/or function of several peripheral T cell subpopulations, including T reg cells.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/imunologia , Sinapses Imunológicas/imunologia , Linfócitos T Reguladores/imunologia , Timócitos/imunologia , Animais , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Linfócitos T CD8-Positivos/citologia , Sinapses Imunológicas/genética , Camundongos , Camundongos Knockout , Receptores de Antígenos/genética , Receptores de Antígenos/imunologia , Linfócitos T Reguladores/citologia , Timócitos/citologia , Timo/citologia , Timo/imunologia
8.
Arthritis Rheumatol ; 68(6): 1551-62, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26714180

RESUMO

OBJECTIVE: Transforming growth factor ß (TGFß) plays a prominent role in the establishment of immunologic tolerance, and mice lacking TGFß1 die of multiorgan inflammation early in life. TGFß controls the differentiation of CD4+ lymphocytes into Treg cells or proinflammatory Th17 cells. Although this dual capacity is modulated by the presence of additional cytokines around the activated cells, TGFß also dissociates Th17/Treg cell differentiation in a dose-dependent manner by mechanisms still unknown. The purpose of this study was to explore the contribution of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) to the modulation of TGFß activity during the differentiation of CD4+ cells and in the control of immunologic tolerance in mice with collagen-induced arthritis (CIA). METHODS: The in vitro and in vivo Treg cell and Th17 cell differentiation and the development of CIA were compared in wild-type mice and BAMBI-deficient mice. RESULTS: BAMBI was induced after activation by TGFß and fixed the appropriate intensity level of TGFß signaling in CD4+ cells. Its deficiency protected mice against the development of CIA by a Treg cell- and TGFß-dependent mechanism. Mechanistically, BAMBI was found to regulate CD25 expression and interleukin-2 (IL-2) signaling in Treg cells and in IL-2- and/or TGFß-activated CD4+ cells and modulated Treg cell and Th17 cell differentiation both in vitro and in vivo. CONCLUSION: Taken together, the results indicate that BAMBI is a component of a rheostat-like mechanism that, through the control of TGFß and IL-2 signaling strength, regulates the differentiation of CD4+ lymphocytes and the development of autoimmune arthritis.


Assuntos
Artrite Experimental/imunologia , Doenças Autoimunes/imunologia , Proteínas Morfogenéticas Ósseas/fisiologia , Diferenciação Celular , Interleucina-2/fisiologia , Proteínas de Membrana/fisiologia , Linfócitos T Reguladores/fisiologia , Células Th17/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Linfócitos T CD4-Positivos/fisiologia , Masculino , Camundongos , Transdução de Sinais
9.
Proteomics ; 15(19): 3382-93, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26175002

RESUMO

Collagen-type-II-induced arthritis (CIA) is an autoimmune disease, which involves a complex host systemic response including inflammatory and autoimmune reactions. CIA is milder in CD38(-/-) than in wild-type (WT) mice. ProteoMiner-equalized serum samples were subjected to 2D-DiGE and MS-MALDI-TOF/TOF analyses to identify proteins that changed in their relative abundances in CD38(-/-) versus WT mice either with arthritis (CIA(+) ), with no arthritis (CIA(-) ), or with inflammation (complete Freund's adjuvant (CFA)-treated mice). Multivariate analyses revealed that a multiprotein signature (n = 28) was able to discriminate CIA(+) from CIA(-) mice, and WT from CD38(-/-) mice within each condition. Likewise, a distinct multiprotein signature (n = 16) was identified which differentiated CIA(+) CD38(-/-) mice from CIA(+) WT mice, and lastly, a third multiprotein signature (n = 18) indicated that CD38(-/-) and WT mice could be segregated in response to CFA treatment. Further analyses showed that the discriminative power to distinguish these groups was reached at protein species level and not at the protein level. Hence, the need to identify and quantify proteins at protein species level to better correlate proteome changes with disease processes. It is crucial for plasma proteomics at the low-abundance protein species level to apply the ProteoMiner enrichment. All MS data have been deposited in the ProteomeXchange with identifiers PXD001788, PXD001799 and PXD002071 (http://proteomecentral.proteomexchange.org/dataset/PXD001788, http://proteomecentral.proteomexchange.org/dataset/PXD001799 and http://proteomecentral.proteomexchange.org/dataset/PXD002071).


Assuntos
Artrite Experimental/sangue , Inflamação/sangue , Proteoma/análise , ADP-Ribosil Ciclase 1/genética , Animais , Artrite Experimental/complicações , Artrite Experimental/fisiopatologia , Adjuvante de Freund , Inflamação/induzido quimicamente , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Eletroforese em Gel Diferencial Bidimensional
10.
PLoS One ; 9(1): e84895, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24454761

RESUMO

CD5 is a lymphoid-specific transmembrane glycoprotein constitutively expressed on thymocytes and mature T and B1a lymphocytes. Current data support the view that CD5 is a negative regulator of antigen-specific receptor-mediated signaling in these cells, and that this would likely be achieved through interaction with CD5 ligand/s (CD5L) of still undefined nature expressed on immune or accessory cells. To determine the functional consequence of loss of CD5/CD5L interaction in vivo, a new transgenic mouse line was generated (shCD5EµTg), expressing a circulating soluble form of human CD5 (shCD5) as a decoy to impair membrane-bound CD5 function. These shCD5EµTg mice showed an enhanced response to autologous antigens, as deduced from the presentation of more severe forms of experimentally inducible autoimmune disease (collagen-induced arthritis, CIA; and experimental autoimmune encephalitis, EAE), as well as an increased anti-tumoral response in non-orthotopic cancer models (B16 melanoma). This enhancement of the immune response was in agreement with the finding of significantly reduced proportions of spleen and lymph node Treg cells (CD4+CD25+FoxP3+), and of peritoneal IL-10-producing and CD5+ B cells, as well as an increased proportion of spleen NKT cells in shCD5EµTg mice. Similar changes in lymphocyte subpopulations were observed in wild-type mice following repeated administration of exogenous recombinant shCD5 protein. These data reveal the relevant role played by CD5/CD5L interactions on the homeostasis of some functionally relevant lymphocyte subpopulations and the modulation of immune responses to autologous antigens.


Assuntos
Artrite Experimental/imunologia , Antígenos CD5/imunologia , Encefalomielite Autoimune Experimental/imunologia , Neoplasias Experimentais/imunologia , Animais , Sequência de Bases , Antígenos CD5/genética , Primers do DNA , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Reação em Cadeia da Polimerase
11.
Arthritis Rheum ; 65(2): 343-54, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23124840

RESUMO

OBJECTIVE: Despite the importance of Treg cells in the maintenance of immunologic tolerance, the mechanisms that control their generation and activity are unknown. Since the cell cycle inhibitor p27(Kip1) (p27) was involved in T cell anergy, we undertook this study to explore its role in both Treg cell processes. METHODS: The development of type II collagen-induced arthritis (CIA) and lupus-like abnormalities was compared between transgenic mice overexpressing human Bcl-2 in T cells (BCL2-TgT mice) and nontransgenic mice that were deficient or not deficient in p27. The contribution of Treg cells to disease evolution was also explored. Finally, the in vitro activity of Treg cells and their differentiation from naive CD4+ cells was compared between these strains of mice. RESULTS: BCL2-TgT mice were protected against CIA by a Treg cell-dependent mechanism. In association with this protection, the overexpression of Bcl-2 in T cells enhanced the differentiation and activity of Treg cells. Both Bcl-2 effects were independent of its antiapoptotic activity but dependent on its capacity to induce the expression of p27 that augmented the strength of transforming growth factor ß (TGFß) signaling in T cells. Accordingly, down-modulation of p27 expression in BCL2-TgT mice promoted CIA. In addition, p27 deficiency in aged C57BL/6 mice reduced the number and activity of Treg cells and induced the development of mild lupus-like abnormalities. CONCLUSION: Our results point to p27 as a critical regulator of Treg cell differentiation and function through the positive modulation of TGFß signaling strength in T cells.


Assuntos
Artrite Experimental/imunologia , Autoimunidade/imunologia , Diferenciação Celular/imunologia , Inibidor de Quinase Dependente de Ciclina p27/genética , Linfócitos T Reguladores/imunologia , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Autoimunidade/genética , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
12.
Rev. esp. med. legal ; 38(4): 161-171, oct.-dic. 2012.
Artigo em Espanhol | IBECS | ID: ibc-107925

RESUMO

El suicidio es la principal causa de muerte violenta en España, por delante de los accidentes de tráfico, y se estima que cada año se suicidan cerca de 3.500 personas. Los factores de riesgo identificados de la conducta suicida se basan, principalmente, en estudios de intentos de suicidio. La centralización de las autopsias en los Institutos de Medicina Legal facilita la homogenización del método de trabajo y la consistencia de los resultados a nivel práctico-judicial y de investigación. La medicina forense debe proyectarse en la investigación en general y de la conducta suicida en particular, en colaboración con otros equipos de investigación. La investigación debe efectuarse según la normativa ética y administrativa vigente y ser aprobada por el Comité Ético de referencia. Con respecto a la investigación de los factores de riesgo del suicidio, el reclutamiento de casos y controles, la obtención de muestras biológicas, la colaboración en la realización de autopsias psicológicas y los estudios epidemiológicos, son aportaciones esenciales de la medicina forense(AU)


In Spain, suicide is the leading cause of violent death, ahead of motor vehicle accidents, with about 3,500 people dying by this mean in Spain. The risk factors identified are primarily based on studies of suicide attempts. The centralization of autopsies in the Institutes of Legal Medicine allows the homogenization of working methods and the consistency of results for both research and legal purposes. Forensics should focus on medical research in general and on suicidal behaviour in particular, in collaboration with other research teams. Research must be conducted according to existing ethical and administrative legislation. All must be approved by the Ethics Committee of reference. With regard to the investigation of risk factors for suicide, forensics are essential in the recruitment of cases and controls—obtaining biological samples, collaborating in conducting psychological autopsies and epidemiological studies(AU)


Assuntos
Humanos , Masculino , Feminino , Médicos Legistas/legislação & jurisprudência , Médicos Legistas/tendências , Médicos Legistas , Ciências Forenses/métodos , Ciências Forenses/tendências , Fatores de Risco , Suscetibilidade a Doenças/epidemiologia , Ideação Suicida , Tentativa de Suicídio/legislação & jurisprudência , Tentativa de Suicídio/prevenção & controle , Intervenção na Crise/estatística & dados numéricos , Intervenção na Crise/tendências
13.
PLoS One ; 7(3): e33534, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22438945

RESUMO

CD38, a type II transmembrane glycoprotein expressed in many cells of the immune system, is involved in cell signaling, migration and differentiation. Studies in CD38 deficient mice (CD38 KO mice) indicate that this molecule controls inflammatory immune responses, although its involvement in these responses depends on the disease model analyzed. Here, we explored the role of CD38 in the control of autoimmune responses using chicken collagen type II (col II) immunized C57BL/6-CD38 KO mice as a model of collagen-induced arthritis (CIA). We demonstrate that CD38 KO mice develop an attenuated CIA that is accompanied by a limited joint induction of IL-1ß and IL-6 expression, by the lack of induction of IFNγ expression in the joints and by a reduction in the percentages of invariant NKT (iNKT) cells in the spleen. Immunized CD38 KO mice produce high levels of circulating IgG1 and low of IgG2a anti-col II antibodies in association with reduced percentages of Th1 cells in the draining lymph nodes. Altogether, our results show that CD38 participates in the pathogenesis of CIA controlling the number of iNKT cells and promoting Th1 inflammatory responses.


Assuntos
ADP-Ribosil Ciclase 1/deficiência , Artrite Experimental/imunologia , Glicoproteínas de Membrana/deficiência , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Animais , Anticorpos Heterófilos/sangue , Artrite Experimental/genética , Artrite Experimental/patologia , Galinhas , Colágeno Tipo II/imunologia , Citocinas/genética , Expressão Gênica , Imunoglobulina G/sangue , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-1beta/genética , Interleucina-6/genética , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Baço/imunologia , Células Th1/imunologia , Células Th17/imunologia
16.
Arthritis Rheum ; 63(4): 971-80, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21225684

RESUMO

OBJECTIVE: To explore the bidirectional relationship between the development of rheumatoid arthritis (RA) and atherosclerosis using bovine type II collagen (CII)-immunized B10.RIII apoE(-/-) mice, a murine model of spontaneous atherosclerosis and collagen-induced arthritis (CIA). METHODS: Male B10.RIII apoE(-/-) mice and wild-type controls were immunized with 150 µg of CII emulsified in Freund's complete adjuvant (CFA). The clinical, radiologic, and histopathologic severity of CIA, the levels of circulating IgG1 and IgG2a anti-CII antibodies, the expression of proinflammatory and antiinflammatory cytokines in the joints, and the percentages of Th1, Th17, and Treg lymphocytes in the draining lymph nodes were evaluated during CIA induction. In addition, the size of atherosclerotic lesions was assessed in these mice 8 weeks after CIA induction. RESULTS: B10.RIII apoE(-/-) mice that were immunized with CII and CFA developed an exacerbated CIA that was accompanied by increased joint expression of multiple proinflammatory cytokines and by the expansion in the draining lymph nodes of Th1 and Th17 cells. In contrast, the size of vascular lesions in B10.RIII apoE(-/-) mice was not affected by the development of CIA. CONCLUSION: Our findings indicate that a deficiency in apolipoprotein E and/or its consequences in cholesterol metabolism act as accelerating factors in autoimmunity by promoting Th1 and Th17 inflammatory responses.


Assuntos
Apolipoproteínas E/deficiência , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Proliferação de Células , Índice de Gravidade de Doença , Células Th1/patologia , Células Th17/patologia , Animais , Anticorpos/imunologia , Anticorpos/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Artrite Experimental/fisiopatologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Colesterol/metabolismo , Colágeno/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Linfonodos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/patologia
17.
J Autoimmun ; 35(4): 316-24, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20691570

RESUMO

Genetic abnormalities predisposing to autoimmunity generally act in a cooperative manner affecting one or several mechanisms regulating immunological tolerance. In addition, many of these genetic abnormalities are also involved in the development of lymphoproliferative diseases. In the present study, we have determined the possible cooperation between deficiencies in members of the Cip/Kip family of cell cycle regulators (p21(WAF1/Cip1) or p27(kip1)) and the overexpression of human Bcl-2 in B lymphocytes in the induction of autoimmune and lymphoproliferative diseases in non-autoimmune C57BL/6 (B6) mice. Unlike single mutant mice, B6.p21(-/-) mice transgenic for human Bcl-2 in B cells developed a lethal autoimmune syndrome characterized by the production of autoantibodies, the prominent expansion of memory B and CD4(+) T cells and the development of severe glomerular lesions resembling IgA nephropathy. Furthermore, these mice presented a high incidence of B-cell lymphoproliferative disorders. Such genetic cooperation in the induction of autoimmunity was not observed in B6.p27(-/-) mice transgenic for human Bcl-2 in B cells. Altogether, what we have demonstrated here is the existence of preferential interactions among particular regulators of the G(1)/S transition of the cell cycle and B-cell survival in the induction of systemic autoimmune and lymphoproliferative diseases.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Síndrome Linfoproliferativa Autoimune/complicações , Síndrome Linfoproliferativa Autoimune/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Inibidor de Quinase Dependente de Ciclina p21/deficiência , Inibidor de Quinase Dependente de Ciclina p27/deficiência , Modelos Animais de Doenças , Epistasia Genética/genética , Epistasia Genética/imunologia , Humanos , Memória Imunológica , Rim/imunologia , Rim/patologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Transgenes/genética
18.
Eur J Immunol ; 40(3): 754-63, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20017194

RESUMO

The Escherichia coli heat-labile enterotoxin (LT) possesses a powerful mucosal and systemic adjuvant effect. However, little is known about the cellular and molecular basis of the immunostimulatory activity of LT at the mucosal level, and even less information is available on the mechanisms underlying its systemic adjuvant activity. In this study, we show that distinct mechanisms are responsible for the parenteral and mucosal adjuvanticity of LT. Indeed, the systemic administration of LT upregulates the expression of glucocorticoid-induced TNFR-related protein (GITR), but not other activation markers, in naive T cells. Using WT and GITR-deficient mice and LT and its enzymatically inactive mutant LTK63 as adjuvants, we show that the induction of GITR expression in T cells accounts for the systemic immunostimulatory capacity of LT, which requires an intact enzymatic activity. In contrast, the mucosal administration of LT does not induce GITR expression on Peyer's patche T cells and accordingly no differences are observed in the mucosal adjuvanticity of LT between WT and GITR-deficient mice. Altogether, our results demonstrate the distinct effect of LT after parenteral administration when compared with the mucosal delivery, and describe a new mechanism of LT adjuvanticity related to its ability to induce the expression of GITR in CD4(+) T cells.


Assuntos
Toxinas Bacterianas/imunologia , Linfócitos T CD4-Positivos/imunologia , Enterotoxinas/imunologia , Proteínas de Escherichia coli/imunologia , Imunidade nas Mucosas/imunologia , Ativação Linfocitária/imunologia , Receptores de Fator de Crescimento Neural/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Adjuvantes Imunológicos , Animais , Anticorpos Antibacterianos/imunologia , Separação Celular , Citometria de Fluxo , Proteína Relacionada a TNFR Induzida por Glucocorticoide , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Fator de Crescimento Neural/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Eur J Immunol ; 39(2): 439-46, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19180465

RESUMO

Escherichia coli heat-labile enterotoxin (LT) exhibits a broad range of immunomodulatory activities, including the induction of lymphocyte-programmed cell death. In previous studies, we have demonstrated that in vivo LT promotes apoptosis of immature T and B cells through the stimulation of endogenous glucocorticoids. In the present study, we show that the extrinsic cell-death pathway as well as the apoptosis-inducing factor do not participate in the LT-induced elimination of thymocytes. In contrast to developing lymphocytes, LT promotes the death of mature lymphocytes by both glucocorticoid- and Fas death receptor/Fas ligand-dependent mechanisms. However, the dependency of these mechanisms in the LT-induced cell-death activity seems to be different among CD4(+) and CD8(+) T cells. Altogether, our study shows that the same bacterial toxin can induce apoptosis of lymphoid cells through several mechanisms depending on the status of differentiation of these cells.


Assuntos
Adjuvantes Imunológicos/farmacologia , Apoptose/imunologia , Linfócitos B/imunologia , Toxinas Bacterianas/imunologia , Enterotoxinas/imunologia , Proteínas de Escherichia coli/imunologia , Linfócitos T/imunologia , Animais , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos B/efeitos dos fármacos , Toxinas Bacterianas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Enterotoxinas/farmacologia , Proteínas de Escherichia coli/farmacologia , Proteína Ligante Fas/imunologia , Proteína Ligante Fas/metabolismo , Camundongos , Camundongos Transgênicos , Linfócitos T/efeitos dos fármacos , Receptor fas/imunologia , Receptor fas/metabolismo
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