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2.
J Cardiovasc Electrophysiol ; 35(4): 654-663, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38288888

RESUMO

INTRODUCTION: In hypertrophic cardiomyopathy (HCM), atrial fibrillation (AF) has historically been regarded to have a deleterious impact on clinical course, strongly associated with progressive heart failure (HF) symptoms. However, there is a paucity of information regarding the impact of AF on HCM employing validated quality of life (QoL) surveys. Therefore, we evaluated the impact of AF on QoL utilizing patient reported outcome measures (PROMs). METHODS: 218 consecutive HCM patients with or without AF at the Lahey HCM center in 2022 completed PROMs at their most recent visit evaluating HF (Kansas City Cardiomyopathy Questionnaire [KCCQ]) and AF symptoms (AF Effect on QoL [AFEQT]). RESULTS: Among the 218 patients, 50 (23%) had a history of AF and comprise the primary study cohort. AF was diagnosed at 55 ± 10 years of age, median of 5.5 years before PROM, with 66% of patients treated with a rhythm control strategy with antiarrhythmic drug and/or AF ablation. AFEQT indicated that 52% of patients experienced no or minimal AF-related disability, mild to moderate in 22%, and severe in 26%. There was no substantial difference in HCM phenotype in patients with no or minimal AF disability compared to those with severe disability. HF symptoms for most HCM patients with prior AF history was consistent with no or minimal (59%) or only mild (27%) disability as measured by KCCQ overall summary scores. In addition, with multivariate analysis, AF history was associated with less HF symptoms and improved QoL (OR 0.4, p = 0.02). CONCLUSION: In contrast to prior perceptions, HCM patients with prior AF history were less likely to incur HF symptoms impairing QoL compared to HCM patients without AF. After treatment, prior history of AF did not substantially impact current QoL. These data provide a realistic appraisal for the impact that AF has on HCM patients and also offers a measure of reassurance for this patient subgroup.


Assuntos
Fibrilação Atrial , Cardiomiopatia Hipertrófica , Doenças Vasculares , Humanos , Qualidade de Vida , Antiarrítmicos/uso terapêutico , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/terapia , Doenças Vasculares/complicações
3.
Circ Arrhythm Electrophysiol ; 13(12): e009288, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33185144

RESUMO

BACKGROUND: The limited effectiveness of endocardial catheter ablation (CA) for persistent and long-standing persistent atrial fibrillation (AF) treatment led to the development of a minimally invasive epicardial/endocardial ablation approach (Hybrid Convergent) to achieve a more comprehensive lesion set with durable transmural lesions. The multicenter randomized controlled CONVERGE trial (Convergence of Epicardial and Endocardial Ablation for the Treatment of Symptomatic Persistent AF) evaluated the safety of Hybrid Convergent and compared its effectiveness to CA for persistent and long-standing persistent AF treatment. METHODS: One-hundred fifty-three patients were randomized 2:1 to Hybrid Convergent versus CA. Primary effectiveness was freedom from AF/atrial flutter/atrial tachycardia absent new/increased dosage of previously failed/intolerant class I/III antiarrhythmic drugs through 12 months. Primary safety was major adverse events through 30 days. CONVERGE permitted left atrium size up to 6 cm and imposed no limits on AF duration, making it the only ablation trial to substantially include long-standing persistent-AF, that is, 42% patients with long-standing persistent-AF. RESULTS: Of 149 evaluable patients at 12 months, primary effectiveness was achieved in 67.7% (67/99) patients with Hybrid Convergent and 50.0% (25/50) with CA (P=0.036) on/off previously failed antiarrhythmic drugs and in 53.5% (53/99) versus 32.0% (16/50; P=0.0128) respectively off antiarrhythmic drugs. At 18 months using 7-day Holter, 74.0% (53/72) Hybrid Convergent and 55% (23/42) CA patients experienced ≥90% AF burden reduction. A total of 2.9% (3/102) patients had primary safety events within 7 days, and 4.9% (5/102) between 8 and 30 days postprocedure. No deaths, cardiac perforations, or atrioesophageal fistulas occurred. All but one primary safety event resolved. CONCLUSIONS: The Hybrid Convergent procedure has superior effectiveness compared to the CA for the treatment of persistent and long-standing persistent atrial fibrillation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01984346.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Veias Pulmonares/cirurgia , Idoso , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Ablação por Cateter/efeitos adversos , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Veias Pulmonares/fisiopatologia , Recidiva , Fatores de Tempo , Resultado do Tratamento , Reino Unido , Estados Unidos
4.
Respir Res ; 21(1): 77, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228581

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by frequent exacerbation phenotypes independent of disease stage. Increasing evidence shows that the microbiota plays a role in disease progression and severity, but long-term and international multicenter assessment of the variations in viral and bacterial communities as drivers of exacerbations are lacking. METHODS: Two-hundred severe COPD patients from Europe and North America were followed longitudinally for 3 years. We performed nucleic acid detection for 20 respiratory viruses and 16S ribosomal RNA gene sequencing to evaluate the bacterial microbiota in 1179 sputum samples collected at stable, acute exacerbation and follow-up visits. RESULTS: Similar viral and bacterial taxa were found in patients from the USA compared to Bulgaria and Czech Republic but their microbiome diversity was significantly different (P < 0.001) and did not impact exacerbation rates. Virus infection was strongly associated with exacerbation events (P < 5E-20). Human rhinovirus (13.1%), coronavirus (5.1%) and influenza virus (3.6%) constitute the top viral pathogens in triggering exacerbation. Moraxella and Haemophilus were 5-fold and 1.6-fold more likely to be the dominating microbiota during an exacerbation event. Presence of Proteobacteria such as Pseudomonas or Staphylococcus amongst others, were associated with exacerbation events (OR > 0.17; P < 0.02) but more strongly associated with exacerbation frequency (OR > 0.39; P < 4E-10), as confirmed by longitudinal variations and biotyping of the bacterial microbiota, and suggesting a role of the microbiota in sensitizing the lung. CONCLUSIONS: This study highlights bacterial taxa in lung sensitization and viral triggers in COPD exacerbations. It provides a global overview of the diverse targets for drug development and explores new microbiome analysis methods to guide future patient management applications.


Assuntos
Bactérias/isolamento & purificação , Pulmão/microbiologia , Pulmão/virologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/virologia , Vírus/isolamento & purificação , Idoso , Idoso de 80 Anos ou mais , Bactérias/genética , Carga Bacteriana , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Escarro/microbiologia , Escarro/virologia , Fatores de Tempo , Estados Unidos/epidemiologia , Carga Viral , Vírus/genética
5.
JACC Case Rep ; 2(5): 796-801, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-34317350

RESUMO

We present the case of a 57-year-old man with a primary prevention internal cardioverter-defibrillator for severe nonischemic cardiomyopathy. At the time of elective replacement indicator, systolic function had fully recovered, and his generator was not changed. Nearly 5 years post-elective replacement indicator he received appropriate internal cardioverter-defibrillator therapies during a myocardial infarction. (Level of Difficulty: Intermediate.).

7.
Nat Immunol ; 18(9): 959-960, 2017 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-28829441
8.
Cell Rep ; 18(8): 1906-1916, 2017 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28228257

RESUMO

Long-lived plasma cells (PCs) in the bone marrow (BM) are a critical source of antibodies after infection or vaccination, but questions remain about the factors that control PCs. We found that systemic infection alters the BM, greatly reducing PCs and regulatory T (Treg) cells, a population that contributes to immune privilege in the BM. The use of intravital imaging revealed that BM Treg cells display a distinct behavior characterized by sustained co-localization with PCs and CD11c-YFP+ cells. Gene expression profiling indicated that BM Treg cells express high levels of Treg effector molecules, and CTLA-4 deletion in these cells resulted in elevated PCs. Furthermore, preservation of Treg cells during systemic infection prevents PC loss, while Treg cell depletion in uninfected mice reduced PC populations. These studies suggest a role for Treg cells in PC biology and provide a potential target for the modulation of PCs during vaccine-induced humoral responses or autoimmunity.


Assuntos
Células da Medula Óssea/imunologia , Medula Óssea/imunologia , Plasmócitos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/imunologia , Antígeno CTLA-4/imunologia , Imunidade Humoral , Imunofenotipagem/métodos , Camundongos , Camundongos Endogâmicos C57BL
11.
Nat Immunol ; 17(6): 646-55, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27111142

RESUMO

Group 2 innate lymphoid cells (ILC2 cells) are important for type 2 immune responses and are activated by the epithelial cytokines interleukin 33 (IL-33), IL-25 and thymic stromal lymphopoietin (TSLP). Here we demonstrated that IL-1ß was a critical activator of ILC2 cells, inducing proliferation and cytokine production and regulating the expression of epithelial cytokine receptors. IL-1ß also governed ILC2 plasticity by inducing low expression of the transcription factor T-bet and the cytokine receptor chain IL-12Rß2, which enabled the conversion of these cells into an ILC1 phenotype in response to IL-12. This transition was marked by an atypical chromatin landscape characterized by the simultaneous transcriptional accessibility of the locus encoding interferon-γ (IFN-γ) and the loci encoding IL-5 and IL-13. Finally, IL-1ß potentiated ILC2 activation and plasticity in vivo, and IL-12 acted as the switch that determined an ILC2-versus-ILC1 response. Thus, we have identified a previously unknown role for IL-1ß in facilitating ILC2 maturation and plasticity.


Assuntos
Plasticidade Celular , Imunidade Inata , Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Linfócitos/imunologia , Animais , Diferenciação Celular , Plasticidade Celular/imunologia , Células Cultivadas , Citocinas/metabolismo , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Camundongos , Camundongos SCID , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/metabolismo , Transdução de Sinais , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Células Th1/imunologia , Equilíbrio Th1-Th2 , Células Th2/imunologia , Linfopoietina do Estroma do Timo
12.
Nat Immunol ; 17(6): 626-35, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27111143

RESUMO

Innate lymphoid cells (ILCs) are critical mediators of mucosal immunity, and group 1 ILCs (ILC1 cells) and group 3 ILCs (ILC3 cells) have been shown to be functionally plastic. Here we found that group 2 ILCs (ILC2 cells) also exhibited phenotypic plasticity in response to infectious or noxious agents, characterized by substantially lower expression of the transcription factor GATA-3 and a concomitant switch to being ILC1 cells that produced interferon-γ (IFN-γ). Interleukin 12 (IL-12) and IL-18 regulated this conversion, and during viral infection, ILC2 cells clustered within inflamed areas and acquired an ILC1-like phenotype. Mechanistically, these ILC1 cells augmented virus-induced inflammation in a manner dependent on the transcription factor T-bet. Notably, IL-12 converted human ILC2 cells into ILC1 cells, and the frequency of ILC1 cells in patients with chronic obstructive pulmonary disease (COPD) correlated with disease severity and susceptibility to exacerbations. Thus, functional plasticity of ILC2 cells exacerbates anti-viral immunity, which may have adverse consequences in respiratory diseases such as COPD.


Assuntos
Infecções por Haemophilus/imunologia , Haemophilus influenzae/imunologia , Vírus da Influenza A/imunologia , Pulmão/imunologia , Linfócitos/imunologia , Infecções por Orthomyxoviridae/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Células Th1/imunologia , Células Th2/imunologia , Idoso , Animais , Diferenciação Celular , Plasticidade Celular/imunologia , Células Cultivadas , Citocinas/metabolismo , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Fenótipo , Fumar/efeitos adversos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
13.
Immunity ; 42(3): 566-79, 2015 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-25786179

RESUMO

Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.


Assuntos
Imunidade Inata/efeitos dos fármacos , Interleucinas/imunologia , Infecções por Orthomyxoviridae/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Receptores de Interleucina/imunologia , Fumaça/efeitos adversos , Animais , Feminino , Regulação da Expressão Gênica , Humanos , Vírus da Influenza A/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/deficiência , Interleucinas/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/patologia , Macrófagos/imunologia , Macrófagos/patologia , Camundongos Transgênicos , Infecções por Orthomyxoviridae/etiologia , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Transdução de Sinais , Nicotiana/química , Redução de Peso
14.
J Card Fail ; 21(2): 97-102, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25463741

RESUMO

BACKGROUND: The relationship of life-threatening ventricular arrhythmias to specific patterns of adverse LV remodeling has not been reported. We examined the relationship of ventricular tachycardia and/or fibrillation (VT/VF) to the pattern of left ventricular (LV) structural remodeling and to the degree of LV dysfunction in patients with a low ejection fraction (EF). METHODS AND RESULTS: Data from 127 patients with a low EF (≤0.45) and an implantable cardioverter-defibrillator (ICD) were examined and VT/VF identified by means of ICD device interrogation. Echocardiographic data were used to define LV structural remodeling (eccentric hypertrophy, concentric remodeling/hypertrophy, and normal geometry). VT/VF occurred in 26% of the 127 patients. VT/VF was more common in the 60 patients with LV hypertrophy versus the 67 with normal LV mass (40% vs 13%; P = .001) and in the 61 patients with LV enlargement versus the 66 with a normal chamber size (34% vs 18%; P = .04). When LV chamber size, wall mass, and geometry were assessed in a combinatorial fashion, a Kaplan-Meier analysis indicated that the occurrence of VT/VF was highest in the patients with eccentric hypertrophy (43%), intermediate in those with concentric remodeling/hypertrophy (30%), and lowest (12%) in those with normal geometry (all P < .02). The EFs were similar (P = ns) in these 3 groups of distinctly different patterns of remodeling. CONCLUSIONS: Life-threatening ventricular arrhythmias in patients with a low EF are related to the pattern of LV remodeling, not the degree of LV dysfunction. Risk stratification of such patients might be improved by a consideration of the pattern of LV remodeling.


Assuntos
Volume Sistólico/fisiologia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia , Remodelação Ventricular/fisiologia , Idoso , Idoso de 80 Anos ou mais , Desfibriladores Implantáveis/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taquicardia Ventricular/terapia
15.
PLoS One ; 9(2): e88714, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24551140

RESUMO

Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM), we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b(+) DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Hipersensibilidade/imunologia , Hipersensibilidade/parasitologia , Interleucinas/metabolismo , Pulmão/imunologia , Pulmão/parasitologia , Pyroglyphidae/imunologia , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Animais , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Imunidade/efeitos dos fármacos , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Interleucina-1alfa/metabolismo , Interleucina-33 , Pulmão/patologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Imunológicos , Pyroglyphidae/efeitos dos fármacos , Fatores de Tempo
16.
PLoS One ; 8(5): e62889, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23667536

RESUMO

Previous studies have indicated that Il21r (-/-) mice chronically infected with Toxoplasma gondii display a defect in serum IgG; however, the basis for this antibody defect was not defined and questions remain about the role of IL-21 in promoting the production of IL-10, which is required to limit infection-induced pathology during toxoplasmosis. Therefore, Il21 (-/-) mice were challenged with T. gondii to determine whether IL-21 impacts the parasite-specific CD8(+) T cell response, its contribution to thymus-dependent antibody production after infection, and balance between protective and pathogenic responses. Whereas IL-21 has been implicated in the differentiation of IL-10 producing CD4(+) T cells no immune-mediated pathology was evident in Il21 (-/-) mice during the acute response, nor was there a defect in the development of this population in chronically infected Il21 (-/-) mice. However, Il21 (-/-) mice displayed a defect in IgG production after infection that correlated with a decrease in GC B cell numbers, the CD4(+) and CD8(+) T cell numbers in the brain were reduced over the course of the chronic infection leading to a decrease in total IFN-γ production and an increase in parasite numbers associated with susceptibility to toxoplasmic encephalitis. Together, these results identify a key role for IL-21 in shaping the humoral and cellular response to T. gondii, but indicate that IL-21 has a limited role in regulating immunopathology.


Assuntos
Anticorpos Antiprotozoários/biossíntese , Interleucinas/metabolismo , Linfócitos T/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Encéfalo/parasitologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Sobrevivência Celular , Doença Crônica , Encefalite/parasitologia , Regulação da Expressão Gênica/imunologia , Interferon gama/biossíntese , Interleucina-10/biossíntese , Interleucinas/deficiência , Camundongos , Receptores de Interleucina-21/metabolismo , Especificidade da Espécie , Linfócitos T/citologia , Linfócitos T/metabolismo , Toxoplasma/fisiologia
17.
Immunity ; 37(3): 511-23, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22981537

RESUMO

Interferon-γ (IFN-γ) promotes a population of T-bet(+) CXCR3(+) regulatory T (Treg) cells that limit T helper 1 (Th1) cell-mediated pathology. Our studies demonstrate that interleukin-27 (IL-27) also promoted expression of T-bet and CXCR3 in Treg cells. During infection with Toxoplasma gondii, a similar population emerged that limited T cell responses and was dependent on IFN-γ in the periphery but on IL-27 at mucosal sites. Transfer of Treg cells ameliorated the infection-induced pathology observed in Il27(-/-) mice, and this was dependent on their ability to produce IL-10. Microarray analysis revealed that Treg cells exposed to either IFN-γ or IL-27 have distinct transcriptional profiles. Thus, IFN-γ and IL-27 have different roles in Treg cell biology and IL-27 is a key cytokine that promotes the development of Treg cells specialized to control Th1 cell-mediated immunity at local sites of inflammation.


Assuntos
Interferon gama/farmacologia , Interleucina-17/farmacologia , Salmonelose Animal/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Toxoplasmose Animal/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores CXCR3/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT1/metabolismo , Salmonelose Animal/microbiologia , Salmonelose Animal/patologia , Salmonella typhimurium/imunologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Toxoplasma/imunologia , Toxoplasmose Animal/parasitologia , Toxoplasmose Animal/patologia
18.
Infect Immun ; 80(10): 3602-10, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22851754

RESUMO

B cell responses are required for resistance to Toxoplasma gondii; however, the events that lead to production of class-switched antibodies during T. gondii infection have not been defined. Indeed, mice challenged with the parasite exhibited an expansion of T follicular helper cells and germinal center B cells in the spleen. Unexpectedly, this was not associated with germinal center formation and was instead accompanied by profound changes in splenic organization. This phenomenon was transient and was correlated with a decrease in expression of effector proteins that contribute to splenic organization, including lymphotoxins α and ß. The importance of lymphotoxin was confirmed, as the use of a lymphotoxin ß receptor agonist results in partial restoration of splenic structure. Splenectomized mice were used to test the splenic contribution to the antibody response during T. gondii infection. Analysis of splenectomized mice revealed delayed kinetics in the production of parasite-specific antibody, but the mice did eventually develop normal levels of parasite-specific antibody. Together, these studies provide a better understanding of how infection with T. gondii impacts the customized structures required for the optimal humoral responses to the parasite and the role of lymphotoxin in these events.


Assuntos
Linfotoxina-alfa/metabolismo , Baço/patologia , Baço/parasitologia , Toxoplasma , Toxoplasmose Animal/metabolismo , Toxoplasmose Animal/patologia , Animais , Anticorpos Antiprotozoários/sangue , Regulação da Expressão Gênica/imunologia , Regulação da Expressão Gênica/fisiologia , Imunoglobulina G/sangue , Imunoglobulina G/classificação , Imunoglobulina M/sangue , Linfotoxina-alfa/genética , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Organismos Livres de Patógenos Específicos , Baço/citologia
19.
Adv Immunol ; 115: 1-44, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22608254

RESUMO

Like many cytokines, IL-27 has pleiotropic properties that can limit or enhance ongoing immune responses depending on context. Thus, under certain circumstances, IL-27 can promote TH1 differentiation and has been linked to the activation of CD8(+) T cells and enhanced humoral responses. However, IL-27 also has potent inhibitory properties and mice that lack IL-27 mediated signaling develop exaggerated inflammatory responses in the context of infection or autoimmunity. This chapter reviews in depth the biology of IL-27, including the initial discovery, characterization, and signaling mediated by IL-27 as well as more recent insights into the molecular and cellular basis for its pleiotropic effects. Many of these advances are relevant to human diseases and highlight the potential of therapies that harness the regulatory properties of IL-27.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucinas/imunologia , Receptores de Interleucina/imunologia , Transdução de Sinais/imunologia , Animais , Autoimunidade , Linfócitos T CD4-Positivos/patologia , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Interleucinas/genética , Camundongos , Subunidades Proteicas/genética , Subunidades Proteicas/imunologia , Receptores de Interleucina/genética , Equilíbrio Th1-Th2
20.
J Immunol ; 187(3): 1091-5, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21715693

RESUMO

Follicular helper T (T(FH)) cells are critical for germinal center (GC) formation. The processes that drive their generation and effector potential remain unclear. In this study, we define requirements for MHC class II APCs in murine T(FH) cell formation by either transiently ablating or restricting Ag presentation to dendritic cells (DCs). We find that cognate interactions with DCs are necessary and sufficient to prime CD4(+) T cells toward a CXCR5(+)ICOS(+)Bcl6(+) T(FH) cell intermediate. However, in the absence of additional APCs, these T(FH) cells fail to produce IL-21. Furthermore, in vitro priming of naive T cells by B cells engenders optimal production of IL-21, which induces a GC B cell transcriptional profile. These results support a multistep model for effector T(FH) cell priming and GC initiation, in which DCs are necessary and sufficient to induce a T(FH) cell intermediate that requires additional interactions with distinct APCs for full effector function.


Assuntos
Apresentação de Antígeno/imunologia , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ativação Linfocitária/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Transferência Adotiva , Animais , Linfócitos B/imunologia , Comunicação Celular/genética , Diferenciação Celular/genética , Imunofenotipagem , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Subpopulações de Linfócitos T/transplante , Linfócitos T Auxiliares-Indutores/classificação
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