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PURPOSE: The Johns Hopkins Physician-Scientist Training Program (PSTP) was implemented to overcome well-documented challenges in training and retaining physician-scientists by providing physician-scientist pathway training for residents and clinical fellows. The program's core tenets include monthly seminars, individualized feedback on project proposals, access to mentors, and institutional funding opportunities. This study evaluated the effectiveness and outcomes of the PTSP and provides a framework for replication. METHOD: A query of institutional demographic data and bibliometric variables of the PSTP participants (2017-2020) at a single academic medical center was conducted in 2021. In addition, a voluntary survey collected personal and program evaluation information. RESULTS: Of 145 PSTP scholars, 59 (41%) were women, and 41 (31%), 8 (6%), and 6 (5%) of scholars self-identified as Asian, Hispanic, and Black, respectively. Thirty-three (23%) scholars received PSTP research support or career development microgrants. Of 66 PSTP graduates, 29 (44%) remained at Johns Hopkins as clinical fellows or faculty. Of 48 PSTP graduates in a post-training position, 42 (88%) were in academia, with the majority, 29 (76%), holding the rank of assistant professor. Fifty-nine of 140 available participants responded to the survey (42% response rate). The top-cited reason for joining the PSTP was exposure to mentors and administration (50/58 respondents, 86%), followed by seeking scholarly opportunities (37/58 respondents, 64%). Most scholars intended to continue a career as a physician-scientist. CONCLUSIONS: The PSTP provides internal research support and institutional oversight. Although establishing close mentor-mentee relationships requires individualized approaches, the PSTP provided structured academic pathways that enhanced participating scholars' ability to apply for grants and jobs. The vast majority continued their careers as physician-scientists after training. In light of the national evidence of a "leaky physician-scientist pipeline," programs such as the PSTP can be critical to entry into early academic career positions and institutional retention.
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Flooding is expected to increase due to intensification of extreme precipitation events, sea-level rise, and urbanization. Low-cost water level sensors have the ability to fill a critical data gap on the presence, depth, and duration of street-level floods by measuring flood profiles (i.e., flood stage hydrographs) in real-time with a time interval on the order of minutes. Hyperlocal flood data collected by low-cost sensors have many use cases for a variety of stakeholders including municipal agencies, community members, and researchers. Here we outline examples of potential uses of flood sensor data before, during, and after flood events, based on dialog with stakeholders in New York City. These uses include inputs to predictive flood models, generation of real-time flood alerts for community members and emergency response teams, storm recovery assistance and cataloging of storm impacts, and informing infrastructure design and investment for long-term flood resilience project planning.
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Inundações , UrbanizaçãoRESUMO
The JAK/STAT1 pathway is generally activated by cytokines, providing essential antiviral defense. Here, we identify that STAT1 activation is independent of cytokines and JAKs at the early infection stage of some viruses, including influenza A virus (IAV). Instead, STAT1 is activated mainly through spleen tyrosine kinase (Syk) downstream of retinoic acid-inducible gene-I/mitochondrial antiviral-signaling protein (RIG-I/MAVS) signaling. Syk deletion profoundly impairs immediate innate immunity, as evidenced by the finding that Syk deletion attenuates tyrosine phosphorylation of STAT1 and reduces the expressions of interferon-stimulated genes (ISGs) in vitro and in vivo. The antiviral response to IAV infection is also significantly suppressed in the STAT1Y701F knockin mice. The results demonstrate that STAT1 activation is dependent on Syk rather than the cytokine-activated JAK signaling at the early stage of viral infection, which is critical for initial antiviral immunity. Our finding provides insights into the complicated mechanisms underlying host immune responses to viral infection.
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Imunidade Inata/imunologia , Fator de Transcrição STAT1/imunologia , Quinase Syk/imunologia , Viroses/imunologia , Animais , Chlorocebus aethiops , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Fosforilação , Quinase Syk/metabolismo , Células VeroAssuntos
Centros Médicos Acadêmicos/organização & administração , Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Faculdades de Medicina/organização & administração , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Humanos , Equipamento de Proteção Individual/provisão & distribuição , Pneumonia Viral/diagnóstico , SARS-CoV-2 , Estados UnidosRESUMO
Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1-5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.
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Catecolaminas/antagonistas & inibidores , Catecolaminas/metabolismo , Citocinas/efeitos adversos , Síndrome , Animais , Fator Natriurético Atrial/farmacologia , Complexo CD3/antagonistas & inibidores , Catecolaminas/biossíntese , Citocinas/imunologia , Epinefrina/metabolismo , Feminino , Humanos , Imunoterapia Adotiva , Técnicas In Vitro , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Norepinefrina/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , alfa-Metiltirosina/farmacologiaRESUMO
Purpose The purpose of this paper is to offer six principles that health system leaders can apply to establish a governance and management system for the quality of care and patient safety. Design/methodology/approach Leaders of a large academic health system set a goal of high reliability and formed a quality board committee in 2011 to oversee quality and patient safety everywhere care was delivered. Leaders of the health system and every entity, including inpatient hospitals, home care companies, and ambulatory services staff the committee. The committee works with the management for each entity to set and achieve quality goals. Through this work, the six principles emerged to address management structures and processes. Findings The principles are: ensure there is oversight for quality everywhere care is delivered under the health system; create a framework to organize and report the work; identify care areas where quality is ambiguous or underdeveloped (i.e. islands of quality) and work to ensure there is reporting and accountability for quality measures; create a consolidated quality statement similar to a financial statement; ensure the integrity of the data used to measure and report quality and safety performance; and transparently report performance and create an explicit accountability model. Originality/value This governance and management system for quality and safety functions similar to a finance system, with quality performance documented and reported, data integrity monitored, and accountability for performance from board to bedside. To the authors' knowledge, this is the first description of how a board has taken this type of systematic approach to oversee the quality of care.
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Conselho Diretor/organização & administração , Qualidade da Assistência à Saúde/organização & administração , Instituições de Assistência Ambulatorial/organização & administração , Serviços de Assistência Domiciliar/organização & administração , Administração Hospitalar , Humanos , Objetivos Organizacionais , Segurança do Paciente/normas , Qualidade da Assistência à Saúde/normasRESUMO
Importance: The Johns Hopkins Community Health Partnership was created to improve care coordination across the continuum in East Baltimore, Maryland. Objective: To determine whether the Johns Hopkins Community Health Partnership (J-CHiP) was associated with improved outcomes and lower spending. Design, Setting, and Participants: Nonrandomized acute care intervention (ACI) and community intervention (CI) Medicare and Medicaid participants were analyzed in a quality improvement study using difference-in-differences designs with propensity score-weighted and matched comparison groups. The study spanned 2012 to 2016 and took place in acute care hospitals, primary care clinics, skilled nursing facilities, and community-based organizations. The ACI analysis compared outcomes of participants in Medicare and Medicaid during their 90-day postacute episode with those of a propensity score-weighted preintervention group at Johns Hopkins Community Health Partnership hospitals and a concurrent comparison group drawn from similar Maryland hospitals. The CI analysis compared changes in outcomes of Medicare and Medicaid participants with those of a propensity score-matched comparison group of local residents. Interventions: The ACI bundle aimed to improve transition planning following discharge. The CI included enhanced care coordination and integrated behavioral support from local primary care sites in collaboration with community-based organizations. Main Outcomes and Measures: Utilization measures of hospital admissions, 30-day readmissions, and emergency department visits; quality of care measures of potentially avoidable hospitalizations, practitioner follow-up visits; and total cost of care (TCOC) for Medicare and Medicaid participants. Results: The CI group had 2154 Medicare beneficiaries (1320 [61.3%] female; mean age, 69.3 years) and 2532 Medicaid beneficiaries (1483 [67.3%] female; mean age, 55.1 years). For the CI group's Medicaid participants, aggregate TCOC reduction was $24.4 million, and reductions of hospitalizations, emergency department visits, 30-day readmissions, and avoidable hospitalizations were 33, 51, 36, and 7 per 1000 beneficiaries, respectively. The ACI group had 26â¯144 beneficiary-episodes for Medicare (13â¯726 [52.5%] female patients; mean patient age, 68.4 years) and 13â¯921 beneficiary-episodes for Medicaid (7392 [53.1%] female patients; mean patient age, 52.2 years). For the ACI group's Medicare participants, there was a significant reduction in aggregate TCOC of $29.2 million with increases in 90-day hospitalizations and 30-day readmissions of 11 and 14 per 1000 beneficiary-episodes, respectively, and reduction in practitioner follow-up visits of 41 and 29 per 1000 beneficiary-episodes for 7-day and 30-day visits, respectively. For the ACI group's Medicaid participants, there was a significant reduction in aggregate TCOC of $59.8 million and the 90-day emergency department visit rate decreased by 133 per 1000 episodes, but hospitalizations increased by 49 per 1000 episodes and practitioner follow-up visits decreased by 70 and 182 per 1000 episodes for 7-day and 30-day visits, respectively. In total, the CI and ACI were associated with $113.3 million in cost savings. Conclusions and Relevance: A care coordination model consisting of complementary bundled interventions in an urban academic environment was associated with lower spending and improved health outcomes.
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Instituições de Assistência Ambulatorial , Serviços de Saúde Comunitária , Análise Custo-Benefício , Custos de Cuidados de Saúde , Hospitais , Aceitação pelo Paciente de Cuidados de Saúde , Qualidade da Assistência à Saúde , Idoso , Baltimore , Serviços de Saúde Comunitária/economia , Serviços de Saúde Comunitária/normas , Redução de Custos , Serviço Hospitalar de Emergência , Feminino , Hospitalização , Humanos , Masculino , Medicaid , Medicare , Pessoa de Meia-Idade , Readmissão do Paciente , Atenção Primária à Saúde , Melhoria de Qualidade , Instituições de Cuidados Especializados de Enfermagem , Estados UnidosRESUMO
To address the challenging health care needs of the population served by an urban academic medical center, we developed the Johns Hopkins Community Health Partnership (J-CHiP), a novel care coordination program that provides services in homes, community clinics, acute care hospitals, emergency departments, and skilled nursing facilities. This case study describes a comprehensive program that includes: a community-based intervention using multidisciplinary care teams that work closely with the patient's primary care provider; an acute care intervention bundle with collaborative team-based care; and a skilled nursing facility intervention emphasizing standardized transitions and targeted use of care pathways. The program seeks to improve clinical care within and across settings, to address the non-clinical determinants of health, and to ultimately improve healthcare utilization and costs. The case study introduces: a) main program features including rationale, goals, intervention design, and partnership development; b) illness burden and social barriers of the population contributing to care challenges and opportunities; and c) lessons learned with steps that have been taken to engage both patients and providers more actively in the care model. Urban health systems, including academic medical centers, must continue to innovate in care delivery through programs like J-CHiP to meet the needs of their patients and communities.
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Centros Médicos Acadêmicos , Planejamento em Saúde Comunitária , Comportamento Cooperativo , Atenção à Saúde/organização & administração , Estudos de Casos Organizacionais , Adulto , Idoso , Baltimore , Serviços de Saúde Comunitária , Atenção à Saúde/economia , Feminino , Hospitais Urbanos , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Centrada no Paciente , Atenção Primária à Saúde , Serviços Urbanos de SaúdeRESUMO
Adaptor proteins play a critical role in the assembly of signalling complexes after engagement of platelet receptors by agonists such as collagen, ADP and thrombin. Recently, using proteomics, the Dok (downstream of tyrosine kinase) adapter proteins were identified in human and mouse platelets. In vitro studies suggest that Dok-1 binds to platelet integrin ß3, but the underlying effects of Dok-1 on αIIbß3 signalling, platelet activation and thrombosis remain to be elucidated. In the present study, using Dok-1-deficient (Dok-1-/-) mice, we determined the phenotypic role of Dok-1 in αIIbß3 signalling. We found that platelets from Dok-1-/- mice displayed normal aggregation, activation of αIIbß3 (assessed by binding of JON/A), P-selectin surface expression (assessed by anti-CD62P), and soluble fibrinogen binding. These findings indicate that Dok-1 does not affect "inside-out" platelet signalling. Compared with platelets from wild-type (WT) mice, platelets from Dok-1-/- mice exhibited increased clot retraction (p < 0.05 vs WT), increased PLCγ2 phosphorylation, and enhanced spreading on fibrinogen after thrombin stimulation (p < 0.01 vs WT), demonstrating that Dok-1 negatively regulates αIIbß3 "outside-in" signalling. Finally, we found that Dok-1-/- mice exhibited significantly shortened bleeding times and accelerated carotid artery thrombosis in response to photochemical injury (p < 0.05 vs WT mice). We conclude that Dok-1 modulates thrombosis and haemostasis by negatively regulating αIIbß3 outside-in signalling.
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Proteínas de Ligação a DNA/sangue , Fosfoproteínas/sangue , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Proteínas de Ligação a RNA/sangue , Trombose/prevenção & controle , Animais , Tempo de Sangramento , Trombose das Artérias Carótidas/sangue , Trombose das Artérias Carótidas/genética , Trombose das Artérias Carótidas/prevenção & controle , Retração do Coágulo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Fibrinogênio/metabolismo , Hemostasia , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Selectina-P/sangue , Fosfolipase C gama/sangue , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Ativação Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Trombose/sangue , Trombose/genéticaRESUMO
Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine.
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Centros Médicos Acadêmicos , Pesquisa Biomédica , Humanos , IncertezaRESUMO
Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-ß-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-ß-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-ß-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-ß-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT.
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Doença Enxerto-Hospedeiro/imunologia , Helmintos/imunologia , Intestinos/imunologia , Intestinos/parasitologia , Neoplasias/imunologia , Doença Aguda , Transferência Adotiva , Animais , Transplante de Medula Óssea , Citocinas/biossíntese , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/mortalidade , Helmintíase Animal/imunologia , Imunomodulação , Imunofenotipagem , Masculino , Camundongos , Neoplasias/metabolismo , Neoplasias/mortalidade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
In this article, the authors describe an initiative that established an infrastructure to manage quality and safety efforts throughout a complex health care system and that improved performance on core measures for acute myocardial infarction, heart failure, pneumonia, surgical care, and children's asthma. The Johns Hopkins Medicine Board of Trustees created a governance structure to establish health care system-wide oversight and hospital accountability for quality and safety efforts throughout Johns Hopkins Medicine. The Armstrong Institute for Patient Safety and Quality was formed; institute leaders used a conceptual model nested in a fractal infrastructure to implement this initiative to improve performance at two academic medical centers and three community hospitals, starting in March 2012. The initiative aimed to achieve ≥ 96% compliance on seven inpatient process-of-care core measures and meet the requirements for the Delmarva Foundation and Joint Commission awards. The primary outcome measure was the percentage of patients at each hospital who received the recommended process of care. The authors compared health system and hospital performance before (2011) and after (2012, 2013) the initiative. The health system achieved ≥ 96% compliance on six of the seven targeted measures by 2013. Of the five hospitals, four received the Delmarva Foundation award and two received The Joint Commission award in 2013. The authors argue that, to improve quality and safety, health care systems should establish a system-wide governance structure and accountability process. They also should define and communicate goals and measures and build an infrastructure to support peer learning.
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Atenção à Saúde/organização & administração , Avaliação de Processos em Cuidados de Saúde , Melhoria de Qualidade/organização & administração , Centros Médicos Acadêmicos , Adulto , Asma/terapia , Criança , Insuficiência Cardíaca/terapia , Hospitalização , Hospitais Comunitários , Humanos , Maryland , Infarto do Miocárdio/terapia , Assistência Perioperatória , Pneumonia/terapiaRESUMO
Natural killer (NK) cells belong to the innate immune system; they can control virus infections and developing tumors by cytotoxicity and producing inflammatory cytokines. Most studies of mouse NK cells, however, have focused on conventional NK (cNK) cells in the spleen. Recently, we described two populations of liver NK cells, tissue-resident NK (trNK) cells and those resembling splenic cNK cells. However, their lineage relationship was unclear; trNK cells could be developing cNK cells, related to thymic NK cells, or a lineage distinct from both cNK and thymic NK cells. Herein we used detailed transcriptomic, flow cytometric, and functional analysis and transcription factor-deficient mice to determine that liver trNK cells form a distinct lineage from cNK and thymic NK cells. Taken together with analysis of trNK cells in other tissues, there are at least four distinct lineages of NK cells: cNK, thymic, liver (and skin) trNK, and uterine trNK cells. DOI: http://dx.doi.org/10.7554/eLife.01659.001.
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Linhagem da Célula , Células Matadoras Naturais/imunologia , Fígado/imunologia , Pele/imunologia , Baço/imunologia , Timo/imunologia , Útero/imunologia , Animais , Biomarcadores/metabolismo , Células Cultivadas , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Imunofenotipagem , Células Matadoras Naturais/metabolismo , Fígado/citologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Pele/citologia , Pele/metabolismo , Baço/citologia , Baço/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Útero/citologia , Útero/metabolismoRESUMO
T cell Ig and mucin domain (Tim) 3 is a surface molecule expressed throughout the immune system that can mediate both stimulatory and inhibitory effects. Previous studies have provided evidence that Tim-3 functions to enforce CD8 T cell exhaustion, a dysfunctional state associated with chronic stimulation. In contrast, the role of Tim-3 in the regulation of CD8 T cell responses to acute and transient stimulation remains undefined. To address this knowledge gap, we examined how Tim-3 affects CD8 T cell responses to acute Listeria monocytogenes infection. Analysis of wild-type (WT) mice infected with L. monocytogenes revealed that Tim-3 was transiently expressed by activated CD8 T cells and was associated primarily with acquisition of an effector phenotype. Comparison of responses to L. monocytogenes by WT and Tim-3 knockout (KO) mice showed that the absence of Tim-3 significantly reduced the magnitudes of both primary and secondary CD8 T cell responses, which correlated with decreased IFN-γ production and degranulation by Tim-3 KO cells stimulated with peptide Ag ex vivo. To address the T cell-intrinsic role of Tim-3, we analyzed responses to L. monocytogenes infection by WT and Tim-3 KO TCR-transgenic CD8 T cells following adoptive transfer into a shared WT host. In this setting, the accumulation of CD8 T cells and the generation of cytokine-producing cells were significantly reduced by the lack of Tim-3, demonstrating that this molecule has a direct effect on CD8 T cell function. Combined, our results suggest that Tim-3 can mediate a stimulatory effect on CD8 T cell responses to an acute infection.
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Linfócitos T CD8-Positivos/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Receptores Virais/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Proliferação de Células , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Citometria de Fluxo , Receptor Celular 2 do Vírus da Hepatite A , Interações Hospedeiro-Patógeno/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Listeria monocytogenes/fisiologia , Listeriose/microbiologia , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores Virais/genética , Receptores Virais/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
NFIL3 is a transcription factor that regulates multiple immunologic functions. In myeloid cells, NFIL3 is IL-10 inducible and has a key role as a repressor of IL-12p40 transcription. NFIL3 is a susceptibility gene for the human inflammatory bowel diseases. In this article, we describe spontaneous colitis in Nfil3(-/-) mice. Mice lacking both Nfil3 and Il10 had severe early-onset colitis, suggesting that NFIL3 and IL-10 independently regulate mucosal homeostasis. Lymphocytes were necessary for colitis, because Nfil3/Rag1 double-knockout mice were protected from disease. However, Nfil3/Rag1 double-knockout mice adoptively transferred with wild-type CD4(+) T cells developed severe colitis compared with Rag1(-/-) recipients, suggesting that colitis was linked to defects in innate immune cells. Colitis was abrogated in Nfil3/Il12b double-deficient mice, identifying Il12b dysregulation as a central pathogenic event. Finally, germ-free Nfil3(-/-) mice do not develop colonic inflammation. Thus, NFIL3 is a microbiota-dependent, IL-10-independent regulator of mucosal homeostasis via IL-12p40.
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Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/microbiologia , Interleucina-10/genética , Subunidade p40 da Interleucina-12/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Microbiota/imunologia , Transferência Adotiva , Animais , Proteínas de Arabidopsis/biossíntese , Fatores de Transcrição de Zíper de Leucina Básica/genética , Células Cultivadas , Colo/imunologia , Colo/patologia , Predisposição Genética para Doença , Subunidade p40 da Interleucina-12/genética , Subunidade p19 da Interleucina-23/genética , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th1/imunologia , Células Th17/imunologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
Development of the natural killer (NK) cell lineage is dependent on the transcription factor Nfil3 (or E4BP4), which is thought to act downstream of IL-15 signaling. Nfil3-deficient mice lack NK cells, whereas other lymphocyte lineages (B, T, and NKT cells) remain largely intact. We report the appearance of Ly49H-expressing NK cells in Nfil3(-/-) mice infected with mouse cytomegalovirus (MCMV) or recombinant viruses expressing the viral m157 glycoprotein. Nfil3(-/-) NK cells at the peak of antigen-driven expansion were functionally similar to NK cells from infected wild-type mice with respect to IFN-γ production and cytotoxicity, and could comparably produce long-lived memory NK cells that persisted in lymphoid and nonlymphoid tissues for >60 d. We demonstrate that generation and maintenance of NK cell memory is an Nfil3-independent but IL-15-dependent process. Furthermore, specific ablation of Nfil3 in either immature NK cells in the bone marrow or mature peripheral NK cells had no observable effect on NK cell lineage maintenance or homeostasis. Thus, expression of Nfil3 is crucial only early in the development of NK cells, and signals through activating receptors and proinflammatory cytokines during viral infection can bypass the requirement for Nfil3, promoting the proliferation and long-term survival of virus-specific NK cells.