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1.
Curr Opin Immunol ; 70: 129-137, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34242927

RESUMO

In addition to their role as antibody producing cells, B cells make a critical contribution to adaptive immune responses by functioning as professional antigen-presenting cells (APC). Distinctive features of B cells as APC include the expression of the B cell receptor (BCR) for antigen and regulated expression of HLA-DO. Here, we discuss recent progress in investigation of B cells as APC. We start with an update on the canonical MHC class II antigen presentation pathway in B cells and alternative pathways, including generation of extracellular vesicles. Turning to APC function, we highlight the roles of B cells as thymic APC, as APC for T follicular helper (TFH), as APC for CD4 memory T cells and as presenters of idiotypic BCR determinants. We also note recent examples that link B cell Ag-presentation to disease. Emerging evidence indicates that, in addition to unique features of B cells compared to other professional APC, there is appreciable heterogeneity among B cells, arising from, for example, B cell activation state or the microenvironment.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Animais , Humanos
2.
Front Immunol ; 10: 1970, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31481960

RESUMO

The role of intestinal epithelial cells (IECs) in mucosal tolerance and immunity remains poorly understood. We present a method for inducing MHC class II (MHC-II) in human enteroids, "mini-guts" derived from small intestinal crypt stem cells, and show that the intracellular MHC-II peptide-pathway is intact and functional in IECs. Our approach enables human enteroids to be used for novel in vitro studies into IEC MHC-II regulation and function during health and disease.


Assuntos
Antígenos de Histocompatibilidade Classe II , Mucosa Intestinal/imunologia , Organoides/imunologia , Humanos
3.
Front Immunol ; 9: 2144, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319613

RESUMO

As the primary barrier between an organism and its environment, epithelial cells are well-positioned to regulate tolerance while preserving immunity against pathogens. Class II major histocompatibility complex molecules (MHC class II) are highly expressed on the surface of epithelial cells (ECs) in both the lung and intestine, although the functional consequences of this expression are not fully understood. Here, we summarize current information regarding the interactions that regulate the expression of EC MHC class II in health and disease. We then evaluate the potential role of EC as non-professional antigen presenting cells. Finally, we explore future areas of study and the potential contribution of epithelial surfaces to gut-lung crosstalk.


Assuntos
Apresentação de Antígeno , Células Epiteliais/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Mucosa Intestinal/imunologia , Mucosa Respiratória/imunologia , Microbioma Gastrointestinal/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Mucosa Intestinal/citologia , Pulmão/citologia , Pulmão/imunologia , Mucosa Respiratória/citologia
4.
Am J Surg ; 215(1): 28-36, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28823594

RESUMO

BACKGROUND: The transfer of critically ill patients from the operating room (OR) to the surgical intensive care unit (SICU) involves handoffs between multiple providers. Incomplete handoffs lead to poor communication, a major contributor to sentinel events. Our aim was to determine whether handoff standardization led to improvements in caregiver involvement and communication. METHODS: A prospective intervention study was designed to observe thirty one patient handoffs from OR to SICU for 49 critical parameters including caregiver presence, peri-operative details, and time required to complete key steps. Following a six month implementation period, thirty one handoffs were observed to determine improvement. RESULTS: A significant improvement in presence of physician providers including intensivists and surgeons was observed (p = 0.0004 and p < 0.0001, respectively). Critical details were communicated more consistently, including procedure performed (p = 0.0048), complications (p < 0.0001), difficult airways (p < 0.0001), ventilator settings (p < 0.0001) and pressor requirements (p = 0.0134). Conversely, handoff duration did not increase significantly (p = 0.22). CONCLUSIONS: Implementation of a standardized protocol for handoffs between OR and SICU significantly improved caregiver involvement and reduced information omission without affecting provider time commitment.


Assuntos
Cuidados Críticos/normas , Unidades de Terapia Intensiva/normas , Admissão do Paciente/normas , Equipe de Assistência ao Paciente/normas , Transferência da Responsabilidade pelo Paciente/normas , Cuidados Pós-Operatórios/normas , Melhoria de Qualidade/organização & administração , Comunicação , Cuidados Críticos/organização & administração , Cuidados Críticos/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Relações Interprofissionais , Admissão do Paciente/estatística & dados numéricos , Equipe de Assistência ao Paciente/organização & administração , Equipe de Assistência ao Paciente/estatística & dados numéricos , Transferência da Responsabilidade pelo Paciente/organização & administração , Transferência da Responsabilidade pelo Paciente/estatística & dados numéricos , Segurança do Paciente/normas , Segurança do Paciente/estatística & dados numéricos , Cuidados Pós-Operatórios/métodos , Cuidados Pós-Operatórios/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Melhoria de Qualidade/estatística & dados numéricos , Fatores de Tempo
5.
J Matern Fetal Neonatal Med ; 29(13): 2098-103, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27480208

RESUMO

OBJECTIVE: Similar pro-inflammatory responses are present in pre-eclampsia (PE) and necrotizing enterocolitis (NEC). We hypothesized that maternal PE is an independent risk factor for the development of NEC. METHODS: A retrospective database of all live births (2008-2011) at a tertiary center was constructed. Infant and maternal characteristics were gathered. Babies born to mothers with or without PE were compared. Data were analyzed using Mann-Whitney U, Pearson's χ(2), binary logistic regression and relative risks. RESULTS: Incidence of NEC was 1.5% in non-PE and 4.6% in the PE group (p < 0.001), but once controlled for gestational age and birth weight, the difference lost statistical significance. PE babies were more frequently preterm (41.4% versus 14.5%, p < 0.001) and had intrauterine growth restriction (IUGR) (10.2% versus 6.3%, p < 0.001). Within preterm babies, 9.0% of non-PE and 10.8% of PE babies developed NEC (p = 0.25). Effect of PE was significant in sub-group of IUGR babies, with NEC in 1.5% of non-PE and 13.6% in PE babies (p < 0.001). CONCLUSIONS: Maternal PE is an independent risk factor for the development of NEC in some sub-groups of babies, most notably with IUGR. Fetal hypoxia caused by abnormal placentation in PE leads to restricted growth, and may be the underlying mechanism that predisposes the newborn to NEC.


Assuntos
Enterocolite Necrosante/epidemiologia , Enterocolite Necrosante/etiologia , Pré-Eclâmpsia/epidemiologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Recém-Nascido , Masculino , Gravidez , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
6.
Am J Surg ; 211(6): 1095-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26547406

RESUMO

BACKGROUND: The purpose of this study was to examine whether incorporating digital and video multimedia components improved surgical time-out performance of a surgical safety checklist. METHODS: A prospective pilot study was designed for implementation of a multimedia time-out, including a patient video. Perceptions of the staff participants were surveyed before and after intervention (Likert scale: 1, strongly disagree to 5, strongly agree). RESULTS: Employee satisfaction was high for both time-out procedures. However, employees appreciated improved clarity of patient identification (P < .05) and operative laterality (P < .05) with the digital method. About 87% of the respondents preferred the digital version to the standard time-out (75% anesthesia, 89% surgeons, 93% nursing). Although the duration of time-outs increased (49 and 79 seconds for standard and digital time-outs, respectively, P > .001), there was significant improvement in performance of key safety elements. CONCLUSION: The multimedia time-out allows improved participation by the surgical team and is preferred to a standard time-out process.


Assuntos
Lista de Checagem , Equipe de Assistência ao Paciente/organização & administração , Segurança do Paciente , Garantia da Qualidade dos Cuidados de Saúde , Procedimentos Cirúrgicos Operatórios/métodos , Time Out na Assistência à Saúde/organização & administração , Feminino , Humanos , Masculino , Erros Médicos/prevenção & controle , Multimídia/estatística & dados numéricos , Salas Cirúrgicas/organização & administração , Projetos Piloto , Cuidados Pré-Operatórios , Estudos Prospectivos , Gestão da Segurança/métodos , Estados Unidos
7.
Circ Heart Fail ; 8(3): 582-94, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25740839

RESUMO

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for ≈50% of all cases of HF and currently has no effective treatment. Diastolic dysfunction underlies HFpEF; therefore, elucidation of the mechanisms that mediate relaxation can provide new potential targets for treatment. Cardiac myosin-binding protein-C (cMyBP-C) is a thick filament protein that modulates cross-bridge cycling rates via alterations in its phosphorylation status. Thus, we hypothesize that phosphorylated cMyBP-C accelerates the rate of cross-bridge detachment, thereby enhancing relaxation to mediate diastolic function. METHODS AND RESULTS: We compared mouse models expressing phosphorylation-deficient cMyBP-C(S273A/S282A/S302A)-cMyBP-C(t3SA), phosphomimetic cMyBP-C(S273D/S282D/S302D)-cMyBP-C(t3SD), and wild-type-control cMyBP-C(tWT) to elucidate the functional effects of cMyBP-C phosphorylation. Decreased voluntary running distances, increased lung/body weight ratios, and increased brain natriuretic peptide levels in cMyBP-C(t3SA) mice demonstrate that phosphorylation deficiency is associated with signs of HF. Echocardiography (ejection fraction and myocardial relaxation velocity) and pressure/volume measurements (-dP/dtmin, pressure decay time constant τ-Glantz, and passive filling stiffness) show that cMyBP-C phosphorylation enhances myocardial relaxation in cMyBP-C(t3SD) mice, whereas deficient cMyBP-C phosphorylation causes diastolic dysfunction with HFpEF in cMyBP-C(t3SA) mice. Simultaneous force and [Ca(2+)]i measurements on intact papillary muscles show that enhancement of relaxation in cMyBP-C(t3SD) mice and impairment of relaxation in cMyBP-C(t3SA) mice are not because of altered [Ca(2+)]i handling, implicating that altered cross-bridge detachment rates mediate these changes in relaxation rates. CONCLUSIONS: cMyBP-C phosphorylation enhances relaxation, whereas deficient phosphorylation causes diastolic dysfunction and phenotypes resembling HFpEF. Thus, cMyBP-C is a potential target for treatment of HFpEF.


Assuntos
Proteínas de Transporte/metabolismo , Insuficiência Cardíaca/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Função Ventricular Esquerda , Animais , Pressão Sanguínea , Proteínas de Transporte/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diástole , Genótipo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Cinética , Camundongos Transgênicos , Mutação , Fenótipo , Fosforilação , Processamento de Proteína Pós-Traducional , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia
8.
Transl Res ; 165(4): 449-63, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25468481

RESUMO

Pre-eclampsia (preE) is a multifaceted complication found uniquely in the pregnant patient and one that has puzzled scientists for years. PreE is not a single disorder, but a complex syndrome that is produced by various pathophysiological triggers and mechanisms affecting about 5% of obstetrical patients. PreE is a major cause of premature delivery and maternal and fetal morbidity and mortality. PreE is characterized by de novo development of hypertension and proteinuria after 20 weeks of gestation and affects nearly every organ system, with the most severe consequences being eclampsia, pulmonary edema, intrauterine growth restriction, and thrombocytopenia. PreE alters the intrauterine environment by modulating the pattern of hormonal signals and activating the detrimental cellular signaling that has been transported to the fetus. The fetus has to adapt to this intrauterine environment with detrimental signals. The adaptive changes increase the risk of disease later in life. This review defines the predisposition and causes of preE and the cellular signaling detrimental to maternal health during preE. Moreover, the risk factors for diseases that are transmitted to the offspring have been addressed in this review. The detrimental signaling molecules that have been overexpressed in preE patients raises the possibility that those signals could be therapeutically blocked one day.


Assuntos
Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Feminino , Humanos , Pré-Eclâmpsia/etiologia , Gravidez , Fatores de Risco , Transdução de Sinais
9.
Am J Physiol Cell Physiol ; 307(7): C622-33, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25080486

RESUMO

Hepatic stellate cells (HSCs) generate matrix, which in turn may also regulate HSCs function during liver fibrosis. We hypothesized that HSCs may endocytose matrix proteins to sense and respond to changes in microenvironment. Primary human HSCs, LX2, or mouse embryonic fibroblasts (MEFs) [wild-type; c-abl(-/-); or Yes, Src, and Fyn knockout mice (YSF(-/-))] were incubated with fluorescent-labeled collagen or gelatin. Fluorescence-activated cell sorting analysis and confocal microscopy were used for measuring cellular internalization of matrix proteins. Targeted PCR array and quantitative real-time PCR were used to evaluate gene expression changes. HSCs and LX2 cells endocytose collagens in a concentration- and time-dependent manner. Endocytosed collagen colocalized with Dextran 10K, a marker of macropinocytosis, and 5-ethylisopropyl amiloride, an inhibitor of macropinocytosis, reduced collagen internalization by 46%. Cytochalasin D and ML7 blocked collagen internalization by 47% and 45%, respectively, indicating that actin and myosin are critical for collagen endocytosis. Wortmannin and AKT inhibitor blocked collagen internalization by 70% and 89%, respectively, indicating that matrix macropinocytosis requires phosphoinositide-3-kinase (PI3K)/AKT signaling. Overexpression of dominant-negative dynamin-2 K44A blocked matrix internalization by 77%, indicating a role for dynamin-2 in matrix macropinocytosis. Whereas c-abl(-/-) MEF showed impaired matrix endocytosis, YSF(-/-) MEF surprisingly showed increased matrix endocytosis. It was also associated with complex gene regulations that related with matrix dynamics, including increased matrix metalloproteinase 9 (MMP-9) mRNA levels and zymographic activity. HSCs endocytose matrix proteins through macropinocytosis that requires a signaling network composed of PI3K/AKT, dynamin-2, and c-abl. Interaction with extracellular matrix regulates matrix dynamics through modulating multiple gene expressions including MMP-9.


Assuntos
Colágeno/metabolismo , Endocitose , Matriz Extracelular/metabolismo , Células Estreladas do Fígado/metabolismo , Actinas/metabolismo , Animais , Células Cultivadas , Microambiente Celular , Dinamina II/metabolismo , Fibrose , Regulação da Expressão Gênica , Genes abl , Genes src , Células Estreladas do Fígado/patologia , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinase/metabolismo , Pinocitose , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fyn/deficiência , Proteínas Proto-Oncogênicas c-fyn/genética , Proteínas Proto-Oncogênicas c-yes/deficiência , Proteínas Proto-Oncogênicas c-yes/genética , Fatores de Tempo
10.
J Pediatr Surg ; 49(5): 727-32, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24851757

RESUMO

PURPOSE: The aim of this study was to determine the relationship of birth weight and gestational age with regulatory T cells (Tregs) in cord blood of human newborns. METHODS: Cord blood mononuclear cells (CBMCs) of 210 newborns were analyzed using flow cytometry to identify Tregs (CD3(+), CD4(+), CD25(high), FoxP3(high)) and measure FoxP3 mean fluorescence intensity (MFI). Suppressive index (SI) was calculated as FoxP3 MFI per Treg. RESULTS: Mode of delivery had no significant effect on Tregs at birth. Term babies with growth restriction had fewer Tregs than their appropriate weight counterparts but equivalent SI. Preterm babies had higher percentages of Tregs, but lower SI than term controls. SI steadily increased through gestation. CONCLUSIONS: Intrauterine growth restriction is correlated with fewer circulating Tregs and prematurity with decreased functionality of Tregs compared to term appropriate weight infants. This may have implications in diseases such as necrotizing enterocolitis that disproportionately affect premature and lower birth weight infants.


Assuntos
Sangue Fetal/imunologia , Retardo do Crescimento Fetal/imunologia , Recém-Nascido Prematuro/imunologia , Linfócitos T Reguladores/metabolismo , Peso ao Nascer , Complexo CD3/sangue , Antígenos CD4/sangue , Citometria de Fluxo , Fatores de Transcrição Forkhead/sangue , Idade Gestacional , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Estudos Prospectivos
11.
Exp Neurol ; 231(2): 247-60, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21781963

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used to relieve pain and inflammation in humans via cyclooxygenase inhibition. Our recent research suggests that certain NSAIDs including ibuprofen suppress intracellular RhoA signal and improve significant axonal growth and functional recovery following axonal injury in the CNS. Several NSAIDs have been shown to reduce generation of amyloid-beta42 peptide via inactivation of RhoA signal, supporting potent RhoA-repressing function of selected NSAIDs. In this report, we demonstrate that RhoA-inhibiting NSAIDs ibuprofen and indomethacin dramatically reduce cell death of oligodendrocytes in cultures or along the white matter tracts in rats with a spinal cord injury. More importantly, we demonstrate that treatments with the RhoA-inhibiting NSAIDs significantly increase axonal myelination along the white matter tracts following a traumatic contusion spinal cord injury. In contrast, non-RhoA-inhibiting NSAID naproxen does not have such an effect. Thus, our results suggest that RhoA inactivation with certain NSAIDs benefits recovery of injured CNS axons not only by promoting axonal elongation, but by enhancing glial survival and axonal myelination along the disrupted axonal tracts. This study, together with previous reports, supports that RhoA signal is an important therapeutic target for promoting recovery of injured CNS and that RhoA-inhibiting NSAIDs provide great therapeutic potential for CNS axonal injuries in adult mammals.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Axônios/efeitos dos fármacos , Ibuprofeno/farmacologia , Indometacina/farmacologia , Bainha de Mielina/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Axônios/metabolismo , Células Cultivadas , Feminino , Ibuprofeno/uso terapêutico , Indometacina/uso terapêutico , Bainha de Mielina/metabolismo , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia
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