RESUMO
We present a case of cutaneous granulomatous disease associated with rubella virus in a 4-year-old girl without an identifiable immunodeficiency. In this case, a combination of anti-inflammatory, anti-viral, and anti-neutrophil therapies successfully treated vision-threatening eyelid, conjunctival, scleral, and orbital inflammation.
Assuntos
Síndromes de Imunodeficiência , Dermatopatias , Feminino , Humanos , Pré-Escolar , Vírus da Rubéola , Granuloma/tratamento farmacológico , Dermatopatias/complicações , Pálpebras , Inflamação/complicaçõesRESUMO
Pathogens can release extracellular vesicles (EVs) for cell-cell communication and host modulation. EVs from Plasmodium falciparum, the deadliest malaria parasite species, can transfer drug resistance genes between parasites. EVs from late-stage parasite-infected RBC (iRBC-EVs) are immunostimulatory and affect endothelial cell permeability, but little is known about EVs from early stage iRBC. We detected the parasite virulence factor PfEMP1, which is responsible for iRBC adherence and a major contributor to disease severity, in EVs, only up to 12-hr post-RBC invasion. Furthermore, using PfEMP1 transport knockout parasites, we determined that EVs originated from inside the iRBC rather than the iRBC surface. Proteomic analysis detected 101 parasite and 178 human proteins in iRBC-EVs. Primary human monocytes stimulated with iRBC-EVs released low levels of inflammatory cytokines and showed transcriptomic changes. Stimulation with iRBC-EVs from PfEMP1 knockout parasites induced more gene expression changes and affected pathways involved in defence response, stress response, and response to cytokines, suggesting a novel function of PfEMP1 when present in EVs. We show for the first time the presence of PfEMP1 in early stage P. falciparum iRBC-EVs and the effects of these EVs on primary human monocytes, uncovering a new mechanism of potential parasite pathogenesis and host interaction.
Assuntos
Malária Falciparum/genética , Plasmodium falciparum/genética , Proteômica , Proteínas de Protozoários/genética , Animais , Adesão Celular/genética , Comunicação Celular/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Eritrócitos/parasitologia , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Interações Hospedeiro-Parasita/genética , Humanos , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Monócitos/metabolismo , Monócitos/parasitologia , Plasmodium falciparum/patogenicidadeAssuntos
Colite Ulcerativa , Dermatologia , Pioderma Gangrenoso , Humanos , Pioderma Gangrenoso/diagnóstico , Técnica Delphi , ConsensoRESUMO
Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of ß-adrenergic signaling induced similar effects to chronic stress, and pharmacological ß-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural ß-adrenergic signaling regulates pancreatic cancer progression and suggest ß-blockade as a novel strategy to complement existing therapies for pancreatic cancer.
Assuntos
Pâncreas/inervação , Neoplasias Pancreáticas/metabolismo , Receptores Adrenérgicos beta/metabolismo , Estresse Psicológico/complicações , Sistema Nervoso Simpático/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Linhagem Celular Tumoral , Doença Crônica , AMP Cíclico/metabolismo , Progressão da Doença , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/patologia , Restrição Física , Transdução de SinaisAssuntos
Promoção da Saúde , Comunicação Persuasiva , Neoplasias Cutâneas/prevenção & controle , Mídias Sociais , Rede Social , Adulto , Criança , Estudos Transversais , Medo , Feminino , Comportamentos Relacionados com a Saúde , Promoção da Saúde/métodos , Humanos , Masculino , Ilustração Médica , Melanoma/prevenção & controle , Motivação , Neoplasias Induzidas por Radiação/prevenção & controle , Neoplasias Induzidas por Radiação/psicologia , Utilização de Procedimentos e Técnicas , Roupa de Proteção , Neoplasias Cutâneas/psicologia , Protetores SolaresRESUMO
Clinical studies suggest that stress-related biobehavioral factors can accelerate the progression of hematopoietic cancers such as acute lymphoblastic leukemia (ALL), but it is unclear whether such effects are causal or what biological pathways mediate such effects. Given the network of sympathetic nervous system (SNS) fibers that innervates the bone marrow to regulate normal (non-leukemic) hematopoietic progenitor cells, we tested the possibility that stress-induced SNS signaling might also affect ALL progression. In an orthotopic mouse model, Nalm-6 human pre-B ALL cells were transduced with the luciferase gene for longitudinal bioluminescent imaging and injected i.v. into male SCID mice for bone marrow engraftment. Two weeks of daily restraint stress significantly enhanced ALL tumor burden and dissemination in comparison to controls, and this effect was blocked by the ß-adrenergic antagonist, propranolol. Although Nalm-6 ALL cells expressed mRNA for ß1- and ß3-adrenergic receptors, they showed no evidence of cAMP signaling in response to norepinephrine, and norepinephrine failed to enhance Nalm-6 proliferation in vitro. These results show that chronic stress can accelerate the progression of human pre-B ALL tumor load via a ß-adrenergic signaling pathway that likely involves indirect regulation of ALL biology via alterations in the function of other host cell types such as immune cells or the bone marrow microenvironment.
Assuntos
Leucemia Experimental/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Estresse Psicológico/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Leucemia Experimental/psicologia , Masculino , Camundongos , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/psicologia , Propranolol/farmacologia , Restrição Física , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/imunologiaRESUMO
Pyoderma gangrenosum is a rare inflammatory skin disease classified within the group of neutrophilic dermatoses and clinically characterized by painful, rapidly evolving cutaneous ulcers with undermined, irregular, erythematous-violaceous edges. Pyoderma gangrenosum pathogenesis is complex and involves a profound dysregulation of components of both innate and adaptive immunity in genetically predisposed individuals, with the follicular unit increasingly recognized as the putative initial target. T helper 17/T helper 1-skewed inflammation and exaggerated inflammasome activation lead to a dysregulated neutrophil-dominant milieu with high levels of tumor necrosis factor-α, interleukin (IL)-1ß, IL-1α, IL-8, IL-12, IL-15, IL-17, IL-23, and IL-36. Low-evidence studies and a lack of validated diagnostic and response criteria have hindered the discovery and validation of new effective treatments for pyoderma gangrenosum. We review established and emerging treatments for pyoderma gangrenosum. A therapeutic algorithm based on available evidence is also provided. For emerging treatments, we review target molecules and their role in the pathogenesis of pyoderma gangrenosum.
Assuntos
Dermatite , Pioderma Gangrenoso , Dermatite/complicações , Humanos , Inflamação , Neutrófilos , Pioderma Gangrenoso/diagnóstico , Pioderma Gangrenoso/tratamento farmacológico , Pioderma Gangrenoso/etiologiaRESUMO
Mature red blood cells (RBCs) lack internal organelles and canonical defense mechanisms, making them both a fascinating host cell, in general, and an intriguing choice for the deadly malaria parasite Plasmodium falciparum (Pf), in particular. Pf, while growing inside its natural host, the human RBC, secretes multipurpose extracellular vesicles (EVs), yet their influence on this essential host cell remains unknown. Here we demonstrate that Pf parasites, cultured in fresh human donor blood, secrete within such EVs assembled and functional 20S proteasome complexes (EV-20S). The EV-20S proteasomes modulate the mechanical properties of naïve human RBCs by remodeling their cytoskeletal network. Furthermore, we identify four degradation targets of the secreted 20S proteasome, the phosphorylated cytoskeletal proteins ß-adducin, ankyrin-1, dematin and Epb4.1. Overall, our findings reveal a previously unknown 20S proteasome secretion mechanism employed by the human malaria parasite, which primes RBCs for parasite invasion by altering membrane stiffness, to facilitate malaria parasite growth.
Assuntos
Transporte Biológico/fisiologia , Eritrócitos/metabolismo , Interações Hospedeiro-Parasita/fisiologia , Malária Falciparum/metabolismo , Plasmodium falciparum/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Citoesqueleto/metabolismo , Eritrócitos/citologia , Eritrócitos/parasitologia , Humanos , Malária Falciparum/parasitologia , Proteínas de Membrana/metabolismo , Fosforilação , Plasmodium falciparum/crescimento & desenvolvimento , ProteômicaRESUMO
STING is an innate immune cytosolic adaptor for DNA sensors that engage malaria parasite (Plasmodium falciparum) or other pathogen DNA. As P. falciparum infects red blood cells and not leukocytes, how parasite DNA reaches such host cytosolic DNA sensors in immune cells is unclear. Here we show that malaria parasites inside red blood cells can engage host cytosolic innate immune cell receptors from a distance by secreting extracellular vesicles (EV) containing parasitic small RNA and genomic DNA. Upon internalization of DNA-harboring EVs by human monocytes, P. falciparum DNA is released within the host cell cytosol, leading to STING-dependent DNA sensing. STING subsequently activates the kinase TBK1, which phosphorylates the transcription factor IRF3, causing IRF3 to translocate to the nucleus and induce STING-dependent gene expression. This DNA-sensing pathway may be an important decoy mechanism to promote P. falciparum virulence and thereby may affect future strategies to treat malaria.
Assuntos
Citosol/imunologia , DNA de Protozoário/imunologia , Vesículas Extracelulares/imunologia , Malária Falciparum/imunologia , Proteínas de Membrana/imunologia , Plasmodium falciparum/imunologia , Linhagem Celular , Núcleo Celular/metabolismo , Microscopia Crioeletrônica , Citosol/metabolismo , DNA de Protozoário/metabolismo , Eritrócitos , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/ultraestrutura , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon/imunologia , Fator Regulador 3 de Interferon/metabolismo , Malária Falciparum/parasitologia , Proteínas de Membrana/metabolismo , Monócitos , Fosforilação , Plasmodium falciparum/genética , Plasmodium falciparum/patogenicidade , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/metabolismo , RNA de Protozoário/imunologia , RNA de Protozoário/metabolismo , Transdução de SinaisRESUMO
IMPORTANCE: With the increased use of data from electronic medical records for research, it is important to validate International Classification of Diseases, Ninth Revision (ICD-9) codes for their respective diagnoses. OBJECTIVE: To assess the accuracy of using ICD-9 codes to identify ocular inflammatory diseases. DESIGN, SETTING, AND PARTICIPANTS: Retrospective secondary database analysis. The setting was Kaiser Permanente Hawaii, an integrated managed care consortium that serves approximately 15% of the general Hawaiian population. Participants were patients with ICD-9 diagnosis codes that might be associated with a diagnosis of ocular inflammation seen at Kaiser Permanente Hawaii between January 1, 2006, and December 31, 2007. The data collection and analysis took place from January 2011 to August 2015. MAIN OUTCOMES AND MEASURES: The main outcome was the positive predictive value (PPV) of ICD-9 codes for identifying specific types of ocular inflammatory disease. The PPVs were calculated by determining the ratio of the confirmed cases found by medical record review to the total number of cases identified by ICD-9 code. RESULTS: Of the 873 patients identified by a comprehensive list of ICD-9 codes for ocular inflammatory diseases, 224 cases were confirmed as uveitis after medical record review. Using a set of uveitis-specific codes and eliminating patients with a history of ocular surgery, the overall PPV for uveitis was 61% (95% CI, 56%-66%). The PPVs for individual uveitis codes ranged from 0% to 100%, and 11 uveitis codes had a PPV exceeding 80%. Herpes zoster ophthalmicus and scleritis/episcleritis ICD-9 codes had PPVs of 91% (95% CI, 86%-95%) and 60% (95% CI, 54%-66%), respectively. CONCLUSIONS AND RELEVANCE: Our results suggest that using ICD-9 codes alone to capture uveitis and scleritis/episcleritis diagnoses is not sufficient in the Kaiser Permanente Hawaii healthcare system, although there were specific uveitis codes with high PPVs. However, the electronic medical record can reliably be used to identify herpes zoster ophthalmicus cases. Medical record review, as was done in this study, is recommended to elucidate diagnoses for uveitis and scleritis/episcleritis.
Assuntos
Infecções Oculares Virais/diagnóstico , Herpes Zoster Oftálmico/diagnóstico , Sistema de Registros , Esclerite/diagnóstico , Uveíte/diagnóstico , Distribuição por Idade , Infecções Oculares Virais/epidemiologia , Feminino , Havaí/epidemiologia , Herpes Zoster Oftálmico/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Esclerite/epidemiologia , Esclerite/virologia , Distribuição por Sexo , Uveíte/epidemiologia , Uveíte/virologiaRESUMO
Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.
Assuntos
Sistema Linfático/fisiologia , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Doença Crônica , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais , Transdução de Sinais/fisiologia , Estresse Fisiológico , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismoRESUMO
Natural regulatory T (nT(reg)) cells are important for maintaining tolerance to self- and foreign antigens, and they are thought to develop from thymocytes that receive strong T cell receptor (TCR)-mediated signals in the thymus. TCR engagement leads to the activation of phospholipase C-γ1, which generates the lipid second messenger diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate. We used mice that lack the ζ isoform of DAG kinase (DGKζ), which metabolizes DAG to terminate its signaling, to enhance TCR-mediated signaling and identify critical signaling events in nT(reg) cell development. Loss of DGKζ resulted in increased numbers of thymic CD25(+)Foxp3(-)CD4(+) nT(reg) cell precursors and Foxp3(+)CD4(+) nT(reg) cells in a cell-autonomous manner. DGKζ-deficient T cells exhibited increased nuclear translocation of the nuclear factor κB subunit c-Rel, as well as enhanced extracellular signal-regulated kinase (ERK) phosphorylation in response to TCR stimulation, suggesting that these downstream pathways may contribute to nT(reg) cell development. Indeed, reducing c-Rel abundance or blocking ERK phosphorylation abrogated the increased generation of nTreg cells by DGKζ-deficient thymocytes. The extent of ERK phosphorylation correlated with TCR-mediated acquisition of Foxp3 in immature thymocytes in vitro. Furthermore, the development of nT(reg) cells was augmented in mice in which ERK activation was selectively enhanced in T cells. Together, these data suggest that DGKζ regulates the development of nT(reg) cells by limiting the extent of activation of the ERK and c-Rel signaling pathways.
Assuntos
Diferenciação Celular/imunologia , Diacilglicerol Quinase/deficiência , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Reguladores/citologia , Timo/imunologia , Animais , Western Blotting , Antígenos CD4/metabolismo , Diacilglicerol Quinase/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Proto-Oncogênicas c-rel/metabolismo , Linfócitos T Reguladores/imunologia , Timo/citologiaRESUMO
Metastasis to distant tissues is the chief driver of breast cancer-related mortality, but little is known about the systemic physiologic dynamics that regulate this process. To investigate the role of neuroendocrine activation in cancer progression, we used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer. Stress-induced neuroendocrine activation had a negligible effect on growth of the primary tumor but induced a 30-fold increase in metastasis to distant tissues including the lymph nodes and lung. These effects were mediated by ß-adrenergic signaling, which increased the infiltration of CD11b(+)F4/80(+) macrophages into primary tumor parenchyma and thereby induced a prometastatic gene expression signature accompanied by indications of M2 macrophage differentiation. Pharmacologic activation of ß-adrenergic signaling induced similar effects, and treatment of stressed animals with the ß-antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues. The effects of stress on distant metastasis were also inhibited by in vivo macrophage suppression using the CSF-1 receptor kinase inhibitor GW2580. These findings identify activation of the sympathetic nervous system as a novel neural regulator of breast cancer metastasis and suggest new strategies for antimetastatic therapies that target the ß-adrenergic induction of prometastatic gene expression in primary breast cancers.