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BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
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Proteína AIRE , Interferon gama , Inibidores de Janus Quinases , Poliendocrinopatias Autoimunes , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Proteína AIRE/deficiência , Proteína AIRE/genética , Proteína AIRE/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Quimiocina CXCL9/genética , Interferon gama/genética , Interferon gama/imunologia , Inibidores de Janus Quinases/uso terapêutico , Camundongos Knockout , Nitrilas/uso terapêutico , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/tratamento farmacológico , Poliendocrinopatias Autoimunes/imunologia , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Pirimidinas/uso terapêutico , Linfócitos T/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Projetos Piloto , Modelos Animais de Doenças , Criança , Adolescente , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Episodic angioedema with eosinophilia (EAE) is a rare multilineage cyclic syndrome of unknown etiology characterized by episodes of angioedema, myalgia, fatigue, and fever that occur every 3 to 8 weeks and resolve between episodes without therapy. Cyclic elevations in serum IL-5 levels and neutrophils precede the increase in absolute eosinophil count (AEC) in most patients. OBJECTIVE: We sought to assess the role of IL-5-driven eosinophilia in the clinical manifestations of EAE. METHODS: An open-label pilot study of mepolizumab (700 mg intravenously monthly for 3 months followed by sequential dose reduction to the Food and Drug Administration-approved dose of 300 mg subcutaneously monthly) was conducted. The primary end point was reduction in the number and severity of clinical symptoms as assessed by patient-reported symptom questionnaires. Secondary end points were greater than or equal to 75% reduction in peak AEC after 1 dose of mepolizumab and sustained reduction in AEC after 3 doses of mepolizumab. Exploratory end points included effects of mepolizumab treatment on other cell lineages (numbers and surface marker expression), levels of plasma mediators, and biomarkers of eosinophil activation. RESULTS: Four female and 1 male (median age, 45 years) participants with EAE were enrolled. None of the 5 participants experienced a reduction in the number of symptomatic flares on mepolizumab therapy, and 1 participant withdrew before study completion because of lack of improvement. Peak AEC was reduced by 75% or more in 3 participants after the first dose of mepolizumab and in 4 participants after 3 doses. CONCLUSIONS: In a small cohort of participants with EAE, mepolizumab was unsuccessful in substantially reducing clinical symptoms despite reduction in AEC.
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Angioedema , Anticorpos Monoclonais Humanizados , Eosinofilia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Projetos Piloto , Interleucina-5 , Eosinofilia/tratamento farmacológico , EosinófilosRESUMO
The Consortium of Eosinophilic Gastrointestinal disease Researchers (CEGIR) and The International Gastrointestinal Eosinophil Researchers (TIGERS) organized a day-long symposium at the 2024 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured new discoveries in basic and translational research and debates on the mechanisms and management of eosinophilic gastrointestinal diseases (EGIDs). Updates on recent clinical trials and consensus guidelines were also presented. Herein, we summarize the updates on EGIDs presented at the symposium.
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The imatinib-sensitive fusion gene FIP1L1::PDGFRA is the most frequent molecular abnormality identified in patients with eosinophilic myeloid neoplasms. Rapid recognition of this mutation is essential given the poor prognosis of PDGFRA-associated myeloid neoplasms prior to the availability of imatinib therapy. We report a case of a patient in whom delayed diagnosis resulted in cardiac transplantation for eosinophilic endomyocardial fibrosis. The delay in diagnosis was due, in part, to a false-negative result in fluorescence in situ hybridization (FISH) testing for FIP1L1::PDGFRA. To explore this further, we examined our cohort of patients presenting with confirmed or suspected eosinophilic myeloid neoplasms and found 8 additional patients with negative FISH results despite a positive reverse-transcriptase polymerase chain reaction test for FIP1L1::PDGFRA. More importantly, false-negative FISH results delayed the median time to imatinib treatment by 257 days. These data emphasize the importance of empiric imatinib therapy in patients with clinical features suggestive of PDGFRA-associated disease.
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Transtornos Mieloproliferativos , Neoplasias , Humanos , Mesilato de Imatinib/uso terapêutico , Diagnóstico Tardio , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Hibridização in Situ Fluorescente , Benzamidas , Proteínas de Fusão Oncogênica/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited. OBJECTIVES: This study sought to describe NRH prevalence, associated features, and impact in patients with XLA. METHODS: Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons. RESULTS: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per µL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002). CONCLUSIONS: NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.
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Agamaglobulinemia/complicações , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Hiperplasia/etiologia , Adolescente , Adulto , Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/sangue , Agamaglobulinemia/genética , Agamaglobulinemia/patologia , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Hiperplasia/sangue , Hiperplasia/genética , Hiperplasia/patologia , Fígado/patologia , Masculino , Mutação , Contagem de Plaquetas , Estudos Retrospectivos , Adulto JovemRESUMO
The discovery of the autoimmune regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.
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Síndromes de Imunodeficiência/genética , Mutação/genética , Poliendocrinopatias Autoimunes/genética , Fatores de Transcrição/genética , Animais , Autoimunidade , Tolerância Central , Humanos , Proteína AIRERESUMO
PURPOSE: Prophylactic antibiotics (PA) and immunoglobulin replacement (IGRT) are commonly used in specific antibody deficiency (SAD); however, optimal treatment is not well-established. Our purpose is to compare treatment outcomes with IGRT and/or PA among SAD patients. METHODS: A retrospective chart review of SAD patients treated at two tertiary centers between January 2012 and May 2017 was performed. Clinical and laboratory data, and rates of infections prior to and after treatment with IGRT or PA were analyzed. Descriptive analyses, between-group comparisons of rates of infection after 1 year of treatment, and a stepwise logistic regression model were employed to explore factors contributing to treatment outcomes. RESULTS: We identified 65 SAD patients with mean age were 18 years (2-71 years). The baseline mean number of infections in the PA group and IGRT group was 4.71 (SD 3.15) and 7.73 (SD 6.65), respectively. Twenty-nine (44.6%) received IGRT, 7 (10.7%) received PA, 7 (10.7%) received both IGRT and PA, 15 (23.1%) failed PA and switched to IGRT, and 7 did not receive any specific treatment. After 1 year of treatment, the difference in the mean number of infections in PA vs. IGRT was not statistically significant [2.86 (2.73) vs. 4.44 (4.74), p = 0.27]. Reporting autoimmunity increased the odds for persistent infections (OR = 4.29; p = 0.047), while higher IgG levels decreased the odds for persistent infections (OR = 0.68, p = 0.018). CONCLUSIONS: PA and IGRT are equally effective as first line in preventing infections in SAD patients. However, patients who fail PA would benefit from IGRT.
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Antibacterianos/uso terapêutico , Imunoglobulinas/uso terapêutico , Doenças da Imunodeficiência Primária/tratamento farmacológico , Adolescente , Adulto , Idoso , Antibioticoprofilaxia/métodos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE OF REVIEW: Fungal infections have steadily increased in incidence, emerging as a significant cause of morbidity and mortality in patients with iatrogenic immunosuppression. Simultaneously, we have witnessed a growing population of newly described inherited immune disorders that have enhanced our understanding of the human immune response against fungi. In the present review, we provide an overview and diagnostic roadmap to inherited disorders which confer susceptibility to superficial and invasive fungal infections. RECENT FINDINGS: Inborn errors of fungal immunity encompass a heterogeneous group of disorders, some of which confer fungal infection-specific susceptibility, whereas others also feature broader infection vulnerability and/or noninfectious manifestations. Infections by Candida, Aspergillus, endemic dimorphic fungi, Pneumocystis, and dermatophytes along with their organ-specific presentations provide clinicians with important clues in the assessment of patients with suspected immune defects. SUMMARY: The absence of iatrogenic risk factors should raise suspicion for inborn errors of immunity in children and young adults with recurrent or severe fungal diseases. Expeditious diagnosis and prompt initiation of antifungal therapy and management of complications are paramount to achieve remission of fungal disease in the setting of primary immunodeficiency disorders.
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Predisposição Genética para Doença , Micoses , Criança , Humanos , Micoses/genéticaRESUMO
OBJECTIVES: Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized by infiltration of eosinophils into the esophagus. Primary treatment approaches include topical corticosteroids and/or food elimination. The aim of the present study was to compare the effectiveness of combination therapy (topical corticosteroid plus test-based food elimination [FS]) with single therapy (topical corticosteroid [S] or test-based food elimination [F]). METHODS: Chart review of patients with EoE at Texas Children's Hospital (age <21 years) was performed. Clinical and histological statuses were evaluated after a 3-month treatment with either single or combination therapy. Comparisons were analyzed using Fisher exact test, Kruskal-Wallis tests, and multiple logistic regression models. RESULTS: Among 670 charts, 63 patients (1-21 years, median 10.3 years) with clinicopathologic diagnoses of EoE were identified. Combination FS therapy was provided to 51% (nâ=â32) and single treatment (S, F) to 27% (nâ=â17) or 22% (nâ=â14) of patients, respectively. Clinical responses were noted in 91% (nâ=â29), 71% (nâ=â12), and 64% (nâ=â14) of patients in the FS, S, and F groups, respectively. The odds of clinically improving were 4.6 times greater (95% confidence interval: 1.1-18.8) with combination versus single therapy. The median peak number of eosinophils per high-power field after 3-month therapy was not significantly different in the S, F, and FS groups. CONCLUSIONS: The combination of topical corticosteroids with specific food elimination is as effective in achieving clinical and histological remissions as the single-treatment approaches. Responses were achieved with the combination in patients who had previously failed single-agent therapy. Prospective research of this combination approach in young patients with EoE is needed.
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Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Dietoterapia/métodos , Esofagite Eosinofílica/terapia , Administração Tópica , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Pesquisa Comparativa da Efetividade , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/patologia , Feminino , Seguimentos , Humanos , Lactente , Modelos Logísticos , Masculino , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To identify the inflammatory mediators around the time of pneumonia onset associated with concurrent or later onset of pressure ulcers (PUs). DESIGN: Retrospective. SETTING: Acute hospitalization and inpatient rehabilitation unit of a university medical center. PARTICIPANTS: Individuals (N=86) with traumatic spinal cord injury (SCI) were included in the initial analyses. Fifteen of the 86 developed pneumonia and had inflammatory mediator data available. Of these 15, 7 developed PUs and 8 did not. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Twenty-three inflammatory mediators in plasma and urine were assayed. The differences in concentrations of plasma and urine inflammatory mediators between the closest time point before and after the diagnosis of pneumonia were calculated. RESULTS: Initial chi-square analysis revealed a significant (P=.02) association between pneumonia and PUs. Individuals with SCI and diagnosed pneumonia had nearly double the risk for developing PUs compared with those with no pneumonia. In individuals with pneumonia, Mann-Whitney U exact tests suggested an association (P<.05) between the formation of a first PU and a slight increase in plasma concentrations of tumor necrosis factor-alpha (TNF-α), and a decrease in urine concentrations of TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-15 after onset of pneumonia. CONCLUSIONS: These findings suggest that a relatively small increase in plasma TNF-α, and decreases in urine TNF-α, GM-CSF, and IL-15 from just before to just after the diagnosis of pneumonia could be markers for an increased risk of PUs in individuals with pneumonia after traumatic SCI.
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Mediadores da Inflamação/sangue , Mediadores da Inflamação/urina , Pneumonia/complicações , Úlcera por Pressão/etiologia , Traumatismos da Medula Espinal/complicações , Distribuição de Qui-Quadrado , Estudos Transversais , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/urina , Humanos , Interleucina-15/urina , Masculino , Projetos Piloto , Pneumonia/sangue , Pneumonia/urina , Estudos Retrospectivos , Fatores de Risco , Traumatismos da Medula Espinal/sangue , Traumatismos da Medula Espinal/urina , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/urinaRESUMO
Cholinergic denervation has been associated with falls and slower gait speed and ß-amyloid deposition with greater severity of axial motor impairments in Parkinson disease (PD). However, little is known about the association between the presence of extra-nigral pathological conditions and freezing of gait (FoG). Patients with PD (n = 143; age, 65.5 ± 7.4 years, Hoehn and Yahr stage, 2.4 ± 0.6; Montreal Cognitive Assessment score, 25.9 ± 2.6) underwent [(11) C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11) C]dihydrotetrabenazine dopaminergic PET imaging, and clinical, including FoG, assessment in the dopaminergic "off" state. A subset of subjects (n = 61) underwent [(11) C]Pittsburgh compound-B ß-amyloid positron emission tomography (PET) imaging. Normative data were used to dichotomize abnormal ß-amyloid uptake or cholinergic deficits. Freezing of gait was present in 20 patients (14.0%). Freezers had longer duration of disease (P = 0.009), more severe motor disease (P < 0.0001), and lower striatal dopaminergic activity (P = 0.013) compared with non-freezers. Freezing of gait was more common in patients with diminished neocortical cholinergic innervation (23.9%, χ(2) = 5.56, P = 0.018), but not in the thalamic cholinergic denervation group (17.4%, χ(2) = 0.26, P = 0.61). Subgroup analysis showed higher frequency of FoG with increased neocortical ß-amyloid deposition (30.4%, Fisher Exact test: P = 0.032). Frequency of FoG was lowest with absence of both pathological conditions (4.8%), intermediate in subjects with single extra-nigral pathological condition (14.3%), and highest with combined neocortical cholinopathy and amyloidopathy (41.7%; Cochran-Armitage trend test, Z = 2.63, P = 0.015). Within the group of freezers, 90% had at least one of the two extra-nigral pathological conditions studied. Extra-nigral pathological conditions, in particular the combined presence of cortical cholinopathy and amyloidopathy, are common in PD with FoG and may contribute to its pathophysiology. © 2014 International Parkinson and Movement Disorder Society.
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Reação de Congelamento Cataléptica/fisiologia , Transtornos Neurológicos da Marcha/diagnóstico por imagem , Transtornos Neurológicos da Marcha/etiologia , Doença de Parkinson/complicações , Tomografia por Emissão de Pósitrons , Substância Negra/patologia , Acetilcolinesterase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Benzotiazóis , Isótopos de Carbono , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tetrabenazina/análogos & derivados , Tiazóis , Proteínas Vesiculares de Transporte de Monoamina/metabolismoRESUMO
Extracellular ß-nicotinamide adenine dinucleotide (NAD(+)) is anti-inflammatory. We hypothesized that NAD(+) would modulate the anti-inflammatory cytokine Transforming Growth Factor (TGF)-ß1. Indeed, NAD(+) led to increases in both active and latent cell-associated TGF-ß1 in RAW 264.7 mouse macrophages as well as in primary peritoneal macrophages isolated from both C3H/HeJ (TLR4-mutant) and C3H/HeOuJ (wild-type controls for C3H/HeJ) mice. NAD(+) acts partially via cyclic ADP-ribose (cADPR) and subsequent release of Ca(2+). Treatment of macrophages with the cADPR analog 3-deaza-cADPR or Ca(2+) ionophores recapitulated the effects of NAD(+) on TGF-ß1, whereas the cADPR antagonist 8-Br-cADPR, Ca(2+) chelation, and antagonism of L-type Ca(2+) channels suppressed these effects. The time and dose effects of NAD(+) on TGF-ß1 were complex and could be modeled both statistically and mathematically. Model-predicted levels of TGF-ß1 protein and mRNA were largely confirmed experimentally but also suggested the presence of other mechanisms of regulation of TGF-ß1 by NAD(+). Thus, in vitro and in silico evidence points to NAD(+) as a novel modulator of TGF-ß1.
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ADP-Ribose Cíclica/metabolismo , Macrófagos/metabolismo , Modelos Biológicos , NAD/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Cálcio/metabolismo , Ionóforos de Cálcio/farmacologia , Linhagem Celular , ADP-Ribose Cíclica/análogos & derivados , ADP-Ribose Cíclica/genética , ADP-Ribose Cíclica/farmacologia , Macrófagos/citologia , Camundongos , Camundongos Mutantes , NAD/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta1/genéticaRESUMO
Human malaria can be caused by the parasite Plasmodium falciparum that is transmitted by female Anopheles mosquitoes. "Immunological crosstalk" between the mammalian and anopheline hosts for Plasmodium functions to control parasite numbers. Key to this process is the mammalian cytokine transforming growth factor-ß1 (TGF-ß1). In mammals, TGF-ß1 regulates inducible nitric oxide (NO) synthase (iNOS) both positively and negatively. In some settings, high levels of NO activate latent TGF-ß1, which in turn suppresses iNOS expression. In the mosquito, ingested TGF-ß1 induces A. stephensi NOS (AsNOS), which limits parasite development and which in turn is suppressed by activation of the mosquito homolog of the mitogen-activated protein kinases MEK and ERK. Computational models linking TGF-ß1, AsNOS, and MEK/ERK were developed to provide insights into this complex biology. An initial Boolean model suggested that, as occurs in mammalian cells, MEK/ERK and AsNOS would oscillate upon ingestion of TGF-ß1. An ordinary differential equation (ODE) model further supported the hypothesis of TGF-ß1-induced multiphasic behavior of MEK/ERK and AsNOS. To achieve this multiphasic behavior, the ODE model was predicated on the presence of constant levels of TGF-ß1 in the mosquito midgut. Ingested TGF-ß1, however, did not exhibit this behavior. Accordingly, we hypothesized and experimentally verified that ingested TGF-ß1 induces the expression of the endogenous mosquito TGF-ß superfamily ligand As60A. Computational simulation of these complex, cross-species interactions suggested that TGF-ß1 and NO-mediated induction of As60A expression together may act to maintain multiphasic AsNOS expression via MEK/ERK-dependent signaling. We hypothesize that multiphasic behavior as represented in this model allows the mosquito to balance the conflicting demands of parasite killing and metabolic homeostasis in the face of damaging inflammation.
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Anopheles/imunologia , Malária Falciparum/imunologia , Modelos Imunológicos , Plasmodium falciparum/imunologia , Animais , Anopheles/metabolismo , Anopheles/parasitologia , Biologia Computacional/métodos , MAP Quinases Reguladas por Sinal Extracelular/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Interações Hospedeiro-Parasita/imunologia , Humanos , Proteínas de Insetos/imunologia , Proteínas de Insetos/metabolismo , Insetos Vetores/imunologia , Insetos Vetores/metabolismo , Insetos Vetores/parasitologia , Sistema de Sinalização das MAP Quinases/imunologia , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Óxido Nítrico/imunologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Plasmodium falciparum/fisiologia , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/imunologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
OBJECTIVE: To gain insights into individual variations in acute inflammation and physiology. DESIGN: Large-animal study combined with mathematical modeling. SETTING: Academic large-animal and computational laboratories. SUBJECTS: Outbred juvenile swine. INTERVENTIONS: Four swine were instrumented and subjected to endotoxemia (100 µg/kg), followed by serial plasma sampling. MEASUREMENTS AND MAIN RESULTS: Swine exhibited various degrees of inflammation and acute lung injury, including one death with severe acute lung injury (PaO(2)/FIO(2) ratio µ200 and static compliance µ10 L/cm H(2)O). Plasma interleukin-1ß, interleukin-4, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-α, high mobility group box-1, and NO(2)/NO(3) were significantly (p µ .05) elevated over the course of the experiment. Principal component analysis was used to suggest principal drivers of inflammation. Based in part on principal component analysis, an ordinary differential equation model was constructed, consisting of the lung and the blood (as a surrogate for the rest of the body), in which endotoxin induces tumor necrosis factor-α in monocytes in the blood, followed by the trafficking of these cells into the lung leading to the release of high mobility group box-1, which in turn stimulates the release of interleukin-1ß from resident macrophages. The ordinary differential equation model also included blood pressure, PaO(2), and FIO(2), and a damage variable that summarizes the health of the animal. This ordinary differential equation model could be fit to both inflammatory and physiologic data in the individual swine. The predicted time course of damage could be matched to the oxygen index in three of the four swine. CONCLUSIONS: The approach described herein may aid in predicting inflammation and physiologic dysfunction in small cohorts of subjects with diverse phenotypes and outcomes.
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Inflamação/fisiopatologia , Modelos Biológicos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/fisiopatologia , Animais , Endotoxemia/induzido quimicamente , Endotoxemia/fisiopatologia , Endotoxinas/farmacologia , Feminino , Proteína HMGB1/sangue , Hemodinâmica/fisiologia , Inflamação/induzido quimicamente , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-4/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Análise de Componente Principal , Fenômenos Fisiológicos Respiratórios , Suínos , Fator de Necrose Tumoral alfa/sangueRESUMO
Our understanding of eosinophil biology, development, and regulation has dramatically increased in the past decade, leading to new paradigms for the role of eosinophils in human health and disease and, perhaps more importantly, providing insights toward novel treatment strategies in the fight against eosinophil-mediated inflammation. In this review, we discuss recent advances regarding the role of eosinophils in host-viral defense, eosinophil heterogeneity, and eosinophil-targeted therapies.
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Clinical effects of anti-cholinergic drugs implicate cholinergic systems alterations in the pathophysiology of some cardinal motor impairments in Parkinson's disease. The topography of affected cholinergic systems deficits and motor domain specificity are poorly understood. Parkinson's disease patients (n = 108) underwent clinical and motor assessment and vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol PET imaging. Volumes-of-interest-based analyses included detailed thalamic and cerebellar parcellations. Successful PET sampling for most of the small-sized parcellations was available in 88 patients. A data-driven approach, stepwise regression using the forward selection method, was used to identify cholinergic brain regions associating with cardinal domain-specific motor ratings. Regressions with motor domain scores for model-selected regions followed by confounder analysis for effects of age of onset, duration of motor disease and levodopa equivalent dose were performed. Among 7 model-derived regions associating with postural instability and gait difficulties domain scores three retained significance in confounder variable analysis: medial geniculate nucleus (standardized ß = -0.34, t = -3.78, P = 0.0003), lateral geniculate nucleus (ß = -0.32, t = -3.4, P = 0.001) and entorhinal cortex (ß = -0.23, t = -2.6, P = 0.011). A sub-analysis of non-episodic postural instability and gait difficulties scores demonstrated significant effects of the medial geniculate nucleus, entorhinal cortex and globus pallidus pars interna. Among 6 tremor domain model-selected regions two regions retained significance in confounder variable analysis: cerebellar vermis section of lobule VIIIb (ß = -0.22, t = -2.4, P = 0.021) and the putamen (ß = -0.23, t = -2.3, P = 0.024). None of the three model-selected variables for the rigidity domain survived confounder analysis. Two out of the four model-selected regions for the distal limb bradykinesia domain survived confounder analysis: globus pallidus pars externa (ß = 0.36, t = 3.9, P = 0.0097) and the paracentral lobule (ß = 0.26, t = 2.5, P = 0.013). Emphasizing the utility of a systems-network conception of the pathophysiology of Parkinson's disease cardinal motor features, our results are consistent with specific deficits in basal forebrain corticopetal, peduncupontine-laterodorsal tegmental complex, and medial vestibular nucleus cholinergic pathways, against the background of nigrostriatal dopaminergic deficits, contributing significantly to postural instability, gait difficulties, tremor and distal limb bradykinesia cardinal motor features of Parkinson's disease. Our results suggest significant and distinct consequences of degeneration of cholinergic peduncupontine-laterodorsal tegmental complex afferents to both segments of the globus pallidus. Non-specific regional cholinergic nerve terminal associations with rigidity scores likely reflect more complex multifactorial signalling mechanisms with smaller contributions from cholinergic pathways.
RESUMO
Inflammation is a complex, non-linear process central to many of the diseases that affect both developed and emerging nations. A systems-based understanding of inflammation, coupled to translational applications, is therefore necessary for efficient development of drugs and devices, for streamlining analyses at the level of populations, and for the implementation of personalized medicine. We have carried out an iterative and ongoing program of literature analysis, generation of prospective data, data analysis, and computational modeling in various experimental and clinical inflammatory disease settings. These simulations have been used to gain basic insights into the inflammatory response under baseline, gene-knockout, and drug-treated experimental animals for in silico studies associated with the clinical settings of sepsis, trauma, acute liver failure, and wound healing to create patient-specific simulations in polytrauma, traumatic brain injury, and vocal fold inflammation; and to gain insight into host-pathogen interactions in malaria, necrotizing enterocolitis, and sepsis. These simulations have converged with other systems biology approaches (e.g., functional genomics) to aid in the design of new drugs or devices geared towards modulating inflammation. Since they include both circulating and tissue-level inflammatory mediators, these simulations transcend typical cytokine networks by associating inflammatory processes with tissue/organ impacts via tissue damage/dysfunction. This framework has now allowed us to suggest how to modulate acute inflammation in a rational, individually optimized fashion. This plethora of computational and intertwined experimental/engineering approaches is the cornerstone of Translational Systems Biology approaches for inflammatory diseases.
Assuntos
Inflamação/etiologia , Modelos Biológicos , Biologia de Sistemas , Cicatrização/imunologia , Animais , Ensaios Clínicos como Assunto , Citocinas/imunologia , Modelos Animais de Doenças , HumanosRESUMO
The immune system is central to our interactions with the world in which we live and importantly dictates our response to potential allergens, toxins, and pathogens to which we are constantly exposed. Understanding the mechanisms that underlie protective host immune responses against microbial pathogens is vital for the development of improved treatment and vaccination strategies against infections. To that end, inherited immunodeficiencies that manifest with susceptibility to bacterial, viral, and/or fungal infections have provided fundamental insights into the indispensable contribution of key immune pathways in host defense against various pathogens. In this mini-review, we summarize the findings from a series of recent publications in which inherited immunodeficiencies have helped illuminate the interplay of human immunity and resistance to infection.