Childrens Hospital Of Philadelphia Research Institute

Philadelphia, PA, United States

Childrens Hospital Of Philadelphia Research Institute

Philadelphia, PA, United States
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Angelo L.S.,Texas Childrens Hospital | Angelo L.S.,Baylor College of Medicine | Banerjee P.P.,Texas Childrens Hospital | Banerjee P.P.,Baylor College of Medicine | And 10 more authors.
Immunologic Research | Year: 2015

Human natural killer (NK) cells display a wide array of surface and intracellular markers that indicate various states of differentiation and/or levels of effector function. These NK cell subsets exist simultaneously in peripheral blood and may vary among individuals. We examined variety among selected NK cell receptors expressed by NK cells from normal donors, as well as the distribution of select NK cell subsets and NK cell receptor expression over time in several individual donors. Peripheral blood mononuclear cells were evaluated using flow cytometry via fluorochrome-conjugated antibodies against a number of NK cell receptors. Results were analyzed for both mean fluorescence intensity (MFI) and the percent positive cells for each receptor. CD56bright and CD56dim NK cell subsets were also considered separately, as was variation in receptor expression in NK cell subsets over time in selected individuals. Through this effort, we provide ranges of NK cell surface receptor expression for a local adult population as well as provide insight into intra-individual variation. © 2015, Springer Science+Business Media New York.

Spitsin S.,Childrens Hospital Of Philadelphia Research Institute | Meshki J.,Childrens Hospital Of Philadelphia Research Institute | Winters A.,Childrens Hospital Of Philadelphia Research Institute | Tuluc F.,Childrens Hospital Of Philadelphia Research Institute | And 4 more authors.
Journal of Leukocyte Biology | Year: 2017

The neuropeptide SP has physiologic and pathophysiologic roles in CNS and peripheral tissues and is involved in crosstalk between nervous and immune systems in various conditions, including HIV and SIV infection. Increased SP levels were demonstrated in plasma of HIV+ individuals as well as in the CNS of SIV-infected, nonhuman primates. SP increases HIV infection in macrophages through interaction with its receptor, NK1R. The SP effect on immune system is both pro- and anti-inflammatory and includes up-regulation of a number of cytokines and cell receptors. The main goal of this study was to determine whether there is interplay between monocyte exposure to SP and recruitment into sites of inflammation. We now demonstrate that exposure of either human macrophages or PBMCs to SP leads to increased production of chemokines, including MCP-1, for which expression is limited to cells of the myeloid lineage. This effect is inhibited by the NK1R antagonist, aprepitant. Exposure to conditioned medium derived from SP-treated PBMCs resulted in increased monocyte migration through semipermeable membranes and an in vitro human BBB model. Monocyte migration was blocked by anti–MCP-1 antibodies. Our results suggest that increased SP levels associated with HIV and other inflammatory conditions may contribute to increased monocyte migration into the CNS and other tissues through a MCP-1–dependent mechanism. © Society for Leukocyte Biology.

Kassam-Adams N.,Childrens Hospital Of Philadelphia | Kassam-Adams N.,University of Pennsylvania | Marsac M.L.,Childrens Hospital Of Philadelphia | Marsac M.L.,University of Pennsylvania | And 3 more authors.
European Journal of Psychotraumatology | Year: 2015

Background: Recommended approaches for secondary prevention of posttrauma mental health difficulties in children require empirically sound predictive screening to determine which children require more intensive monitoring or targeted intervention. Although there are several promising screening tools for injured children, none has emerged as the gold standard, and little replication data are available regarding their performance. Objective: To evaluate a predictive screening protocol for risk of later posttraumatic stress (PTS) and depression outcomes and address a crucial lack of replication studies by examining performance of two previously published screening tools (Screening Tool for Early Predictors of PTSD [STEPP] and Child Trauma Screening Questionnaire [CTSQ]). Method: The study enrolled 290 children hospitalized after acute injury. A three-part screening protocol, including acute PTS and depression symptoms and other empirically derived risk factors, was administered in hospital as part of a stepped care study. PTS and depression symptoms and health-related quality of life (HRQoL) were assessed 6 months post-injury. Results: The screening protocol demonstrated excellent sensitivity (1.00) and good specificity (0.73) for prediction of 6-month PTS, moderate sensitivity (0.64) and good specificity (0.74) for 6-month depression, and excellent negative predictive value for both outcomes. Among children screening at risk, HRQoL was poorer at 6 months post-injury. Replication analyses found predictive utility (sensitivity and specificity) was low for the STEPP and moderate for the CTSQ. Conclusions: This study provides additional evidence that early post-injury screening could identify children at higher risk for persistent PTS symptoms and limited support for predicting post-injury depression. Findings support acute PTS symptoms as key early risk markers. The predictive value of a negative screening result (i.e., knowing who is not at risk) may be especially important in choosing where to target limited follow-up resources. It is crucial that future investigations provide additional replication data regarding existing screening tools and evaluate additional or alternate items (proposed a priori) to improve predictive power. © 2015 Nancy Kassam-Adams et al.

Lin R.,Childrens Hospital Of Philadelphia Research Institute | Rittenhouse D.,Childrens Hospital Of Philadelphia Research Institute | Sweeney K.,Childrens Hospital Of Philadelphia Research Institute | Potluri P.,Childrens Hospital Of Philadelphia Research Institute | And 2 more authors.
PLoS Genetics | Year: 2015

The heavy consumption of ethanol can lead to alcohol use disorders (AUDs) which impact patients, their families, and societies. Yet the genetic and physiological factors that predispose humans to AUDs remain unclear. One hypothesis is that alterations in mitochondrial function modulate neuronal sensitivity to ethanol exposure. Using Drosophila genetics we report that inactivation of the mitochondrial outer membrane translocator protein 18kDa (TSPO), also known as the peripheral benzodiazepine receptor, affects ethanol sedation and tolerance in male flies. Knockdown of dTSPO in adult male neurons results in increased sensitivity to ethanol sedation, and this effect requires the dTSPO depletion-mediated increase in reactive oxygen species (ROS) production and inhibition of caspase activity in fly heads. Systemic loss of dTSPO in male flies blocks the development of tolerance to repeated ethanol exposures, an effect that is not seen when dTSPO is only inactivated in neurons. Female flies are naturally more sensitive to ethanol than males, and female fly heads have strikingly lower levels of dTSPO mRNA than males. Hence, mitochondrial TSPO function plays an important role in ethanol sensitivity and tolerance. Since a large array of benzodiazepine analogues have been developed that interact with the peripheral benzodiazepine receptor, the mitochondrial TSPO might provide an important new target for treating AUDs. © 2015 Lin et al.

Hartzell C.A.,Stanford University | Jankowska K.I.,Childrens Hospital Of Philadelphia Research Institute | Jankowska K.I.,University of Pennsylvania | Burkhardt J.K.,Childrens Hospital Of Philadelphia Research Institute | And 2 more authors.
eLife | Year: 2016

T cell receptor (TCR) engagement opens Ca2+ release-activated Ca2+ (CRAC) channels and triggers formation of an immune synapse between T cells and antigen-presenting cells. At the synapse, actin reorganizes into a concentric lamellipod and lamella with retrograde actin flow that helps regulate the intensity and duration of TCR signaling. We find that Ca2+ influx is required to drive actin organization and dynamics at the synapse. Calcium acts by promoting actin depolymerization and localizing actin polymerization and the actin nucleation promotion factor WAVE2 to the periphery of the lamellipod while suppressing polymerization elsewhere. Ca2+- dependent retrograde actin flow corrals ER tubule extensions and STIM1/Orai1 complexes to the synapse center, creating a self-organizing process for CRAC channel localization. Our results demonstrate a new role for Ca2+ as a critical regulator of actin organization and dynamics at the synapse, and reveal potential feedback loops through which Ca2+ influx may modulate TCR signaling. © Hartzell et al.

Basile K.J.,Childrens Hospital Of Philadelphia | Guy V.C.,Childrens Hospital Of Philadelphia | Schwartz S.,Main Line Health System | Grant S.F.A.,Childrens Hospital Of Philadelphia | And 2 more authors.
Current Diabetes Reports | Year: 2014

Despite the notion that there is a degree of commonality to the biological etiology of type 1 diabetes (T1D) and type 2 diabetes (T2D), the lack of overlap in the genetic factors underpinning each of them suggests very distinct mechanisms. A disorder considered to be at the “intersection” of these two diseases is “latent autoimmune diabetes in adults” (LADA). Interestingly, genetic signals from both T1D and T2D are also seen in LADA, including the key HLA and transcription factor 7-like 2 (TCF7L2) loci, but the magnitudes of these effects are more complex than just pointing to LADA as being a simple admixture of T1D and T2D. We review the current status of the understanding of the genetics of LADA and place it in the context of what is known about the genetics of its better-studied “cousins,” T1D and T2D, especially with respect to the myriad of discoveries made over the last decade through genome-wide association studies. © 2014, Springer Science+Business Media New York.

PubMed | Childrens Hospital Of Philadelphia Research Institute
Type: Case Reports | Journal: The Journal of clinical investigation | Year: 2012

The Fc receptor on NK cells, FcRIIIA (CD16), has been extensively studied for its role in mediating antibody-dependent cellular cytotoxicity (ADCC). A homozygous missense mutation in CD16 (encoding a L66H substitution) is associated with severe herpesvirus infections in rare patients. Here, we identified a new patient with this CD16 mutation and compared the patients NK cells to those of the originally reported patient. Patients with the L66H mutation had intact ADCC, but deficient spontaneous NK cell cytotoxicity and decreased surface expression of CD2, a coactivation receptor. Mechanistic studies in a human NK cell line, NK-92, demonstrated that CD16 expression correlated with CD2 surface levels and enabled killing of a melanoma cell line typically resistant to CD16-deficient NK-92 cells. An association between CD16 and CD2 was identified biochemically and at the immunological synapse, which elicited CD16 signaling after CD2 engagement. Stable expression of CD16 L66H in NK-92 cells recapitulated the patient phenotype, abrogating association of CD16 with CD2 as well as CD16 signaling after CD2 ligation. Thus, CD16 serves a role in NK cell-mediated spontaneous cytotoxicity through a specific association with CD2 and represents a potential mechanism underlying a human congenital immunodeficiency.

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