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Significant common environmental effects on leukocyte subpopulations.

ABSTRACT: Major efforts are invested in the analysis of phenotypic variation in a population of individuals. While many of these studies focus on the genetic basis of phenotypic variation via measurements of DNA polymorphic sites, the environmental effects are still elusive. Here we propose a methodology, called CCCE ('Cell Composition Common Environment'), to identify environmental effects on the composition of immune cell functionalities. Specifically, CCCE is focused on the common experiences that are shared between siblings (the 'common environment'), designed to correct for cell subpopulation heterogeneity, and is based on a multicolor flow cytometry analysis across a large cohort of human monozygotic and dizygotic twins. We demonstrate that the CCCE methodology can provide insights on the relations between common environmental effects and the heterogenic functions of several immune cell types, such as NK cells effector functions and coagulation-related capabilities of monocytes. The software described in this article is available at http://csgi.tau.ac.il/CCCE.

SUBMITTER: Botzman M

PROVIDER: S-EPMC5915319 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Significant common environmental effects on leukocyte subpopulations.

Botzman Maya M Gat-Viks Irit I

PloS one 20180424 4

Major efforts are invested in the analysis of phenotypic variation in a population of individuals. While many of these studies focus on the genetic basis of phenotypic variation via measurements of DNA polymorphic sites, the environmental effects are still elusive. Here we propose a methodology, called CCCE ('Cell Composition Common Environment'), to identify environmental effects on the composition of immune cell functionalities. Specifically, CCCE is focused on the common experiences that are ...[more]

PMID: 29689083

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Project description:BackgroundThe in vitro pharmacology of baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level.MethodsPeripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC50) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24?h obtained from JAKi-treated subjects. Time above IC50 and average daily percent inhibition of pSTAT formation were calculated for each JAKi, cytokine, and cell type.ResultsDistinct JAKis displayed different in vitro pharmacologic profiles. For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower IC50 values and increased time above IC50 translating to a greater overall inhibition of STAT signaling during the dosing interval. All JAKis tested inhibited JAK1/2-dependent cytokines (e.g., IL-6 and interferon [IFN]-?), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-?, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), but often to significantly differing degrees.ConclusionsDifferent JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. Notably, baricitinib inhibited JAK1/3 signaling to a lesser extent than upadacitinib and tofacitinib, while upadacitinib, baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF.

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Significant common environmental effects on leukocyte subpopulations.

Publications

Significant common environmental effects on leukocyte subpopulations.

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