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Defining the boundaries of a healthy immune response using standardized immune monitoring tools

Abstract : The project Milieu Intérieur aims to study the genetic and environmental factors that can have a major impact on occurring immunological variance in healthy human population. This characterization requires the use of standardized immunophenotyping technologies for integrating diverse, complex datasets. With this goal in mind, we used an optimized suite of standardized whole-blood stimulation systems to study the human induced immune response in physiological condition and developed a unique standardized protocol to analyze the ARN signatures upon whole-blood stimulation to test the hypothesis that responses to complex stimuli can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, which captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. This provides new strategies for dimension reduction of large datasets and for deconvolution of innate immune responses, applicable for characterizing novel immunomodulatory molecules.In a second related study, we aimed to identify the environmental and genetic factors driving innate and adaptive immune cell parameters in homeostatic conditions. To do so, we combined semi-automated flow cytometric analysis of blood leukocytes and genome-wide DNA genotyping in the 1,000 healthy donors included in the collection. We show that smoking, age, gender and latent cytomegalovirus infection, are main drivers of human variation (i.e. numbers of Treg and MAIT cells). These results demonstrated that innate cell parameters are strongly controlled by genetic factors, whereas adaptive cells are driven by life-long environmental exposures. In addition, to help on the public data mining, we developed interactive R-Shiny application including healthy donor reference values for both studies.All together, these results indicate that we developed powerful tools for human system biology approaches to support personalized medecine.
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https://theses.hal.science/tel-01572191
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Submitted on : Saturday, August 5, 2017 - 1:01:26 AM
Last modification on : Thursday, April 7, 2022 - 10:10:33 AM

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2017PA066004.pdf
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  • HAL Id : tel-01572191, version 1

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Alejandra Urrutia. Defining the boundaries of a healthy immune response using standardized immune monitoring tools. Immunology. Université Pierre et Marie Curie - Paris VI, 2017. English. ⟨NNT : 2017PA066004⟩. ⟨tel-01572191⟩

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