Milieu Intérieur project takes an unprecedented look at the human immune system by examining the genetic and environmental factors contributing to the variability of immune responses.

Consortium members

Publications

• Rhesus negative males have an enhanced IFN gamma-mediated immune response to influenza A virus

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  Jamie A Sugrue, Megan Smith, Celine Posseme, Bruno Charbit, Milieu Interieur Consortium; Nollaig M Bourke, Darragh Duffy, Cliona O'Farrelly

  ABSTRACT: The Rhesus D antigen (RhD) has been associated with susceptibility to several viral infections. Reports suggest that RhD-negative individuals are better protected against infectious diseases and have overall better health. However, potential mechanisms contributing to these associations have not yet been defined. Here, we used transcriptomic and genomic data from the Milieu Interieur cohort of 1000 healthy individuals to explore the effect of Rhesus status on the immune response. We used the rs590787 SNP in the RHD gene to classify the 1000 donors as either RhD-positive or -negative. Whole blood was stimulated with LPS, polyIC, and the live influenza A virus and the NanoString human immunology panel of 560 genes used to assess donor immune response and to investigate sex-specific effects. Using regression analysis, we observed no significant differences in responses to polyIC or LPS between RhD-positive and -negative individuals. However, upon sex-specific analysis, we observed over 40 differentially expressed genes (DEGs) between RhD-positive (n = 384) and RhD-negative males (n = 75) after influenza virus stimulation. Interestingly these Rhesus-associated differences were not seen in females. Further investigation, using gene set enrichment analysis, revealed enhanced IFNγ signalling in RhD-negative males. This amplified IFNγ signalling axis may explain the increased viral resistance previously described in RhD-negative individuals.

  Genes and Immunity
  2022 Apr; 23(2):93-98

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• Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes

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  Barthelemy Caron, Etienne Patin, Maxime Rotival, Bruno Charbit, Matthew L Albert, Lluis Quintana-Murci, Darragh Duffy, Antonio Rausell, Milieu Intérieur Consortium

  Background: Blood plasma proteins play an important role in immune defense against pathogens, including cytokine signaling, the complement system, and the acute-phase response. Recent large-scale studies have reported genetic (i.e., protein quantitative trait loci, pQTLs) and non-genetic factors, such as age and sex, as major determinants to inter-individual variability in immune response variation. However, the contribution of blood-cell composition to plasma protein heterogeneity has not been fully characterized and may act as a mediating factor in association studies. Methods: Here, we evaluated plasma protein levels from 400 unrelated healthy individuals of western European ancestry, who were stratified by sex and two decades of life (20-29 and 60-69 years), from the Milieu Intérieur cohort. We quantified 229 proteins by Luminex in a clinically certified laboratory and their levels of variation were analyzed together with 5.2 million single-nucleotide polymorphisms. With respect to non-genetic variables, we included 254 lifestyle and biochemical factors, as well as counts of seven circulating immune cell populations measured by hemogram and standardized flow cytometry. Results: Collectively, we found 152 significant associations involving 49 proteins and 20 non-genetic variables. Consistent with previous studies, age and sex showed a global, pervasive impact on plasma protein heterogeneity, while body mass index and other health status variables were among the non-genetic factors with the highest number of associations. After controlling for these covariates, we identified 100 and 12 pQTLs acting in cis and trans, respectively, collectively associated with 87 plasma proteins and including 19 novel genetic associations. Genetic factors explained the largest fraction of the variability of plasma protein levels, as compared to non-genetic factors. In addition, blood-cell fractions, including leukocytes, lymphocytes, monocytes, neutrophils, eosinophils, basophils, and platelets, had a larger contribution to inter-individual variability than age and sex and appeared as confounders of specific genetic associations. Finally, we identified new genetic associations with plasma protein levels of five monogenic Mendelian disease genes including two primary immunodeficiency genes (Ficolin-3 and FAS). Conclusions: Our study identified novel genetic and non-genetic factors associated to plasma protein levels which may inform health status and disease management.

  Genome Medicine
  2022 Mar 9;14(1):28

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Events

• 18 October -
  18 OctoberConference2nd Milieu Intérieur Population and Systems Immunology Symposium25 Rue du Docteur Roux, Paris, France
  

  
• 01 NovemberConferenceHuman Evolution - From Fossils to Ancient and Modern Genomes (Virtual Conference)Online
• 18 SeptemberConference27th European Paediatric rheumatology congress. Online
  

  

News

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  Milieu Intérieur welcomes PhD Students (2021-2024)

  In the PhD call held in 2020, 3 projects were selected that aim to leverage the data of the Milieu Intérieur (MI) cohort for understanding immune variability. The MI team welcomes three excellent PhD students who have been funded to work on these projects for 3 years. 

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  Job Vacancy - Postdoc in Quantitative and Population Genetics

  The Quintana-Murci laboratory (Unit of Human Evolutionary Genetics, CNRS UMR2000) is recruiting a post-doctoral researcher in quantitative and population genetics at Institut Pasteur, Paris.

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  The Milieu Intérieur Project and COVID-19

  Researchers from the Milieu Intérieur consortium have contributed significantly to understand and provide solutions to the COVID-19 pandemic and continue to do so.

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