Understanding human immune function using the resources from the Human Functional Genomics Project

Netea, Mihai G.; Joosten, Leo A. B.; Li, Yang; Kumar, Vinod; Oosting, Marije; Smeekens, Sanne P.; Jaeger, Martin; Horst, Rob ter; Schirmer, Melanie; Vlamakis, Hera; Notebaart, Richard A.; Pavelka, Norman; Aguirre-Gamboa, Raúl; Swertz, Morris A.; Tunjungputri, Rahajeng N.; Heijden, Wouter van de; Franzosa, Eric A.; Ng, Aylwin; Graham, Daniel B.; Lassen, Kara G.; Schraa, Kiki; Netea‐Maier, Romana T.; Smit, Johannes W. A.; Mast, Quirijn de; Veerdonk, Frank van de; Kullberg, Bart Jan; Tack, Cees J.; Munckhof, Inge van de; Rutten, Joost H.W.; Graaf, Jacqueline van der; Franke, Lude; Hofker, Marten H.; Jonkers, Iris; Platteel, Mathieu; Maatman, Astrid; Fu, Jingyuan; Zhernakova, Alexandra; Meer, J.W.M. van der; Dinarello, Charles A.; Ven, André van der; Huttenhouwer, Curtis; Koenen, Hans J. P. M.; Joosten, Irma; Xavier, Ramnik J.; Wijmenga, Cisca

doi:10.1038/nm.4140

Cited by 66 publications

(56 citation statements)

References 9 publications

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“…Supporting this hypothesis, a positive correlation between blood platelet counts and plasma IL-1β concentrations was recently reported in a cohort of 500 Caucasian healthy volunteers (Netea et al, 2016; Tunjungputri et al, 2018). However, blood leukocyte counts were equally correlated with plasma levels of IL-1β in that cohort, hindering the precise contribution of platelets for the plasma IL-1β concentrations described (Tunjungputri et al, 2018).…”

Section: Resultssupporting

confidence: 54%

Platelets fuel the inflammasome activation of innate immune cells

Rolfes

Ribeiro

Hawwari

et al. 2019

Preprint

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ABSTRACTThe inflammasomes control the bioactivity of pro-inflammatory cytokines of the interleukin (IL)-1 family. The inflammasome assembled by NLRP3 has been predominantly studied in homogenous cell populations in vitro, neglecting the influence of cellular interactions that occur in vivo. Here, we show that platelets, the second most abundant cells in the blood, boost the inflammasome capacity of human macrophages and neutrophils, and are critical for IL-1 production by monocytes. Platelets license NLRP3 transcription, thereby enhancing ASC nucleation, caspase-1 activity, and IL-1β maturation. Platelet depletion attenuated LPS-induced IL-1β in vivo, and platelet counts correlate with plasma concentrations of IL-1β in malaria patients. Furthermore, a platelet gene signature was enriched among the highest expressed transcripts in IL-1β-driven autoinflammatory diseases. The platelet-mediated enhancement of inflammasome activation was independent of cell-to-cell contacts, platelet-derived lipid mediators, purines, nucleic acids and a host of platelet cytokines, and involved the triggering of calcium sensing receptors on macrophages by a calcium-dependent protein commonly released by platelets and megakaryocytes. Finally, we report that platelets provide an additional layer of regulation of inflammasomes in vivo.

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Section: Resultssupporting

confidence: 54%

Platelets fuel the inflammasome activation of innate immune cells

Rolfes

Ribeiro

Hawwari

et al. 2019

Preprint

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“…We generated the Decon-cell predictive models using data from the 500FG cohort 13 , where quantification of immune cell types was carried out using FACS 14 and RNA-Seq based bulk whole blood transcriptome profiling were available for 89 samples 15 . By using a cross-validation approach we were able to accurately predict 34 out of 73 cell subtypes using solely whole blood gene expression.…”

Section: Introductionmentioning

confidence: 99%

Deconvolution of bulk blood eQTL effects into immune cell subpopulations

Aguirre-Gamboa

Klein

Tommaso

et al. 2019

Preprint

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Expression quantitative trait loci (eQTL) studies are used to interpret the function of disease-associated genetic risk factors. To date, most eQTL analyses have been conducted in bulk tissues, such as whole blood and tissue biopsies, which are likely to mask the cell type context of the eQTL regulatory effects. Although this context can be investigated by generating transcriptional profiles from purified cell subpopulations, the current methods are labor-intensive and expensive. Here we introduce a new method, Decon2, a statistical framework for estimating cell proportions using expression profiles from bulk blood samples (Decon-cell) and consecutive deconvolution of cell type eQTLs (Decon-eQTL). The estimated cell proportions from Decon-cell agree with experimental measurements across cohorts (R ≥ 0.77). Using Decon-cell we can predict the proportions of 34 circulating cell types for 3,194 samples from a population-based cohort. Next we identified 16,362 whole blood eQTLs and assign them to a cell type with Decon-eQTL using the predicted cell proportions from Decon-cell. Deconvoluted eQTLs show excellent allelic directional concordance with those of eQTL(≥ 96%) and chromatin mark QTL (≥87%) studies that used either purified cell subpopulations or single-cell RNA-seq.Our new method provides a way to assign cell type effects to eQTLs from bulk blood, which is useful in pinpointing the most relevant cell type for a certain complex disease. Decon2 is available as an R package and Java application (https://github.com/molgenis/systemsgenetics/tree/master/Decon2), and as a web tool ( www.molgenis.org/deconvolution ).

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“…The field of autoimmunity research will benefit from emulating some of the efforts in cancer research, in particular the establishment of large consortia, centralized tissue biobanks, and databanks, such as the ones provided by The Cancer Genome Atlas (TCGA; http://cancergenome.nih.gov) and the International Cancer Genome Consortium (ICGC; https://dcc.icgc.org) (236). The recent announcement for the Human Functional Genomics Project (237), which aims at understanding the interindividual variation of human immune responses in health and disease, should contribute to providing the basis for stratifying patients for personalized treatment strategies.…”

Section: Resultsmentioning

confidence: 99%

Understanding Human Autoimmunity and Autoinflammation Through Transcriptomics

Banchereau

Cepika

Banchereau

et al. 2017

Annu. Rev. Immunol.

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Transcriptomics, the high-throughput characterization of RNAs, has been instrumental in defining pathogenic signatures in human autoimmunity and autoinflammation. It enabled the identification of new therapeutic targets in IFN-, IL-1- and IL-17-mediated diseases. Applied to immunomonitoring, transcriptomics is starting to unravel diagnostic and prognostic signatures that stratify patients, track molecular changes associated with disease activity, define personalized treatment strategies, and generally inform clinical practice. Herein, we review the use of transcriptomics to define mechanistic, diagnostic, and predictive signatures in human autoimmunity and autoinflammation. We discuss some of the analytical approaches applied to extract biological knowledge from high-dimensional data sets. Finally, we touch upon emerging applications of transcriptomics to study eQTLs, B and T cell repertoire diversity, and isoform usage.

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Understanding human immune function using the resources from the Human Functional Genomics Project

Cited by 66 publications

References 9 publications

Platelets fuel the inflammasome activation of innate immune cells

Platelets fuel the inflammasome activation of innate immune cells

Deconvolution of bulk blood eQTL effects into immune cell subpopulations

Understanding Human Autoimmunity and Autoinflammation Through Transcriptomics

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