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Phage-displayed immunoprecipitation sequencing (PhIP-seq) has enabled high-throughput profiling of human antibody repertoires. However, a comprehensive overview of environmental and genetic determinants shaping human adaptive immunity is lacking. In this study, we investigated the effects of genetic, environmental, and intrinsic factors on the variation in human antibody repertoires. We characterized serological antibody repertoires against 344,000 peptides using PhIP-seq libraries from a wide range of microbial and environmental antigens in 1,443 participants from a population cohort. We detected individual-specificity, temporal consistency, and co-housing similarities in antibody repertoires. Genetic analyses showed the involvement of the HLA , IGHV , and FUT2 gene regions in antibody-bound peptide reactivity. Furthermore, we uncovered associations between phenotypic factors (including age, cell counts, sex, smoking behavior, and allergies, among others) and particular antibody-bound peptides. Our results indicate that human antibody epitope repertoires are shaped by both genetics and environmental exposures and highlight specific signatures of distinct phenotypes and genotypes. [Display omitted] • PhIP-seq libraries from microbial and environmental antigens in a population cohort • Antibody-bound peptide co-reactivity highlights bacterial mimicry • Common genetic variants in HLA, IGHV, and FUT2 determinate antibody reactivity • Antibody reactivity is associated with widespread phenotypical factors In this study, Andreu-Sánchez et al. utilize phage-displayed immunoprecipitation sequencing to investigate the environmental and genetic determinants shaping human adaptive immunity. The results suggest that both genetics and environmental exposures shape human antibody epitope repertoires, with specific signatures of distinct phenotypes and genotypes. Furthermore, co-occurring antibody responses suggest a link between bacterial immunity and the development of allergies or autoimmunity. [ABSTRACT FROM AUTHOR]

Summary As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages. Important biological pathways that contain cytokine QTLs map to pattern recognition receptors ( TLR1-6-10 cluster), cytokine and complement inhibitors, and the kallikrein system. The cytokine QTLs show enrichment for monocyte-specific enhancers, are more often located in regions under positive selection, and are significantly enriched among SNPs associated with infections and immune-mediated diseases. PaperClip [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell (hiPSC)-derived intestinal organoids are valuable tools for researching developmental biology and personalized therapies, but their closed topology and relative immature state limit applications. Here, we use organ-on-chip technology to develop a hiPSC-derived intestinal barrier with apical and basolateral access in a more physiological in vitro microenvironment. To replicate growth factor gradients along the crypt-villus axis, we locally expose the cells to expansion and differentiation media. In these conditions, intestinal epithelial cells self-organize into villus-like folds with physiological barrier integrity, and myofibroblasts and neurons emerge and form a subepithelial tissue in the bottom channel. The growth factor gradients efficiently balance dividing and mature cell types and induce an intestinal epithelial composition, including absorptive and secretory lineages, resembling the composition of the human small intestine. This well-characterized hiPSC-derived intestine-on-chip system can facilitate personalized studies on physiological processes and therapy development in the human small intestine., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Effective immunity requires a complex network of cellular and humoral components that interact with each other and are influenced by different environmental and host factors. We used a systems biology approach to comprehensively assess the impact of environmental and genetic factors on immune cell populations in peripheral blood, including associations with immunoglobulin concentrations, from ∼500 healthy volunteers from the Human Functional Genomics Project. Genetic heritability estimation showed that variations in T cell numbers are more strongly driven by genetic factors, while B cell counts are more environmentally influenced. Quantitative trait loci (QTL) mapping identified eight independent genomic loci associated with leukocyte count variation, including four associations with T and B cell subtypes. The QTLs identified were enriched among genome-wide association study (GWAS) SNPs reported to increase susceptibility to immune-mediated diseases. Our systems approach provides insights into cellular and humoral immune trait variability in humans., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)