Host and Environmental Factors Influencing Individual Human Cytokine Responses

• Published in: Cell Vol. 167; no. 4; pp. 1111 - 1124.e13
• Main Authors: ter Horst, Rob, Jaeger, Martin, Smeekens, Sanne P., Oosting, Marije, Swertz, Morris A., Li, Yang, Kumar, Vinod, Diavatopoulos, Dimitri A., Jansen, Anne F.M., Lemmers, Heidi, Toenhake-Dijkstra, Helga, van Herwaarden, Antonius E., Janssen, Matthijs, van der Molen, Renate G., Joosten, Irma, Sweep, Fred C.G.J., Smit, Johannes W., Netea-Maier, Romana T., Koenders, Mieke M.J.F., Xavier, Ramnik J., van der Meer, Jos W.M., Dinarello, Charles A., Pavelka, Norman, Wijmenga, Cisca, Notebaart, Richard A., Joosten, Leo A.B., Netea, Mihai G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.11.2016
• Subjects: Adolescent; Adult; age; Aged; Aging; alpha-1-antitrypsin; Animals; Arthritis - immunology; Blood - immunology; Body Mass Index; cytokines; Cytokines - genetics; Cytokines - immunology; data collection; environment; environmental factors; Female; fungi; gender; Gene-Environment Interaction; genetics; genomics; host; Human Genome Project; Humans; immune response; Infections - immunology; Infections - microbiology; Infections - virology; Inflammation - immunology; Inflammation - microbiology; intestinal microorganisms; Leukocytes, Mononuclear - immunology; Macrophages - immunology; Male; Mice; microbiome; Middle Aged; season; Seasons; Sex Characteristics; vitamin D; environment; genetics; gender; vitamin D; host; season; cytokines; microbiome; age; alpha-1-antitrypsin
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2016.10.018

Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project, we assessed the effect of environmental and non-genetic host factors of the genetic make-up of the host and of the intestinal microbiome on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral, and non-microbial metabolic stimuli in 534 healthy subjects. In this first study, we show a strong impact of non-genetic host factors (e.g., age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies. [Display omitted] [Display omitted] •HFGP cohort: host/environment, genetics, and microbiome affect cytokine production•IFN-γ and IL-22, but not IL-17 and Mo-derived cytokine responses, decrease with age•Gender affects cytokine responses, resulting in disease susceptibility differences•Cytokine responses are season dependent, influenced by AAT concentrations As part of the Human Functional Genomics Project, mapping of environmental and non-genetic host factors reveals critical associations between age, gender, and annual seasonality in inter-individual variability of immune cell function.