Variation in the Human Immune System Is Largely Driven by Non-Heritable Influences
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There is considerable heterogeneity in immunological parameters between individuals, but its sources are largely unknown. To assess the relative contribution of heritable versus non-heritable factors, we have performed a systems-level analysis of 210 healthy twins between 8 and 82 years of age. We measured 204 different parameters, including cell population frequencies, cytokine responses, and serum proteins, and found that 77% of these are dominated (>50% of variance) and 58% almost completely determined (>80% of variance) by non-heritable influences. In addition, some of these parameters become more variable with age, suggesting the cumulative influence of environmental exposure. Similarly, the serological responses to seasonal influenza vaccination are also determined largely by non-heritable factors, likely due to repeated exposure to different strains. Lastly, in MZ twins discordant for cytomegalovirus infection, more than half of all parameters are affected. These results highlight the largely reactive and adaptive nature of the immune system in healthy individuals.
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Monozygotic twins show age-related divergence of inflammatory biomarker levels, suggesting that the nonheritable influence on inflammation increases with time.
“However, monozygotic twins show age-related divergence of inflammatory biomarker levels, suggesting that the nonheritable influence on inflammation increases with time (118).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [118]
In 210 healthy twins aged 8 to 82 years, non-heritable factors were the strongest contributors to differences in chronic inflammation across individuals, and environmental exposures called the exposome are the main drivers of systemic chronic inflammation.
“a study of 210 healthy twins between 8 and 82 years old, which found that non-heritable factors are the strongest contributors to differences in chronic inflammation across individuals72 and that exposure to environmental factors, which have been collectively called the exposome, are the main drivers of SCI.”
From Chronic inflammation in the etiology of disease across the life span (2019) · cites this paper as [72]
Some studies have found that human CMV infection in older individuals is associated with increased cardiovascular and all-cause mortality, negative immune risk profile, inflammageing, and lower antibody responses to influenza.
“Some studies have found that human CMV infection in older individuals is associated with increased cardiovascular and all-cause mortality, negative immune risk profile, inflammageing, and lower antibody responses to influenza125–129.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [128]
Environmental influences, especially previous immune exposure, are the main source of immune variation among humans, not genetic differences.
“Previous work has shown that immune variation within the human population is driven primarily by environmental factors such as prior immune exposure, rather than genetic factors (Brodin et al., 2015).”
From Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans (2019) · cites this paper as Brodin et al., 2015
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Self-citation
- Authors
- Brodin, P., Jojic, V., Gao, T., Bhattacharya, S., Angel, C. J. L., Furman, D., Shen-Orr, S., Dekker, C. L., Swan, G. E., Butte, A. J., Maecker, H. T., & Davis, M. M.
- Affiliations
- Science for Life Laboratory (SE)
- University of North Carolina at Chapel Hill (US)
- Stanford Medicine (US)
- Technion – Israel Institute of Technology (IL)
- Lucile Packard Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Davis, Mark M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 160
- Issue
- 1-2
- Pages
- 37-47
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4302727
- OpenAlex
- W1978297432
- Cited by
- 1,065
- References
- 48
- Citations by year
- 2026: 67 · 2025: 82 · 2024: 93 · 2023: 84 · 2022: 85 · 2021: 115 · 2020: 106 · 2019: 102 · 2018: 109 · 2017: 96 · 2016: 80 · 2015: 45 · 2014: 1
- FWCI
- 75.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001085)
- National Institute on Drug Abuse (R01DA011170, R01DA023063, DA011170, DA023063)
- National Institute of Allergy and Infectious Diseases (AI090019, U19AI090019, U19AI057229)
- National Institute of Environmental Health Sciences (R21ES022153, ES022153)
- National Center for Research Resources (UL1RR025744)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- monozygotic twins, cytokine response, serum proteins, environmental exposure, cytomegalovirus infection
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Blood Proteins, Child, Cytomegalovirus Infections, Humans, Immunity, Influenza Vaccines, Middle Aged, Twins, Dizygotic, Twins, Monozygotic, Cytokines, Young Adult
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