The Genetic Architecture of the Human Immune System: A Bioresource for Autoimmunity and Disease Pathogenesis

Roederer, Mario; Quaye, Lydia; Mangino, Massimo; Beddall, Margaret H.; Mahnke, Yolanda D.; Chattopadhyay, Pratip K.; Tosi, Isabella; Napolitano, L; Barberio, Manuela Terranova; Menni, Cristina; Villanova, Federica; Meglio, Paola Di; Spector, Tim D.; Nestle, Frank O.

doi:10.1016/j.cell.2015.02.046

Cited by 271 publications

(346 citation statements)

References 62 publications

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“…We analyzed human immune cell frequency data from multiple cohorts, described in further detail in Materials and Methods. These are referred to as the Stanford cohorts of 398 individuals, 226 MZ and dizygotic (DZ) twins from a published twin study (4), 23 individuals from a published longitudinal study (11), and 149 previously unpublished subjects (combined in Dataset S1); the Roederer et al (10) cohort, consisting of 669 female twins sampled in the United Kingdom; and the Carr et al (6) cohort, consisting of 670 nontwin subjects, both men and women, sampled in Belgium.…”

Section: Resultsmentioning

confidence: 99%

“…The PBMCs from the Roederer et al (10) Table S1 for a list of cell subtypes in each cohort), thus precluding a combined clustering analysis of the full dataset. The "monocytes" cell population was removed from the Roederer et al (10) cohort as it was missing in 7.6% of the 729 patients. Of the remaining 32 populations, 11 had missing data in at most 1.6% of patients.…”

Section: Methodsmentioning

confidence: 99%

“…We first analyzed immune cell composition data from a total of 1,575 healthy individuals across multiple cohorts, both published (6,10) and previously unpublished (149 individuals) in addition to our previously published data (4), combined in Dataset S1. We also took advantage of a set of diverse functional responses measured in 329 individuals from a number of Stanford cohorts (refs.…”

Section: Significancementioning

confidence: 99%

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Continuous immunotypes describe human immune variation and predict diverse responses

Kaczorowski

Shekhar

Nkulikiyimfura

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

113

123

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The immune system consists of many specialized cell populations that communicate with each other to achieve systemic immune responses. Our analyses of various measured immune cell population frequencies in healthy humans and their responses to diverse stimuli show that human immune variation is continuous in nature, rather than characterized by discrete groups of similar individuals. We show that the same three key combinations of immune cell population frequencies can define an individual's immunotype and predict a diverse set of functional responses to cytokine stimulation. We find that, even though interindividual variations in specific cell population frequencies can be large, unrelated individuals of younger age have more homogeneous immunotypes than older individuals. Across age groups, cytomegalovirus seropositive individuals displayed immunotypes characteristic of older individuals. The conceptual framework for defining immunotypes suggested by our results could guide the development of better therapies that appropriately modulate collective immunotypes, rather than individual immune components.human immune variation | immune cell composition | systems immunology | aging I n the peripheral blood of humans over 100 different immune cell populations can be distinguished based on the expression of cell surface and intracellular markers. These cell populations span various activation and differentiation states within broader classes of principal immune cell lineages in the adaptive and innate immune systems (1). With recent advances in single-cell measurement technologies such as high-dimensional flow cytometry and mass cytometry (2), these different immune cell populations can be simultaneously quantified in an individual sample. Leveraging these developments, recent population studies have profiled the global immune cell composition in healthy adult humans (3-5) and found these to be highly stable within an individual over the course of weeks to months, but highly variable between individuals (3, 6). Although variations in a few immune cell populations are heritable, the majority of immune cell population frequencies and functional responses are largely determined by nonheritable influences in healthy individuals (4). For example, cohabitation has been shown to be a strong influence, emphasizing the importance of shared environmental factors within a household (6). Most of the specific environmental factors that shape human immune systems have yet to be determined, but monozygotic (MZ) twin pairs discordant for human cytomegalovirus (HCMV) seropositivity were more different in the majority of immune measurements compared with seronegative twins (4).Many studies have focused on individual immune cell populations, their functional properties, regulatory roles, and clinical significance. However, a prototypical immune response involves the coordinated action of multiple cell populations (7, 8), providing both inhibitory and stimulatory feedback, leading to a balanced response that fulfills its protective func...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Continuous immunotypes describe human immune variation and predict diverse responses

Kaczorowski

Shekhar

Nkulikiyimfura

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

113

123

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“…Furthermore, gene polymorphisms of ENTPD1 link to the human immune system under homeostatic and inflammatory conditions (e.g. IBD) 9, 10. These lines of evidence suggest that the control of purine metabolism is important in IBD.…”

Section: Introductionmentioning

confidence: 99%

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

et al. 2018

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Inflammatory bowel disease (IBD) is a condition of chronic inflammatory intestinal disorder with increasing prevalence but limited effective therapies. The purine metabolic pathway is involved in various inflammatory processes including IBD. However, the mechanisms through which purine metabolism modulates IBD remain to be established. Here, we found that mucosal expression of genes involved in the purine metabolic pathway is altered in patients with active ulcerative colitis (UC), which is associated with elevated gene expression signatures of the group 3 innate lymphoid cell (ILC3)–interleukin (IL)‐22 pathway. In mice, blockade of ectonucleotidases (NTPDases), critical enzymes for purine metabolism by hydrolysis of extracellular adenosine 5′‐triphosphate (eATP) into adenosine, exacerbates dextran‐sulfate sodium‐induced intestinal injury. This exacerbation of colitis is associated with reduction of colonic IL‐22‐producing ILC3s, which afford essential protection against intestinal inflammation, and is rescued by exogenous IL‐22. Mechanistically, activation of ILC3s for IL‐22 production is reciprocally mediated by eATP and adenosine. These findings reveal that the NTPDase‐mediated balance between eATP and adenosine regulates ILC3 cell function to provide protection against intestinal injury and suggest potential therapeutic strategies for treating IBD by targeting the purine–ILC3 axis.

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“…Moreover, the HLA class Ⅱ (DRB1*0301) is also associated with chronic HCV infection [33] . Genome-wide association studies of autoimmune disease recently revealed multiple associations with the major immune cell subsets and uncovered insights into the control for regulatory Tregs [34] . AITD clearly increases with age, resulting from changes in immune regulation (endogenous factor).…”

Section: Host-dependent Factors In Thyroid Autoimmunitymentioning

confidence: 99%

Hepatitis C virus infection and thyroid autoimmune disorders: A model of interactions between the host and the environment

Pastore¹

2016

WJH

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The hepatitis C virus (HCV) infection is an important public health problem and it is associated with hepatic and extrahepatic manifestations. Autoimmune thyroid diseases are common in HCV infected patients and the standard interferon-based treatment is associated with an increase of the immune-mediated thyroid damage. Recent evidence in the literature analyzed critical points of the mechanisms of thyroid damage, focusing on the balance between the two sides of the interaction: The environment (virus infection with potential crossreaction) and the host (susceptibility genes with consistent immune response). The spectrum of antiviral treatment for chronic HCV infection is rapidly expanding for the development of dual o triple therapy. The availability of interferon-free combined treatment with direct antiviral agents for HCV is very promising, in order to ameliorate the patient compliance and to reduce the development of thyroid autoimmunity.

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The Genetic Architecture of the Human Immune System: A Bioresource for Autoimmunity and Disease Pathogenesis

Cited by 271 publications

References 62 publications

Continuous immunotypes describe human immune variation and predict diverse responses

Continuous immunotypes describe human immune variation and predict diverse responses

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

Hepatitis C virus infection and thyroid autoimmune disorders: A model of interactions between the host and the environment

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