Elsevier

Psychoneuroendocrinology

Volume 82, August 2017, Pages 140-154
Psychoneuroendocrinology

Review
The effects of early life adversity on the immune system

https://doi.org/10.1016/j.psyneuen.2017.05.012Get rights and content

Abstract

Early life adversity (ELA) is associated with a higher risk for diseases in adulthood. Although the pathophysiological effects of ELA are varied, there may be a unifying role for the immune system in all of the long-term pathologies such as chronic inflammatory disorders (autoimmune diseases, allergy, and asthma). Recently, significant efforts have been made to elucidate the long-term effects ELA has on immune function, as well as the mechanisms underlying these immune changes. In this review, we focus on data from human studies investigating immune parameters in relation to post-natal adverse experiences. We describe the current understanding of the ‘ELA immune phenotype’, characterized by inflammation, impairment of the cellular immune system, and immunosenescence. However, at present, data addressing specific immune functions are limited and there is a need for high-quality, well powered, longitudinal studies to unravel cause from effect. Besides the immune system, also the stress system and health behaviors are altered in ELA. We discuss probable underlying mechanisms based on epigenetic programming that could explain the ELA immune phenotype and whether this is a direct effect of immune programming or an indirect consequence of changes in behavior or stress reactivity. Understanding the underlying mechanisms will help define effective strategies to prevent or counteract negative ELA-associated outcomes.

Introduction

Prevalence of early life adversity (ELA) is astonishingly high. In 2010, the World Health Organization estimated that 39% of the global population were exposed to one or more childhood adversities. This problem is not limited to underdeveloped countries: ELA prevalence is similar in high, middle, and low income countries (Kessler et al., 2010). ELA is an overarching term for a multitude of adverse experiences in early life, ranging from parental separation and childhood maltreatment to low socioeconomic status (SES), each of which have been linked to increased risk for mental and physical diseases. Several large cohort studies have investigated these associations and found increased risks for chronic back pain, cardiovascular diseases, type 2 diabetes, allergies and asthma, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, migraine, obesity, psychiatric disorders (depression), substance use disorders, and personality disorders (e.g. Anda et al., 2010, Eriksson et al., 2014, Spitzer et al., 2012, Tomasdottir et al., 2015, Gern et al., 2009). These associations appear to follow a dose-response relationship: the greater the adversity, the higher the risk for diseases (Anda et al., 2010). ELA also appears to be linked to a worse outlook after disease onset, as ELA was associated with reduced treatment response in multiple sclerosis patients (Spitzer et al., 2012), increased symptom severity in fibromyalgia (Loevinger et al., 2012), poorer prognosis in breast cancer patients (Witek Janusek et al., 2013), and premature mortality (Brown et al., 2009).

There may be a unifying role for the immune system in the etiology of these multifactorial diseases associated with ELA. The immune system can be divided into the innate and adaptive immune systems. Innate immunity forms the first line of defense against infections, is more evolutionary conserved, and responds to unspecific molecular patterns of pathogens. The adaptive immune system, on the other hand, is composed of highly specialized B and T cells that are vital for building immunological long-term memory against specific pathogens. These two immune systems are intricately intertwined. The innate immune response is critical for the initiation of the adaptive immune response, whereas the adaptive immune system helps the innate immune cells to clear pathogens by labeling them. In addition, there is a delay of a few days in the response of the adaptive immune system to an infection; the innate immune system plays a crucial role in filling this time gap. It is now becoming clear that there is an ELA-associated immune phenotype affecting specific functions of both innate and adaptive immunity. ELA shapes health at an early age when the foundations are laid for specific diseases such as allergic sensitizations, which develop between birth and age 8 (Rowe et al., 2007, Lendor et al., 2008). However, ELA does not appear to affect all elements of the immune system to the same extent and the molecular mechanisms underlying the development of this phenotype are unknown.

Individuals with a history of ELA have an altered stress response (e.g. Lovallo et al., 2012, Schwaiger et al., 2016) and engage in more risky health behaviors, such as smoking, obesity, alcohol abuse, drug abuse, and sexual risk behavior (Ramiro et al., 2010), which may mediate the relationship between ELA, the immune phenotype, and disease susceptibility. For example, the relationship between ELA and risk for liver disease was reduced by 35–50% when accounting for risky health behaviors (Dong et al., 2003) and life style factors accounted for 50% of the association between ELA and white blood cell counts (Surtees et al., 2003a). However, although health behaviors clearly play a role, they do not appear to fully explain the relationship between ELA and disease risk. The stress system, on the other hand, has a direct effect on immune function and may play a fundamental role in the overall ELA phenotype.

In this review we focus on human studies investigating immune parameters in relation to post-natal adverse experiences. We describe the current understanding of the ELA immune phenotype involving persistent low-grade inflammation, accelerated immunosenescence, and possibly an impairment in cellular immunity. However, it is unclear whether the phenotype we observe is a direct consequence of early life programming of immune cells, or secondary to an altered stress response. Subsequently, we examine two hypotheses as to how the immune phenotype is generated as well as evidence supporting them.

Section snippets

Innate immunity and inflammation

Activation of innate immune cells − e.g. neutrophils, monocytes, macrophages, dendritic cells, and Natural Killer (NK) cells − initiates an inflammatory response, characterized by dilatation of blood vessels, increased blood flow, tissue infiltration of immune cells, and the production of pro-inflammatory markers. Although inflammation is crucial for effective clearance of an infection and tissue repair, an unresolved or overactive inflammatory response leads to chronic low-grade inflammation (

Underlying mechanisms

The molecular mechanisms underlying the development of the ELA-associated immune phenotype are unknown. Here, we propose two refined hypotheses (Fig. 2, Fig. 3). Both hypotheses are based on the idea that ELA causes subtle changes in set points, due to epigenetic mechanisms, inducing long-term changes in the transcriptional and proteomic landscapes (Leenen et al., 2016) and resulting in higher disease risk. We focus on DNA methylation, which is one of the most studied and best characterized

Conclusions

It is clear that ELA has long-term effects on the immune system. We now have a clear picture of the ELA immune phenotype characterized by increased inflammation, impaired cellular immunity, and accelerated immunosenescence. Although no definite mechanism has been established for the genesis of this ELA immune phenotype, there is compelling evidence for both of the hypotheses. However, there is still limited data on which to draw mechanistic conclusions. There is a need for high-quality, well

Funding

This work was financially supported by the Fonds National de Recherche (FNR) Luxembourg (C12/BM/3985792 “EpiPath”) and the Ministry of Higher Education and Research of Luxembourg. These funding bodies were not involved in the design, data collection, analysis, and interpretation of studies reviewed here, nor in the writing of this review. JDT is a management board member of the EU-funded COST action CM1409.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Authors’ contributions

The review was conceived and written by MMCE and JDT, and revised into its final format by MMCE, AK, CPM, and JDT. The final manuscript was read and approved by all authors.

Conflicts of interest

None.

Acknowledgments

We would like to thank Prof. Dr. Hartmut Schächinger from the Department of Clinical Psychophysiology, University of Trier, Germany, for his support and Josiane Kirpach, Sonja Bork, and Alessia Colone from Luxembourg Institute of Health, Luxembourg, for proofreading the final manuscript.

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