Brain, Behavior, and Immunity 36 (2014) 27–28

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Brief Commentary

Developmental psychoneuroimmunology: From bench to bedside Andrea Danese ⇑ MRC Social, Genetic, and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, King’s College London, London, UK Department of Child & Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London, UK National & Specialist Child Traumatic Stress & Anxiety Clinic, South London and Maudsley NHS Foundation Trust, London, UK

Atherosclerosis and other pathophysiological processes leading to chronic, age-related conditions start well before the onset of clinical symptoms, in early life. Therefore, risk factors early in life may influence the onset and progression of life-long health trajectories. One such early-life risk factor is child maltreatment, a severe and chronic interpersonal stressor in childhood. Adults reporting a history of childhood maltreatment are at elevated risk of developing multiple and prolonged depressive episodes over the life-course (Nanni et al., 2012). They are also at elevated risk of cardiovascular disease, type-2 diabetes, and other chronic, age-related conditions (Felitti et al., 1998). Consequently, a substantial amount of research has focused on uncovering the mechanisms through which exposure to psychosocial stressors in childhood is translated into biological risk for disease, a process known as biological embedding (Danese and McEwen, 2012). The pioneering work of Seymour (Gig) Levine, George Solomon, Robert Ader, Chris Coe, and others showed that early life stress is associated with several immune abnormalities in animal models (Ader, 1983; Coe, 1996). Furthermore, chronic inflammation is known to contribute to low mood and atherosclerosis (Miller et al., 2009; Libby et al., 2011), which, in turn, lead to some of the clinical outcomes of child maltreatment. Inspired by these findings, clinical researchers are now beginning to explore whether immune abnormalities, and particularly inflammation, can help explain why maltreated children are at heightened risk of disease. Initial support for the mediating role of inflammation was provided by the finding that maltreated children followed into adult life as part of the Dunedin Multidisciplinary Health and Development Study had significant and graded elevation in levels of multiple circulating inflammation biomarkers in adulthood compared to nonmaltreated children. These abnormalities were independent of the influence of co-occurring early life risks, stress in adulthood, and adult health and health behaviors (Danese et al., 2007). Several other papers have subsequently reported similar findings in relationship with prospective follow-up of maltreated children, retrospective reports of a history of childhood maltreatment by adults, and other adverse childhood experiences similarly linked to poor health outcomes.

⇑ Address: P080, SGDP Centre, Institute of Psychiatry, DeCrespigny Park, London SE5 8AF, UK. Fax: +44 20 7848 0866. E-mail address: [email protected] 0889-1591/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bbi.2013.11.001

The study by Karen Matthews and colleagues (Matthews et al., 2014) in this issue of Brain, Behavior, and Immunity is an important addition to this literature and also elegantly raises questions for future research. Matthews et al studied a relatively wealthy and overweight, mixed-background group of mid-age women from Pittsburg, PA. They described a significant association of adult reports of childhood maltreatment with elevated inflammation levels across a 7-year observational period, and with a greater increase in inflammation levels over time. Body mass index measured concurrently with inflammation explained the elevated inflammation levels across time but not the greater intra-individual changes. This paper is important for at least three main reasons. First, at the most fundamental level, this work tests whether the association between child maltreatment and adult inflammation is replicable. Replication is always important and becomes essential in observational studies, which cannot rely on manipulation and random assignment to avoid confounding by unmeasured covariates. Different population samples often have a different distribution of covariates and, thus, replication suggests that unmeasured covariates do not significantly confound the results. Second, this work is valuable for its focus on longitudinal measures of inflammation, which allowed the Matthews’ team to show that childhood maltreatment is associated with chronic inflammation and with a greater increase in inflammation levels over time. These findings highlight the clinical significance and the progressive nature of immune abnormalities in maltreated individuals. Finally, this work is intriguing for its ability to explore how the effect of childhood maltreatment on inflammation might unfold. Previous data suggested that childhood maltreatment predicts adult obesity (Danese and Tan, 2013) and obesity, in turn, may influence inflammation levels. Consistent with these findings, Matthews et al. showed that obesity accounts for much of the effect of maltreatment on inflammation across time (but not for the intra-individual changes in inflammation levels over time) in their sample. The work by Matthews et al. beautifully exemplifies how developmental psychoneuroimmunology is moving from basic (Ader, 1983; Coe, 1996) to clinical science enriching life-course models of disease. To further develop its translational significance, this fast-growing area of research must address, among others, key questions concerning mediation and reversibility. On the one hand, showing that childhood maltreatment predicts elevated inflamma-

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tion levels is necessary but insufficient to adequately test mediation models, despite the known predictive value of inflammation for chronic, age-related disease and psychopathology. Mediation models need to be tested directly in studies that have collected data on childhood maltreatment, adult clinical outcomes, and immune parameters. On the other hand, if systemic inflammation does significantly mediate the effects of childhood maltreatment on adult disease, it will be important to test whether life-style changes, talking therapies, or medications can reduce inflammation levels in maltreated individuals, and whether these changes remediate the detrimental effects of maltreatment on health. By providing insights on biologically plausible mechanisms of disease, developmental psychoneuroimmunology might eventually help relieve suffering for the most vulnerable. References Ader, R., 1983. Developmental psychoneuroimmunology. Dev. Psychobiol. 16, 251–267.

Coe, C.L., 1996. Developmental psychoneuroimmunology revisited. Brain Behav. Immun. 10, 185–187. Danese, A., McEwen, B.S., 2012. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol. Behav. 106, 29–39. Danese, A., Pariante, C.M., Caspi, A., Taylor, A., Poulton, R., 2007. Childhood maltreatment predicts adult inflammation in a life-course study. Proc. Nat. Acad. Sci. USA 104, 1319–1324. Danese, A., Tan, M., 2013. Childhood maltreatment and obesity: systematic review and meta-analysis. Mol. Psychiatry, e-pub; doi:10.1038/mp.2013.54. Felitti, V.J., Anda, R.F., Nordenberg, D., Williamson, D.F., Spitz, A.M., Edwards, V., Koss, M.P., Marks, J.S., 1998. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The adverse childhood experiences (ACE) study. Am. J. Prev. Med. 14, 245–258. Libby, P., Ridker, P.M., Hansson, G.K., 2011. Progress and challenges in translating the biology of atherosclerosis. Nature 473, 317–325. Matthews, K.A., Chang, Y., Thurston, R.C., Bromberg, J.T., 2014. Child abuse is related to inflammation in mid-life women: role of obesity. Brain Behav. Immun. 36, 29–34. Miller, A.H., Maletic, V., Raison, C.L., 2009. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741. Nanni, V., Uher, R., Danese, A., 2012. Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis. Am. J. Psychiatry 169, 141–151.

Developmental psychoneuroimmunology: from bench to bedside.

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