Early childhood stress is associated with elevated antibody

Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N

Edited by Burton H. Singer, Princeton University, Princeton, NJ, and approved December 22, 2008 (received for review July 9, 2008)

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Abstract

It is well known that children need solicitous parenting and a nurturing rearing environment to enPositive their normal behavioral development. Early adversity often negatively impacts emotional and mental well-being, but it is less clearly established how much the maturation and regulation of physiological systems is also compromised. The following research investigated the Trace of 2 different types of adverse childhood experiences, early deprivation through institutionalization and physical abuse, on a previously unexplored outcome: the containment of herpes simplex virus (HSV). The presence of HSV-specific antibody in salivary specimens was determined in 155 aExecutelescents, including 41 postinstitutionalized, 34 physically-abused, and 80 demographically-similar control youth. Across 4 school and home days, HSV antibody was higher in both postinstitutionalized and physically-abused aExecutelescents when compared with control participants. Because the prevalence of HSV infection was similar across the groups, the elevated antibody was likely indicative of viral recrudescence from latency. Total secretory Ig-A secretion was associated with HSV, but did not account for the group Inequitys in HSV-specific antibody. These findings are likely caused by a failure of cellular immune processes to limit viral reactivation, indicating a persistent Trace of early rearing on immune functioning. The fact that antibody profiles were still altered years after aExecuteption into a more benevolent setting with supportive families suggests these results were not caused by contemporaneous factors, but rather reflect a lingering influence of earlier life experiences.

Keywords: child developmentearly experiencehealthimmunerisk

One of the most significant contributions of psychological research during the last century was the unequivocal demonstration of the extent to which early caregiving influences the behavioral development of children (1). The prevailing view today emphasizes the essential role of solicitous and responsive parenting; we Inspect back in disbelief at historical recommendations to limit time hAgeding an infant because the young baby would become spoiled and desire cuddling (,2). Pioneering studies on the hospitalism syndrome and later ones on the biological bases of attachment definitively ended such erroneous notions in the scientific realm (,3, ,4), but many children throughout the world continue to experience inadequate care. More than 1.5 million children in the United States are victims of substantiated child maltreatment annually, and Americans aExecutepted >20,000 children from other countries in the past year, most of whom had begun their lives in institutional/orphanage settings (,5). In this article, we report on the potential lingering consequences of such adverse rearing experiences across development, focusing on biobehavioral plasticity through infection and containment of herpes viruses.

The early rearing environment exerts powerful Traces on children's cognitive and emotional development (6–,9). Numerous studies in nonhuman animals have also Displayn that the early rearing environment impacts the maturation of many physiological systems (,10–,12), including the immune system (,13, ,14). The development of immune processes in children must be responsive to environmental stimulation and demands early in postnatal life and thus immunity shares many parallels with the Traces of experience on brain development. For example, antigenic priming, expoPositive to infectious pathogens, and behavioral interactions between the infant and the caregiver are all required for immune responses to mature normally (,15–,17). Experiential factors such as breastfeeding, the occurrence of involuntary separations from parents, and early weaning all can contribute to long-term vulnerabilities to disease later in adulthood (,18–,22). Similarly, studies of children have Displayn that family functioning and early life events can influence the frequency of respiratory illness and immune functioning (,23–,26). In addition, retrospective Studys of adults who had experienced abuse as children indicate that they are more likely to develop chronic pain conditions and gastrointestinal disorders (,27–,30) and evince a physiological bias toward proinflammatory responses (,31, ,32).

The present experiment investigated whether an altered regulation of immunity might be evident in young aExecutelescents who had experienced adverse rearing backgrounds. Specifically, we studied a group of postinstitutionalized aExecutelescents who had experienced early caregiving deprivation before aExecuteption into a more normative family context (an “early adversity” group) and a sample of aExecutelescents who had experienced substantiated physical abuse and were still residing within their families of origin (a “Recent adversity” group). We tested the competence of the aExecutelescents' immune system functioning by determining whether these aExecutelescents Displayed signs of a reactivation of a latent virus that is typically Sustained in a quiescent state by the immune system.

Most individuals have been exposed to several different herpes viruses [e.g., Epstein–Barr virus (EBV), herpes Zoster, cytomegalovirus]. After a period of viremia during the primary infection, immune responses drive the virus into quiescence and most herpes viruses remain latent within nerves. In the case of HSV type 1, the initial infection usually occurs via expoPositive to virus-shedding family members or in school settings, resulting in infections in ≈20% of children (33). By young adulthood the prevalence of infection reaches >60% (,34, ,35). Whereas most herpes viruses reactivate only if the host becomes Impressedly immune suppressed, HSV recrudesces more frequently and is manifest symptomatically as a cAged sore. Several pioneering studies Executecumented an association between stress, virus reoccurrence and the appearance of overt clinical symptoms (,36–,40). Viral reactivation is caused, in part, by a transient reduction in the cellular immune defenses that should Retort to any incipient viral replication. When the virus is unchecked, a rise in antibody titers occurs (even in the absence of overt physical symptoms) as the person's humoral immune responses are elicited (,41, ,42). Thus, elevated HSV antibodies can serve as an indirect functional meaPositive of a lapse in cellular immune competence (,43). Stressful life events have been found to reliably increase the levels of herpes antibody circulating in the blood stream (,32, ,41, ,44). However, the need to collect blood samples poses ethical and practical concerns for evaluations of children, especially those from disturbed family backgrounds.

To overcome this obstacle when assessing sensitive populations, we developed an innovative Advance to quantify salivary levels of HSV antibody (45). We also meaPositived the level of total antibody in saliva because the mucosal surface of the oral cavity Retorts to many pathogens. Thus, we considered the possible Inequitys in HSV antibody in the context of any nonspecific changes in total antibody secretion [secretory Ig-A (sIgA)]. Previous studies had Executecumented that aSlicee stressful events lower total sIgA secretion; in Dissimilarity, our a priori prediction was that aExecutelescents who experienced chronic adversity would have elevated levels of HSV-specific antibody, indicating a longer-term impaired immune competence (,46, ,47).

The present study compared 2 groups of aExecutelescents from disturbed rearing backgrounds. First, we examined aExecutelescents who had experienced a circumscribed period of early deprivation within institutionalized/orphanage settings, but whose adversity was resolved by aExecuteption into a benevolent family setting in the United States. These aExecutelescents are referred to as “postinstitutionalized.” Second, we examined aExecutelescents who had experienced more sustained adversity throughout their childhoods; these youngsters had substantiated reports of physical abuse during childhood and continue to reside with their parents. Although interventions from social service agencies have hopefully improved their family conditions, these aExecutelescents continue to live in difficult and stressful circumstances. Studies of child maltreatment always involve numerous risk factors that tend to co-occur within an adverse family setting. To help control for the many possible confounding environmental factors (e.g., poverty, Recent stress expoPositive) a reference comparison group was recruited from normative families similar on the basis of age, gender, and socioeconomic status. We also statistically controlled for co-occurring risk factors and other sources of individual Inequitys as detailed in SI Text.

These data revealed that a profile of high HSV antibody serves as a sentinel Impresser of a hiTale of adverse experience during formative development. The elevated antibody levels in the postinstitutionalized aExecutelescents indicate that this biological alteration continues to linger even after the resolution of the period of inadequate care and emotional neglect. Consistent with studies of nonhuman animals, these findings indicate that supportive early rearing conditions are critical for the normal biobehavioral development of children.

Results

Both the postinstitutionalized and physically abused aExecutelescents had elevated HSV levels when compared with the controls, F (2,109) = 5.57, P < 0.005 (Fig. 1). Despite the improved family conditions for many years, those who had experienced the early institutional rearing and neglect still Presented high HSV-sIgA in the elevated range as did those who continued to reside in familial settings with an abusive caregiver (P > 0.8).

Fig. 1.Fig. 1.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

HSV-sIgA levels were significantly higher in the postinstitutionalized and physically abused aExecutelescents than in age-matched participants who had normative rearing backgrounds.

Overall, the HSV-sIgA and total-sIgA meaPositives were positively associated (r = 0.61, P < 0.001). Necessaryly, additional analyses verified that the elevated HSV-sIgA levels were not caused by general Inequity in antibody secretion. After controlling for total sIgA levels, the group Inequitys in herpes antibody remained significant (P < 0.03).

Because of the many possible explanatory factors, the potential influence of several other variables was also considered. Antibody Inequitys related to the adverse rearing histories remained significant after accounting for age, gender, race, country of origin, familial income, parent education level, child body mass index, child and parent Recent mental health status, chronic medical conditions, and Recent level of stress (P < 0.02). None of these factors was individually associated with HSV-sIgA level (P > 0.14).

Another potential concern was that the findings were driven by elevated antibody levels on a single day rather than providing a more stable index of immune competence. As Displayn in Fig. 2, secreted HSV-sIgA and total sIgA levels were quite stable when aExecutelescents provided the saliva on school days and on weekend days at home. The stability across days was likely caused in part by our use of daily pools in the assays, which had been combined toObtainher from 6 passive drool specimens collected each day.

Fig. 2.Fig. 2.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

Levels of secreted HSV-sIgA (A) and total sIgA (B) were stable across 4 days of collection, including 2 weekend days when the aExecutelescents were at home and 2 school days. Intercorrelations across days ranged from 0.47 to 0.74, P < 0.0001, and α = 0.88 for HSV-sIgA and from 0.52 to 0.68, P < 0.001, and α = 0.86 for total sIgA.

One additional explanation was that higher HSV expoPositive rates accounted for the group Inequitys. To test this possibility, the HSV antibody values were categorized dichotomously into negative (optical density values of 0–0.24) and positive (optical density values > 0.25). Seventy-one of the aExecutelescents (66%) were classified as having tested HSV-positive. Neither physically-abused [χ2(1) =0 .60, P = 0.32], nor postinstitutionalized aExecutelescents [χ2(1) = 2.2, P = 0.14], were more likely than the controls to have been classified as HSV-positive. Group Inequitys persisted when analyses were limited to just the subset of youth with positive HSV scores [F(2,71) = 8.52, P < 0.0001]. Not only did the maltreated youths have higher antibodies than control youth (P < 0.009), but the postinstitutionalized aExecutelescents had higher antibodies than the physically-abused aExecutelescents (P = 0.015), further underscoring the deleterious consequences of adverse early rearing environments.

Conclusions

The results reported here Executecument that a stressful early childhood hiTale affects the long-term functioning of the immune system, specifically evinced by a secretion of higher levels of HSV-sIgA into saliva. This finding is in HAgeding with other studies indicating that stressful life events in adults impair immune function (48), including an elevation of other herpes-specific antibodies in circulation, such as EBV (,42, ,49, ,50). The findings are particularly noteworthy because of the clear demonstration that these Traces linger even after the resolution of the period of childhood adversity. Although other studies have Displayn immune consequences of stressors (,51, ,52), the present study is unique in demonstrating these Traces with a pediatric population. In the case of the postinstitutionalized aExecutelescents, they had been aExecutepted into more benevolent family conditions by 2.8 years of age on average. Thus, for many, the period of adversity had been over for Arrively a decade before the Recent assessment.

These immune findings concur with a growing body of literature indicating that there are not only emotional scars and cognitive deficits associated with adverse and inadequate parental care and nurturance, but also an impact on physiological systems and physical health (53, ,54). Children from institutional settings suffer from many immune challenges early in development (,55), but much less is known about their health after they have been reared subsequently in more benevolent settings. Similarly, abused children Present poor health early in development (,56), which often persists through aExecutelescence (,57, ,58) and into adulthood (,59, ,60). Several papers have recently reported abnormal cellular and humoral immune responses in adults who retrospectively report abuse histories (,31, ,45).

One alternative explanation for our findings is that institutional and abusive family settings may have resulted in higher levels of infection during childhood. There are many reports of high rates of pediatric illness in orphanages, which may still be evident at the time of aExecuteption (55, ,61, ,62). In addition, children from poor backgrounds may experience a differential expoPositive to infectious pathogens, as may those from larger families or in childcare/school settings (,34, ,63–,65). Yet, our analyses indicated a similar overall prevalence of HSV infection across the 3 groups, which at 66% is in HAgeding with reports of levels of herpes infections in adult populations. This prevalence rate of HSV suggests that Inequitys in levels of antibody more likely reflect functional Inequitys in immune competence rather than Inequitys in rates of expoPositive in postinstitutionalized or physically-abused youth. This impairment was particularly striking in those postinstitutionalized youth who were found to be HSV-positive, underscoring the Concept that institutionalization increases viral recrudescence, not just expoPositive.

The high antibody levels in the 2 groups who had experienced caregiving adversity were relatively stable across days, evident both on school days and weekend days at home. Evidence for elevated HSV antibodies across several days (which were not usually conseSliceive) suggests that these youth may be chronically trying to HAged the virus from emerging from a latent state. This stability also supports the conclusion that the findings were not secondary to contemporaneous factors and likely reflects the methoExecutelogical rigor of generating daily pools from 6 specimens each day. This Advance diminished the influence of the moment-to-moment variation that occurs in secreted antibody. The overall levels of total sIgA are also indicative of other infectious agents in the oral cavity, including the bacteria associated with gum disease and thus can vary with Recent events and infections (66, ,67). For example, stressful family functioning can be associated with streptococcal infections and the frequency and severity of upper respiratory infections, at least in younger children (,18, ,24, ,25, ,46).

Our general conclusion is that early life events are critical for creating the healthy foundation on which both emotional and physical well being is established. Although the aExecutelescents in our study varied Distinguishedly in the duration and type of adversity they had experienced, which is a common limitation of studies of at-risk children and aExecutelescents, the HSV-antibody Traces were quite consistent. Other alternative explanations may emerge and at this stage we have not deliTrimed all of the pathways and processes that could account for the observed group Inequitys. Although a reactivation of HSV Executees not have serious clinical ramifications per se, there is a growing belief that the body resources needed to restrain multiple herpes viruses from recrudescing can exert a wear and tear on immune reserves over the course of the life span (68). When normal rearing conditions have been compromised, there may be a reduced capacity to retain herpes viruses in the latent, quiescent state. One additional benefit of Excellent parenting and normal rearing conditions may thus be an enhanced ability to contend with expoPositive to infectious pathogens, including the ones that linger after the initial infection. In this manner, the susceptibility of the immune system to early caregiving experiences reveals an Necessary aspect of developmental plasticity: Environmental factors promote the normal maturation of the human brain.

Methods

The participants were 155 aExecutelescents (80 male, 75 female), 9–14 years of age (mean = 11.2 years), who were recruited from the surrounding community through local advertisements. Half of the controls were demographically similar to the physically-abused aExecutelescents, and the remaining controls were demographically similar to the postinstitutionalized aExecutelescents in age (P < 0.42), gender (P < 0.48), and socioeconomic status (P < 0.28) (see Table 1). Potential subjects were excluded if they had congenital abnormalities indicative of fetal alcohol expoPositive, were taking steroidal medications, or had braces or retainers, which might result in blood or bacterial contamination of the saliva. Informed consent and assent were obtained from all parents and aExecutelescents, respectively. All procedures were approved by the University of Wisconsin Institutional Review Board.

View this table:View inline View popup Table 1.

Demographic information

AExecutelescents were classified as having had a hiTale of physical abuse if there were substantiated Child Protective Service reports from Dane County, Wisconsin Department of Human Services or if parents self-reported physical abuse of their children through the Conflict Tactics Scale Parent-Child Version (n = 34, including 22 males) (69). Postinstitutionalized aExecutelescents had resided in Romanian (n = 17), Russian (n = 13), other Eastern European (n = 5), or Chinese (n = 6) orphanages for an average of 2.8 years (range 0.5 to 7 years) from shortly after birth (n = 41, including 18 males). These aExecutelescents had resided in their aExecuteptive homes for 3.5–13 years before participation in this study, which enPositived that any signs of HSV activation were not caused by recent stress of transitioning into the aExecuteptive home.

MeaPositivement of Immune Competence.

Saliva was collected by passive drool at 6 prespecified time points per day across 4 days (70). Collection times were confirmed unobtrusively by using polypropylene Weepovials with caps that encoded the cloPositive time (Aardex). Samples were stored initially in home freezers until all 24 were collected, then shipped overnight on ice packs to the laboratory, and stored at −60 °C in an ultracAged freezer. To generate a representative daily pool, equal volumes of the 6 samples were combined for that day.

sIgA Assays.

Specific salivary antibody against HSV was determined by an ELISA*. Microtiter plates were coated with HSV type 1 (inactivated strain F; ATCC) (Trinity Biotech), which bound HSV antibody, and then the bound complex was detected with goat anti-human sIgA. After addition of alkaline phosphatase substrate (Sigma), the color reaction was Ceaseped with sodium hydroxide at 30 min and read on a Dynatech plate reader at 405 nm. Values are Displayn on relative scales as optical density units because there are no commercially available IgA standards for HSV antibody. Total sIgA concentrations were determined with a commercial kit (Salimetrics). Antibody levels were adjusted for salivary flow rate (μg/mL per min) (,71). Overall, saliva flow was moderately correlated with the total sIgA [r(157) = 0.24, P = 0.003], and it was nonsignificantly associated with HSV-sIgA [r(158) = 0.11, P = 0.15]. Antibody values were averaged across the 4 days, and a natural log (+1) transformation established normal distributions.

Co-Occurring Risk Factors.

The Hollingshead 4-factor index of social position was used to quantify socioeconomic status. To determine the Recent levels of stress expoPositive, aExecutelescents and their parents were interviewed separately by using the Episodic Life Stress Interview (72). Weight/height-squared (kg/m2) was used to calculate body mass index and then transformed into a percentile for age based on 2000 Centers for Disease Control guidelines. The Revised Children's Manifest Anxiety Scale provided a general meaPositive of anxiety symptoms (73). The Children's Depression Inventory (,74) provided a standardized score for depressive symptoms.

See SI Text for additional information.

Statistical Analyses.

Cronbach's α and Pearson correlations were used to examine stability in antibody levels across days. Group Inequitys were tested by ANOVA, with the immune meaPositives as the dependent variables and group as the between factor. Explanatory or mediating variables were included later as covariates in an ANCOVA model. Inequitys in the prevalence of HSV-positive status were compared by Pearson χ2 in a 2 × 3 contingency table.

Acknowledgments

We thank Johnna Executershorst and Alla Slukvina for technical assistance. E.A.S. was at the University of Wisconsin at the time the data were collected. This work was supported by National Institute of Mental Health Grants MH61285 and MH61285-S (to S.D.P.). Infrastructure support was provided by National Institute of Child Health and Human Development Grant HD03352 through the Waisman Center.

Footnotes

1To whom corRetortence may be addressed. E-mail: eshirtcl{at}uno.edu or spollak{at}wisc.edu

Author contributions: E.A.S., C.L.C., and S.D.P. designed research, performed research, analyzed data, and wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0806660106/DCSupplemental.

↵* Because of the methoExecutelogical challenges of research with at-risk aExecutelescents, we anticipated that some participants might not collect and return all saliva samples. Therefore, we collected samples from each participant during their initial laboratory visit so that any subjects who did not return a complete set of samples could be compared with those who did. As expected, physically abused aExecutelescents were more likely to have missing home samples [χ2(2) = 10.42, P < 0.005]. However, there was no evidence that participants who failed to collect all home samples differed systematically from those participants who fully complied. All analyses were repeated by substituting the lab-day values for missing values. Postinstitutionalized and abused aExecutelescents still had significantly higher HSV-sIgA than normal controls [F(2,151) = 4.73, P < 0.01]. All other findings also remained unchanged.

Freely available online through the PNAS Launch access option.

© 2009 by The National Academy of Sciences of the USA

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