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Phenotype and Mechanisms of Altered Immune Functions induced by Early Life Adversity

Phänotyp und Mechanismen veränderter Immunfunktionen, induziert durch traumatische Erfahrungen in der frühen Kindheit

  • Early life adversity (ELA) is associated with a higher risk for diseases in adulthood. Changes in the immune system have been proposed to underlie this association. Although higher levels of inflammation and immunosenescence have been reported, data on cell-specific immune effects are largely absent. In addition, stress systems and health behaviors are altered in ELA, which may contribute to the generation of the "ELA immune phenotype". In this thesis, we have investigated the ELA immune phenotype on a cellular level and whether this is an indirect consequence of changes in behavior or stress reactivity. To address these questions the EpiPath cohort was established, consisting of 115 young adults with or without ELA. ELA participants had experienced separation from their parents in early childhood and were subsequently adopted, which is a standard model for ELA, whereas control participants grew up with their biological parents. At a first visit, blood samples were taken for analysis of epigenetic markers and immune parameters. A selection of the cohort underwent a standardized laboratory stress test (SLST). Endocrine, immune, and cardiovascular parameters were assessed at several time points before and after stress. At a second visit, participants underwent structural clinical interviews and filled out psychological questionnaires. We observed a higher number of activated T cells in ELA, measured by HLA-DR and CD25 expression. Neither cortisol levels nor health-risk behaviors explained the observed group differences. Besides a trend towards higher numbers of CCR4+CXCR3-CCR6+ CD4 T cells in ELA, relative numbers of immune cell subsets in circulation were similar between groups. No difference was observed in telomere length or in methylation levels of age-related CpGs in whole blood. However, we found a higher expression of senescence markers (CD57) on T cells in ELA. In addition, these cells had an increased cytolytic potential. A mediation analysis demonstrated that cytomegalovirus infection " an important driving force of immunosenescence " largely accounted for elevated CD57 expression. The psychological investigations revealed that after adoption, family conditions appeared to have been similar to the controls. However, PhD thesis MMC Elwenspoek 18 ELA participants scored higher on a depression index, chronic stress, and lower on self-esteem. Psychological, endocrine, and cardiovascular parameters significantly responded to the SLST, but were largely similar between the two groups. Only in a smaller subset of groups matched for gender, BMI, and age, the cortisol response seemed to be blunted in ELA participants. Although we found small differences in the methylation level of the GR promoter, GR sensitivity and mRNA expression levels GR as well as expression of the GR target genes FKBP5 and GILZ were similar between groups. Taken together, our data suggest an elevated state of immune activation in ELA, in which particularly T cells are affected. Furthermore, we found higher levels of T cells immunosenescence in ELA. Our data suggest that ELA may increase the risk of cytomegalovirus infection in early childhood, thereby mediating the effect of ELA on T cell specific immunosenescence. Importantly, we found no evidence of HPA dysregulation in participants exposed to ELA in the EpiPath cohort. Thus, the observed immune phenotype does not seem to be secondary to alterations in the stress system or health-risk behaviors, but rather a primary effect of early life programming on immune cells. Longitudinal studies will be necessary to further dissect cause from effect in the development of the ELA immune phenotype.

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Author:Martha Maria Christine Elwenspoek
Advisor:Claude P. Muller
Document Type:Doctoral Thesis
Date of completion:2018/07/05
Publishing institution:Universität Trier
Granting institution:Universität Trier, Fachbereich 1
Date of final exam:2018/02/07
Release Date:2018/07/05
Tag:Immunfunktion; Mechanismen; traumatische Erfahrungen
early life adversity; immune system; stress
GND Keyword:Kind; Phänotyp
Institutes:Universitätsbibliothek / Universitätsbibliothek
Dewey Decimal Classification:1 Philosophie und Psychologie / 15 Psychologie / 150 Psychologie

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