Psychoendocrine immunology of stress.
Aberrant glucocorticoid receptor levels are associated with stress-related disorders such as depression, and affect social behaviour, mood, learning and memory. Dissecting how tissue-specific GR levels are regulated, in particular in the brain, is the first step towards understanding the mechanisms underlying aberrant GR levels in disease and altered behaviour.
Over the last few years we have shown that the unique variability in the 5’ region of the GR gene, with 9 alternative first exons and 13 splice variants plays a critical role in transcriptional control maintaining homeostasis of the gluco-corticoid receptor (GR). This 5’mRNA heterogeneity, common to all species investigated, remains untrans-lated since the alternative first exons are spliced to exon 2 immediately upstream of the translation initia-tion codon. These alternative first exons are located either immediately upstream of the coding exons in the CpG island (exons B-H and J), or further upstream (exons 1A and 1I). The mechanisms regulating the differential usage of these first exons in different tissues and individuals, and the role of the 5’UTR in the splicing of the coding exons are still poorly understood. Data from our laboratory and others have shown that the multiple first exons represent only a first layer of complexity orchestrated probably by tissue-specific transcription factors. Modulation of alternative first exon activity by epigenetic methylation of their promoters represents a second layer of complexity at least partially controlled by perinatal programming. The alternative promoter usage also appears to affect the 3’ splicing generating the different GR coding variants, GRalpha, GRbeta, and GR-P.
The Department of Immunology is also a Department of the Graduate School for Psychobiology of the University of Trier. Within this academic collaboration, we contribute our expertise in immunology, molecular biology and cell biology, to investigate on a cellular level control mechanism of the main stress response system, the hypothalamic-pituitary-adrenal (HPA) axis and nuclear receptor functions in immune cells and beyond. According to EU and WHO estimates, stress represents the single most important cause of disease, causing costs as high as 3-4 % of the European gross national product. Many of these diseases are related to infections and aberrant immune reactions.
Perinatal Programming and Epigenetics of the Immune System
Perinatal programming refers to the concept that fetal or early postnatal environmental factors, such as nutrition, stress or infectious disease, have a considerable long-term impact on adult phenotype and disease susceptibility. Although initial studies focused on perinatal programming in cardiovascular or nervous systems, it has become clear that early environment may influence a large range of diseases and conditions, including disorders of the immune system. Recent evidence indicates that epigenetic mechanisms, such as methylation of CpG dinucleotides, are involved in the memorization of early-life events. We study the role of DNA methylation in immune cells and animal models, and identify genes responsible for early programming of the immune system.
Current studies in proteomics include:
- Proteomics combined with bioinformatic pathway analysis identified IFN type I and type II signalling pathways as principal targets of immunomodulatory effects of cortisol on LPS-activated macrophages. New isoforms of cortisol-sensitive IFN-inducible proteins were found such as for MX1 and SYWC.
- Proteomic profiling of non-genomic effects of cortisol in a rat model for acute stress revealed new insights in the early stages of a stress response. Nuclear translocated proteins identified belong mainly to transcriptional control and mRNA splicing/processing suggesting the preparation of the cell for a forthcoming transcription.
- Proteomics is also applied to investigate host virus interactions of strain variants; virus induced post translational modifications.