How do immune cell glucocorticoid responses contribute to psychiatric and autoimmune disorders?
How do immune cell glucocorticoid responses contribute to psychiatric and autoimmune disorders?
It is clear that stress responses and immunity are closely entwined, and epidemiological research shows that their complex interplay is key to the development of both psychiatric and autoimmune disorders (Teicher 2013 PMID:23982148, Dube 2009 PMID: 19188532). For example, a major component of the stress response is cortisol release, and depression is associated with hypercortisolaemia and glucocorticoid (GC) resistance. Abnormal responses to GCs likely contribute to the chronic inflammation observed in many patients with depression, as GCs can prime inflammatory responses, and GC-resistant immune cells produce increased levels of pro-inflammatory cytokines. Cytokines can act on the brain to produce the sickness-like behaviours characteristic of depression, and other aspects of GC-induced immune dysregulation (e.g. effects on neutrophils) may also play a role. Epidemiological studies show that psychological stress interacts with genetic risk to lead to depression and psychosis (e.g. Wang 2023 PMID:36717542), but the risk variants involved and the cellular mechanisms of this effect are unknown. We hypothesize that some risk variants for psychiatric disorders act through glucocorticoid responsive regulatory elements in specific immune cell subsets to lead to symptoms. We further hypothesize that by dissecting the cell subset- and context-specific effects of glucocorticoids in health and in patients, we can develop a better biomarker of impaired neuroendocine signalling in psychiatric disorders, opening the door to biomarker development and more personalised approaches to treatment in stress-responsive autoimmune and psychiatric disorders.
You would work with Dr Luis M. Franco and Dr Mary-Ellen Lynall to investigate these hypotheses using immunogenetic and functional genomic techniques, gaining training in cutting edge bioinformatics, statistical genetics, immunology, clinical phenotyping, and (if desired) wet-lab experimental approaches. You would integrate emerging genetic association results in autoimmune and psychiatric disorders with (a) in-house glucocorticoid-response datasets (see https://www.niams.nih.gov/labs/franco-lab) (b) healthy and patient bulk and single cell datasets from our laboratories.
Dr Franco's group in the Functional Immunogenomics Section at the NIAMS focuses on the immunobiology of glucocorticoid responses (e.g. Franco 2019 PMID:30674564).
Dr Lynall's group in the Dept of Psychiatry at Cambridge focuses on immunogenetic analyses and immunophenotyping in psychiatric patients and population cohorts (e.g. Lynall 2022 PMID:36243721).