Multiple psychiatric disorders have been associated with abnormalities in the immune system. As I summarise in my opening chapter (Chapter 1), evidence from human and animal studies suggests that the immune system may be implicated in the pathogenesis of these disorders, at least in a subset of patients. However, the direct evidence for a causal role of immune mechanisms is limited. Moreover, there are currently no good biomarkers that allow us to identify which patients with psychiatric disorders have immune dysfunction, and thus might benefit from alternative treatment approaches. I outline the limits of what is known about the causality of immune dysfunction in psychiatric disorders from the existing literature, much of which focuses on soluble biomarkers in peripheral blood in observational case-control studies. This stimulates consideration of more mechanistically refined biomarkers, with a focus on which immune cell subsets, and what cellular mechanisms, might play a causal role in psychiatric symptoms. In this thesis, I use human genetic data, human immunophenotyping and animal models to investigate whether psychiatric disorders and stress are associated with dysfunction in particular immune cell subsets, and the evidence for a causal, pathogenic role of different immune cells.

In Chapter 2 I describe an analysis of a flow cytometry study of peripheral immune cell subsets in people with depression and age- and sex-matched controls. I used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity. I found that depressed cases, compared to controls, had significantly increased immune cell counts, especially neutrophils, CD4+ T cells and monocytes, and increased inflammatory proteins. Depressed cases were partitioned into two subgroups by forced binary clustering of cell counts: the inflamed depression subgroup had increased myeloid and lymphoid cell counts, increased CRP and IL-6, and was more depressed than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified four subgroups of depressed cases: two of which were associated with increased inflammatory proteins and more severe depression, but differed in terms of myeloid and lymphoid cell counts, raising the possibility that there may be more than one type of ‘inflamed depression’.

Stress is one putative cause of immune dysfunction contributing to the pathogenesis of multiple psychiatric disorders, and recent work has highlighted the potential role of the meningeal compartment of the immune system in behaviour. As described in Chapter 3, I used an animal model to investigate the effects of stress on the peripheral and meningeal immune compartments (the latter being poorly accessible in humans). Using flow cytometry and transcriptomic (including single cell) analyses, I demonstrated dysregulation of both myeloid and lymphoid immune cells in the periphery and meninges, and showed that B cells may influence behaviour by regulating meningeal myeloid cell activation.

In Chapter 4, I investigated the implications of genome wide association studies (GWAS) of psychiatric disorders for cellular immunity. I tested for enrichment of GWAS variants associated with multiple psychiatric disorders (cross-disorder or trans-diagnostic risk), and 5 specific disorders (cis-diagnostic risk), in regulatory elements in immune cells. For this analysis, I used three independent epigenetic datasets representing multiple organ systems and immune cell subsets. Trans-diagnostic and cis-diagnostic risk variants (for schizophrenia and depression) were enriched at epigenetically active sites in brain tissues and in lymphoid cells (T, B and NK cells), especially stimulated CD4+ T cells. There was no evidence for enrichment of either trans-risk or cis-risk variants for schizophrenia or depression in myeloid cells. This suggests a model where stimuli, e.g., stress or infection, activate T cells to unmask the effects of psychiatric risk variants, contributing to the pathogenesis of mental health disorders.

In summary, the results from the human studies highlight the involvement of both the innate and adaptive immune system in psychiatric disorders. They further suggest that there are likely both shared and distinct contributions of cellular immunity to the pathogenesis of different psychiatric disorders. The results from the mouse model support the role of psychological stress in contributing to immune abnormalities in psychiatric disorders and suggest that the effects of stress may in part be mediated by stress-induced alterations in the meningeal immune system. These results are summarised in a concluding chapter (Chapter 5) which highlights outstanding questions, and priorities for future research, in the current understanding of the role of the immune system in mental health disorders.