Immunophenotypes in psychosis: is it a premature inflamm-aging disorder?

Abstract

Immunopsychiatric field has rapidly accumulated evidence demonstrating the involvement of both innate and adaptive immune components in psychotic disorders such as schizophrenia. Nevertheless, researchers are facing dilemmas of discrepant findings of immunophenotypes both outside and inside the brains of psychotic patients, as discovered by recent meta-analyses. These discrepancies make interpretations and interrogations on their roles in psychosis remain vague and even controversial, regarding whether certain immune cells are more activated or less so, and whether they are causal or consequential, or beneficial or harmful for psychosis. Addressing these issues for psychosis is not at all trivial, as immune cells either outside or inside the brain are an enormously heterogeneous and plastic cell population, falling into a vast range of lineages and subgroups, and functioning differently and malleably in context-dependent manners. This review aims to overview the currently known immunophenotypes of patients with psychosis, and provocatively suggest the premature immune "burnout" or inflamm-aging initiated since organ development as a potential primary mechanism behind these immunophenotypes and the pathogenesis of psychotic disorders.

Fig. 1. Immunophenotypes in psychosis.

There are two facets of mismatched systemic changes of immune cells in patients of psychosis. On one facet, blood cytokines and numbers of leukocytes and their innate subsets such as neutrophils and monocytes are increased while activation of innate cells including monocytes and innate lymphoid cells such as NK cells after stimulation are decreased. On the other facet, the mononuclear phagocytic system inside and outside the brain, such as microglia and monocytes, are not synchronically activated in psychosis. That is, there is no overt activation of myeloid cells in the psychotic brain as compared to the immune changes observed in the blood and CSF. α7nAChR α7 nicotinic acetylcholine receptor, CD cluster of differentiation, CRHM1 cholinergic receptor muscarinic 1, CRP C-reactive protein, CSF cerebrospinal fluid, FEP first-episode psychosis, GAD glutamic acid decarboxylase, HLA human leukocyte antigen, HMGB1 high mobility group box 1, IBA1 ionized calcium-binding adapter molecule 1, IFN interferon, IL interleukin, MLR monocyte to lymphocyte ratio, NK natural killer, NLR neutrophil to lymphocyte ratio, NMDAR N-methyl-D-aspartate receptor, S100B S100 calcium-binding protein B, TGF transforming growth factor, TNF tumor necrosis factor, TSPO translocator protein. Green arrows represent no change, blue arrows represent downregulation, and red arrows indicate upregulation.

Fig. 2. A comparison of inflamm-aging phenotypes and psychoimmunophenotypes.

There are both similarities and differences between inflamm-aging and psychoimmunophenotypes. Inflamm-aging is a coin with two sides, e.g., increased myelopoiesis with concomitant decreased lymphopoiesis during aging. At cellular levels, innate immune cells are in a tonic-activated state producing more proinflammatory mediators including free radicals and proinflammatory cytokines. However, when they are stimulated, they cannot react anymore and become paralyzed/non-functional. Simultaneously, adaptive immune cells show decreased numbers of naïve T-cells with concomitant increased proportion of memory T-cells, but they are malfunctional in proliferation, migration, cytokine production, and pathogens killing. In psychosis, while the numbers of WBCs and some of their subsets including neutrophils and monocytes as well as some cytokines are increased, activation of innate cells such as monocytes and NK cells are decreased. Moreover, increase in production and release of autoantibodies as a characteristic of immunosenescence, has also been found in some patients with psychosis. DCs dendritic cells, HSC hematopoietic stem cell, IFN interferon, IL interleukin, MdMs monocyte-derived macrophages, NK natural killer, ROS reactive oxygen species, TGF transforming growth factor, TNF tumor necrosis factor, TSPO translocator protein. Green arrows represent no change, blue arrows represent downregulation, and red arrows indicate upregulation.

Fig. 3. Proposed inflamm-aging-associated mechanisms underlying the pathogenesis of psychosis and comorbidities.

Inflamm-aging-like changes caused by genetic and epigenetic predisposition combined with environmental risk factors may play a central role in contributing to physical aging and brain aging, which leads to psychiatric disorders and commonly associated cardio-metabolic diseases in patients. HPA: Hypothalamus-pituitary gland-adrenal gland. blue arrows represent downregulation and red arrows indicate upregulation.