The immune system may also play a role in mental disorders. Scientists are investigating these links with brain function in greater detail, and new findings show that immune changes may differ by disorder type.
A team involving researchers from Wroclaw Medical University analyzed studies of people with schizophrenia spectrum disorders and mood disorders, including depression and bipolar disorder. They found that the two groups showed distinct patterns of innate immune activity.
Today, we know much more about mental disorders than we did just a few decades ago. Researchers are examining numerous processes occurring throughout the body. One of them is immune system function.
Today, schizophrenia and depression are no longer viewed exclusively as disorders of the brain, as abnormal immune activation may also play an important role in some patients. It may affect neurotransmission, brain plasticity, and the body’s stress response. However, this does not mean that mental disorders are inflammatory diseases, explains Professor Błażej Misiak, MD, PhD, from the Department and Clinic of Psychiatry at Wroclaw Medical University.
The researchers focused on innate immunity, the part of the immune system that enables the body to respond rapidly to potential threats. Toll-like receptors (TLRs) play an important role in this process. They can be thought of as sensors: they recognize different signals and trigger an immune response.
TLRs sit at the beginning of the immune response cascade, making them particularly interesting in psychiatric research. Their activation triggers pathways leading, among other things, to the production of cytokines such as IL-6 and TNF-α, which have long been associated with mental disorders, explains Julia Karska, MD, from the Division of Consultation Psychiatry and Neuroscience, Department of Psychiatry at Wroclaw Medical University, and the first author of the publication.
The researchers pooled the results of 26 previous studies. Together, they included 678 people with schizophrenia spectrum disorders, 523 people with mood disorders and 1,182 healthy controls.
The analysis revealed differences between the groups. People with schizophrenia spectrum disorders had increased expression of TLR4, TLR8 and TLR10. In people with mood disorders, increased expression of TLR2, TLR5 and TLR6 was observed. Because individual receptors respond to different signals, these findings may indicate partially distinct mechanisms of innate immune activation.
Our study showed that schizophrenia spectrum disorders and mood disorders are associated with partially distinct patterns of expression of receptors involved in innate immunity. In schizophrenia spectrum disorders, expression of TLR4, TLR8 and TLR10 was increased, whereas in mood disorders this was the case for TLR2, TLR5 and TLR6, says Julia Karska, MD.
The findings help researchers describe the biological differences associated with individual disorders more precisely.
In our meta-analysis, we identified distinct patterns of innate immune receptor expression: TLR4, TLR8 and TLR10 in schizophrenia spectrum disorders, and TLR2, TLR5 and TLR6 in mood disorders. This suggests the existence of partially distinct immune “signatures”, although the observed differences were small and concerned peripheral blood, emphasizes Professor Błażej Misiak, MD, PhD.
Each TLR recognizes specific types of signals. For example, TLR4 responds to a component found in certain bacteria, while TLR8 recognizes single-stranded RNA. This allows scientists to investigate more precisely which immune response elements are associated with particular disorders.
Because individual TLRs recognize different signals, studying them provides more mechanistic insight into the observed immune changes. Peripheral TLR mRNA is also relatively easy to measure, making these receptors interesting candidates for further research into biomarkers and potential therapeutic targets, explains Julia Karska, MD.
In mood disorders, the increased expression of TLR2, TLR5 and TLR6 is particularly noteworthy. These receptors primarily recognize bacterial signals. This is one reason why the findings are also interesting in the context of research on the gut microbiota.
The distinct profiles are also consistent with hypotheses concerning, among other things, the microbiota-gut-brain axis and bacterial translocation, adds Julia Karska, MD.
This area requires further research. Based on the current findings, it is not possible to determine which specific factors led to the changes observed in the blood.
One goal of modern psychiatry is to understand biological diversity among patients better. People with similar symptoms may differ in the mechanisms associated with the development of their illness and in their response to treatment. In the future, immune profiles could become one source of such information. They could help identify groups of patients with similar biological characteristics.
Patients with similar symptoms may have different biological mechanisms and respond differently to treatment. In the future, immune profiles could complement psychiatric diagnosis and help identify more biologically homogeneous groups of patients, says Professor Błażej Misiak, MD, PhD.
For now, TLRs remain a subject of research. The meta-analysis included observational studies, and the differences identified were small. The authors also point to differences between individual studies in patient characteristics, disease course, treatment, and laboratory methods, among other factors.
Large longitudinal studies and clinical trials are needed to demonstrate that selecting treatment based on such markers actually improves its effectiveness. Our findings therefore point to a promising direction for developing precision psychiatry. Still, they do not yet provide a basis for routine TLR testing or the use of immunomodulatory treatment, emphasizes Professor Błażej Misiak, MD, PhD.
Further research should help determine how stable the observed immune profiles are, what they are associated with, and whether they may be relevant to disease course and treatment response. The authors point, among other things, to the need for longitudinal studies, functional analyses of the immune system, multi-omics studies and neuroimaging.
If their clinical significance is confirmed, immune system “signatures” could become another source of information that helps researchers better understand biological differences between patients.
The immune system has at least 10 types of TLRs. Each is specialized in recognizing specific signals.
TLR4 can recognize a bacterial component, while TLR8 responds, among other things, to single-stranded RNA. This enables the body to trigger a response tailored to the type of signal detected.
The gut and the brain are in constant communication, and the immune system is one of the mediators of this interaction. This is why mental health research is increasingly investigating the microbiota.
Scientists can study immune changes using a blood sample. TLR mRNA expression in blood is one tool they use to investigate biological differences between patient groups.
The future of psychiatry may also involve immunophenotyping, describing patients based on characteristic features of their immune system. This is one area currently being explored in precision psychiatry.
Brain Behavior and Immunity
Systematic review
People
Peripheral toll-like receptor expression indicates distinct innate immune signatures in schizophrenia spectrum and mood disorders: A systematic review and meta-analysis
30-Nov-2026
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.