The researchers found that participants with MDD and low levels of CRP still had significantly higher expression of immune genes compared to those without a depression diagnosis. Credit: Neuroscience News
Summary: A new study uncovers more about the link between the immune system and Major Depressive Disorder (MDD). The research reveals that a higher proportion of MDD patients than previously believed may have an immune component to their condition.
By analyzing the expression of 16 immune-related genes, the study highlights immune activation in many depressed patients, even those not identified through traditional inflammation markers like C-reactive protein (CRP). These findings could lead to more personalized treatment strategies for depression.
The study found increased expression of immune-related genes in people with MDD, suggesting that an activated immune system might be more prevalent in MDD patients than previously estimated.
The immune gene expression was observed independently of CRP levels, implying a broader immune response that isn’t captured by typical inflammation markers.
This research could pave the way for more personalized treatment of MDD, as it broadens the understanding of different immune responses in depressed patients.
Source: King’s College London
New research from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London has used an assessment of gene expression involved in the immune response to show that there could be more patients with MDD with activated immune systems than research has previously estimated.
By identifying the molecular mechanisms involved in this association, the research could pave the way to better identify those patients with an immune component to their depression which would potentially help to provide more personalized approaches to treatment and management of MDD.
The research, published in Translational Psychiatry and funded by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC) and a Wellcome Trust strategy award, builds on previous findings that there is an activated immune response in many people with MDD.
However, most of the research in this area has focussed on the levels of inflammation related proteins like C-reactive protein (CRP). Studies using CRP have found that about 21 to 27 % of people with depression have an activated immune response1 but CRP levels do not capture the complete picture of the immune response.
This new study set out to observe broader immune related characteristics that are not captured by CRP levels.
168 participants were sourced from the Biomarkers in Depression Study (BIODEP). 128 of them had a confirmed diagnosis of MDD and they were then divided into three subgroups according to their levels of CRP in the blood.
Researchers analysed the expression of 16 genes whose activation is involved in the immune response. Gene expression is the initial stage of the process by which the information present in our genes influences our features and behaviour.
The initial analysis found increased expression of immune-related genes in people with MDD compared to the those without a diagnosis of depression.
When comparing MDD patients who did and didn’t have elevated levels of CRP in their blood, there were no differences in the expression of these 16 genes, suggesting this pattern of expression was independent of CRP levels and potentially underlying a different mechanism.
Importantly, researchers then conducted a secondary analysis on all those participants (both with and without a diagnosis of MDD) who had CRP values of less than 1, meaning that they are not considered to have any inflammation.
The researchers found that participants with MDD and low levels of CRP still had significantly higher expression of immune genes compared to those without a depression diagnosis.
Professor Carmine Pariante, Professor of Biological Psychiatry at King’s IoPPN and the study’s senior author said, “Previous research into this field has had a significant focus on C-reactive protein (CRP) levels within people with MDD which is a known marker for inflammation but just part of the immune response.
“Our study has successfully broadened this focus and shown that there is an immune response in the genes of those with MDD that is independent of CRP levels and, crucially, even in those where inflammation is not captured by measuring CRP.
“This means that increased immune activation is present in many more depressed patients than originally thought.”
“These important findings will allow us to identify the molecular pathways involved in depression and also help to more accurately identify those who have different types of immune responses which could pave the way for more personalised approaches to treatment.”
Dr Luca Sforzini, the study’s first author from King’s IoPPN said, “This evidence contributes to strengthen our knowledge on immune-related depression.
“Notably, people with depression and immune alterations are less likely to respond to standard antidepressant medications and may benefit from specific interventions targeting the immune system.
“I am hopeful these findings will aid current and future research in better characterizing individuals with depression based on their immunobiological profiles, offering more effective clinical strategies to a large number of people who are not benefitting from current antidepressants.”
The evidence of an immune-related predisposition in people with depression irrespective of their levels of inflammation as routinely measured can extend our concept of immune related depression.
This work was supported by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC) and a Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium (104025/Z/14/Z).
Higher immune-related gene expression in major depression is independent of CRP levels: results from the BIODEP study
Compelling evidence demonstrates that some individuals suffering from major depressive disorder (MDD) exhibit increased levels of inflammation.
Most studies focus on inflammation-related proteins, such as serum or plasma C-reactive protein (CRP). However, the immune-related modifications associated with MDD may be not entirely captured by CRP alone.
Analysing mRNA gene expression levels, we aimed to identify broader molecular immune-related phenotypes of MDD.
We examined 168 individuals from the non-interventional, case–control, BIODEP study, 128 with a diagnosis of MDD and 40 healthy controls. Individuals with MDD were further divided according to serum high-sensitivity (hs)CRP levels (n = 59 with CRP <1, n = 33 with CRP 1–3 and n = 36 with CRP >3 mg/L).
We isolated RNA from whole blood and performed gene expression analyses using RT-qPCR. We measured the expression of 16 immune-related candidate genes: A2M, AQP4, CCL2, CXCL12, CRP, FKBP5, IL-1-beta, IL-6, ISG15, MIF, GR, P2RX7, SGK1, STAT1, TNF-alpha and USP18. Nine of the 16 candidate genes were differentially expressed in MDD cases vs. controls, with no differences between CRP-based groups. Only CRP mRNA was clearly associated with serum CRP.
In contrast, plasma (proteins) IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-16, IL-17A, IFN-gamma and TNF-alpha, and neutrophils counts, were all differentially regulated between CRP-based groups (higher in CRP >3 vs. CRP <1 and/or controls), reflecting the gradient of CRP values.
Secondary analyses on MDD individuals and controls with CRP values <1 mg/L (usually interpreted as ‘no inflammation’) confirmed MDD cases still had significantly different mRNA expression of immune-related genes compared with controls.
These findings corroborate an immune-related molecular activation in MDD, which appears to be independent of serum CRP levels.
Additional biological mechanisms may then be required to translate this mRNA signature into inflammation at protein and cellular levels. Understanding these mechanisms will help to uncover the true immune abnormalities in depression, opening new paths for diagnosis and treatment.