In a recent study published in the journal Proceedings of the National Academy of Sciences (PNAS), researchers from the United States of America investigated the relationship between stress and autoimmunity by analyzing blood and brain samples from socially stressed mice as well as patients with major depressive disorder (MDD). They found that the mice showed increased serum antibody concentrations and brain-reactive antibodies correlating with depression-like behavior. Additionally, in humans, they found an association between higher peripheral levels of brain-reactive antibodies and increased anhedonia.
Study: Social stress induces autoimmune responses against the brain. Image Credit: Obak / Shutterstock
About 6% of adults in the world are affected by MDD, and about 33% of them are resistant to currently available treatments. There is an observed heterogeneity in MDD patients and a need for an improved mechanistic understanding of the causes of MDD. Evidence suggests that subsets of MDD patients show immune abnormalities. Stress is a significant risk factor for MDD that triggers inflammatory responses linked to depression in mice and humans. The chronic social defeat stress (CSDS) mouse model, dividing mice into stress-susceptible (SUS) and resilient (RES) categories, reflects key aspects of depression.
Although the involvement of the innate immune system in depression has been explored in depth previously, the role of adaptive immunity dysfunction and autoimmunity in depression pathogenesis remains to be understood. Therefore, researchers in the present study examined the potential link between stress, adaptive immune abnormalities, and depression using CSDS mice models and clinical samples from MDD patients.
About the study
The present study performed CSDS for 10 days on C57BL/6J mice of age 6–7 weeks. Social interaction (SI) testing was then performed on the mice, wherein stressed mice were classified as SUS or RES based on the SI ratio (ratio of the time of interaction in the presence and absence of a social target mouse). Immunoglobulin G (IgG) antibody concentrations were measured in sera using an enzyme-linked immunosorbent assay (ELISA).
Further, the researchers visualized the localization of antibody responses post-CSDS. Flow cytometry (FCM) was used to analyze follicular helper T-cells (Tfh), plasma cells (PC), and germinal center B-cells (GCB) in the mesenteric and cervical lymph nodes (mLN, cLN), and spleen (SPL) collected 48 h after CSDS.
To test the hypothesis that social stress triggers antibody responses against antigens expressed in the brain, the post-CSDS brain-reactive antibodies in sera were measured using ELISA. Samples from nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus (HIP) regions of the brain of immune-deficient Rag2−/− mice were collected and analyzed using indirect immunohistochemistry and Western blotting. To understand whether antibody responses relate to stress-susceptibility, B-cells were depleted before exposing mice to CSDS, and SI behavior was tested.
To test the clinical relevance of the findings, levels of IgG and brain-reactive antibodies were measured in the sera of healthy controls (HC) and MDD patients. Temporal Experience of Pleasure Scale (TEPS) was used to assess pleasure experience or anhedonia, and the scores were correlated with brain-reactive antibody levels in sera.
Results and discussion
During the SI test, as compared to unstressed control (CON) mice, both RES and SUS mice moved shorter distances when the social target mouse was absent, with no significant difference in locomotion in the two groups. These results corroborate findings from previous studies. Additionally, SUS mice showed increased levels of IgG in their sera as compared to CON mice, which correlated negatively with the SI ratio. This indicates that social stress induces an antibody response, potentially contributing to social avoidance behavior.
In the FCM analysis, cLN from SUS mice showed a significantly increased percentage of GCB and Tfh as compared to CON and RES. While PC was found to increase in all the lymphoid organs, they were 17 times higher in cLN than in other extracted organs. The findings suggest that CSDS triggers antibody responses in the brain-draining lymph nodes, especially in SUS mice.
Further, the sera from SUS mice showed greater brain reactivity than CON mice, correlating with social avoidance as well as PC levels in cLN. In the visualization study, the NAc regions of SUS mice showed higher fluorescence intensity than those of CON mice. Western blot analysis showed that stress autoantibodies had multiple protein targets within various brain regions. Brain lysates of SUS mice also showed increased IgG levels as compared to controls and correlated strongly with social avoidance behavior. Imaging and 3D reconstruction of the brain regions suggest that after CSDS, brain-reactive IgG antibodies accumulate in the neurovascular unit, potentially contributing to stress susceptibility. The higher SI ratio of B-cell-depleted mice suggests that B-cells contribute to stress susceptibility in the CSDS model.
No significant difference was observed in serum IgG levels between HC and MDD patients in the human sample analysis. However, a trend in brain-reactive IgG was observed for TEPS anticipatory and consummatory pleasure, warranting further research.
In conclusion, the findings of the present study highlight the role of the adaptive immune system in depression and the susceptibility to stress, possibly via autoantibody production. The results indicate the potential benefits of identifying disease-relevant autoantibodies in MDD patients, paving the way for therapeutic approaches to mitigate the symptoms of anhedonia.