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Link between stress and autoimmunity: Latest insights into depression from mice to humans

In a recent study published within the journal Proceedings of the National Academy of Sciences (PNAS), researchers from the US of America investigated the connection between stress and autoimmunity by analyzing blood and brain samples from socially stressed mice in addition to 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. Moreover, 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

Background

About 6% of adults on this planet are affected by MDD, and about 33% of them are immune to currently available treatments. There may be an observed heterogeneity in MDD patients and a necessity for an improved mechanistic understanding of the causes of MDD. Evidence suggests that subsets of MDD patients show immune abnormalities. Stress is a major 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 points 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 stays to be understood. Due to this fact, researchers in the current study examined the potential link between stress, adaptive immune abnormalities, and depression using CSDS mice models and clinical samples from MDD patients.

In regards to the study

The current 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 within the presence and absence of a social goal 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 research follicular helper T-cells (Tfh), plasma cells (PC), and germinal center B-cells (GCB) within the mesenteric and cervical lymph nodes (mLN, cLN), and spleen (SPL) collected 48 h after CSDS.

To check the hypothesis that social stress triggers antibody responses against antigens expressed within 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 grasp whether antibody responses relate to stress-susceptibility, B-cells were depleted before exposing mice to CSDS, and SI behavior was tested.

To check the clinical relevance of the findings, levels of IgG and brain-reactive antibodies were measured within the sera of healthy controls (HC) and MDD patients. Temporal Experience of Pleasure Scale (TEPS) was used to evaluate pleasure experience or anhedonia, and the scores were correlated with brain-reactive antibody levels in sera.

Results and discussion

In the course of the SI test, as in comparison with unstressed control (CON) mice, each RES and SUS mice moved shorter distances when the social goal mouse was absent, with no significant difference in locomotion within the two groups. These results corroborate findings from previous studies. Moreover, SUS mice showed increased levels of IgG of their sera as in comparison with CON mice, which correlated negatively with the SI ratio. This means that social stress induces an antibody response, potentially contributing to social avoidance behavior.

Within the FCM evaluation, cLN from SUS mice showed a significantly increased percentage of GCB and Tfh as in comparison with CON and RES. While PC was found to extend in all of the lymphoid organs, they were 17 times higher in cLN than in other extracted organs. The findings suggest that CSDS triggers antibody responses within 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 in addition to PC levels in cLN. Within the visualization study, the NAc regions of SUS mice showed higher fluorescence intensity than those of CON mice. Western blot evaluation showed that stress autoantibodies had multiple protein targets inside various brain regions. Brain lysates of SUS mice also showed increased IgG levels as in comparison with 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 within the neurovascular unit, potentially contributing to emphasize susceptibility. The upper SI ratio of B-cell-depleted mice suggests that B-cells contribute to emphasize susceptibility within the CSDS model.

No significant difference was observed in serum IgG levels between HC and MDD patients within the human sample evaluation. Nevertheless, a trend in brain-reactive IgG was observed for TEPS anticipatory and consummatory pleasure, warranting further research.

Conclusion

In conclusion, the findings of the current study highlight the role of the adaptive immune system in depression and the susceptibility to emphasize, possibly via autoantibody production. The outcomes indicate the potential advantages of identifying disease-relevant autoantibodies in MDD patients, paving the best way for therapeutic approaches to mitigate the symptoms of anhedonia.

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