Social stress induces autoimmune responses against the brain

Significance

Patients with stress-related disorders, including depression, show high prevalence rates for autoimmune diseases. To explore the relationship between stress and autoimmunity, we analyzed blood and brain samples from socially stressed mice and patients with major depressive disorder. Stress-susceptible mice showed elevated serum antibody levels and induction of antibody responses in brain-draining lymph nodes. Brain-reactive antibodies were produced in stressed mice and antibody concentrations in the brain correlated with depression-like behavior. Similarly, brain-reactive antibody levels in clinical sera were associated with anhedonia severity. Depletion of antibody-producing cells from mice resulted in stress resilience, confirming the contribution of antibody responses to stress susceptibility. Mechanistic insights connecting stress-induced autoimmune responses against the brain may offer therapeutic strategies for stress-related disorders.

Abstract

Clinical studies have revealed a high comorbidity between autoimmune diseases and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes by which stress impacts the adaptive immune system and the implications of such responses to depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. We also confirm that social stress leads to the expansion of specific T and B cell populations within the cervical lymph nodes, where brain-derived antigens are preferentially delivered. Sera from stress-susceptible (SUS) mice exhibited high reactivity against brain tissue, and brain-reactive immunoglobulin G (IgG) antibody levels positively correlated with social avoidance behavior. IgG antibody concentrations in the brain were significantly higher in SUS mice than in unstressed mice, and positively correlated with social avoidance. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. In vivo assessment of IgG antibodies showed they largely accumulate around blood vessels in the brain only in SUS mice. B cell-depleted mice exhibited stress resilience following CSDS, confirming the contribution of antibody-producing cells to social avoidance behavior. This study provides mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses might aid in the treatment of patients with MDD featuring immune abnormalities.