O papel do estresse psicossocial na ativação imune durante o desenvolvimento na vida adulta

Abstract

Psychosocial stress has important role in activating endocrine, immune and central nervous systems. Stress exacerbates many chronic inflammatory conditions and is an important risk factor for several mood disorders. Early exposure to stress can be even more detrimental as it may lead to alterations in stress reactivity/responsivity later in life. Several studies have shown important neuroimmune changes associated with the pathophysiology of mood disorders. Previous studies from our group and others reported a pro‐inflammatory profile and increased cellular activation in patients with bipolar disorder (BD). The objectives of the thesis are: 1) to analyze the stress effects on development using animal model of early life stress (maternal separation); 2) to analyze the neuroimmunendocrine responses to acute stress exposure (Trier Social Stress Test) in BD patients. Data presented here suggests that early life stress results in immune activation, characterized by increased pro‐inflammatory serum levels (specifically IL1‐β). As a consequence of this inflammation, a reduction of parvalbumin containing interneurons, substantial for serotonergic branches development, was also observed. Peripheral inflammation is a biological marker of neuronal damage observed, as interleukin‐10 (IL‐10, main anti‐inflammatory cytokine) central administration overturned the neuronal damages as well as peripheral inflammation per se. In the second study, patients with BD showed blunted sympathetic and neuroendocrine (cortisol) stress responses following acute stress compared to healthy controls. Basal data corroborates the presence of increased cellular activation in BD patients as observed by reduced T regulatory (Treg) cells, increased activated T cells (CD4+CD25+) as well as increased intracellular signaling through increased ERK1/2 and NF‐κB phosphorylation. Furthermore, an inability in reducing immune activation in response to stress was observed as increased percentage of activated T cells and concomitantly reduction in regulatory T cells in BD patients. Such inability in controlling immune response after stress exposure may be explained not only by reduced cortisol levels but also by reduced glucocorticoid sensitivity observed in BD patients. Given that, we conclude that BD patients have important HPA axis alterations that may lead to reduced endocrine reactivity to stress as well as inability to duly modulate immune responses.