Inflaming sex differences in mood disorders

Abstract

Men and women often experience different symptoms or rates of occurrence for a variety of mood disorders. Many of the symptoms of mood disorders overlap with autoimmune disorders, which also have a higher prevalence in women. There is a growing interest in exploring the immune system to provide biomarkers for diagnosis of mood disorders, along with new targets for developing treatments. This review examines known sex differences in the immune system and their relationship to mood disorders. We focus on immune alterations associated with unipolar depression, bipolar depression, and anxiety disorders. We describe work from both basic and clinical research examining potential immune mechanisms thought to contribute to stress susceptibility and associated mood disorders. We propose that sex and age are important, intertwined factors that need to be included in future experimental designs if we are going to harness the power of the immune system to develop a new wave of treatments for mood disorders.

Fig. 1

Genetic and hormonal sex contributes to differences in the immune system. Multiple immune genes such as CXCR3 and CD40LG on the X chromosome escape inactivation resulting in dosage effects. Other genes such as the Wiskott-Aldrich syndrome (WAS) can undergo mutations resulting in male-specific compromise of the immune system. In males, the gene Sry on the Y chromosome is a transcription factor that begins the process of testis differentiation. Testosterone, synthesized and diffused from the testis, acts on androgen receptors to induce apoptosis of stem cells in the bone marrow niche, resulting in reduced immune cells. Testosterone is also aromatized into estrogens to act on estrogen receptors in immune cells. Low levels of estrogens act on T cells to produce a skew toward an anti-inflammatory Th2 profile, whereas high levels of estrogens skew the population towards a Th1 pro-inflammatory profile

Fig. 2

Potential immune mechanisms of sex differences in mood disorders identified from pre-clinical studies of stress. There are sex differences in the populations of lymphocytes and leukocytes released from bone marrow. Females have more circulating leukocytes and lymphocytes than males. Females exhibit little or no glucocorticoid feedback on immune cell activation following stress, which may lead to a dysregulated ratio of pro-inflammatory to anti- inflammatory cytokines in the periphery. In the nucleus accumbens, Claudin-5 a tight junction protein is downregulated in patients with depression and male mice allowing increased permability of the blood brain barrier for cytokines and possibly monocytes and T cells. Within the brain, adult female rodents are reported to have more primed microglia than males, which may alter their activation by stress. In males only, stress increases spine density on medium spiny neurons in the nucleus accumbens