Generalized Anxiety Disorder Linked to High IFN

Generalized Anxiety Disorder Linked to High IFN-γ and TNF-α but Low IL-10 Peripheral Levels

Generalized Anxiety Disorder – High IFN-γ and TNF

A recent Brain, Behavior, and Immunity study provides perhaps the first evidence that Generalized Anxiety Disorder (GAD) is associated with a peripheral imbalance of pro- versus anti- inflammatory cytokines such as interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-10.

Generalized anxiety disorder classified since the 1980s in the Diagnostic and Statistical Manual of Mental Disorder is characterized by excessive, uncontrollable and often irrational worry about events or activities, which affect around 6.8 million adults or 3.1 percent of the U.S. Population.

Evidence accumulated over the last decades indicates the pivotal roles of cytokine signalling to the brain to produce neurochemical, neuroendocrine, neuroimmune, and behavioural changes. The presence of inflammatory responses, and in particular, the role of cytokines in major depression has been addressed in numerous studies. However, neuroinflammatory markers in anxiety disorders have been studied less extensively.

Since signs of immune disturbances in depression were first reported in early 1990s the presence of inflammatory responses and the role of cytokines in major depression have been extensively studied. The high comorbidity of anxiety disorders and major depression and similar effects of antidepressants suggest common neurobiological substrates.

Major depression is the principal comorbidity of GAD. After the first reports by Maes et al. about immune dysfunction in the early 1990s, the role of chronic low-grade inflammation and immune dysregulation in depression is well characterized. Little is known, however, about the possible relation between anxiety and inflammation.

In the case control study, published in Brain, Behavior, and Immunity, Ruihua Hou and colleagues, from the Faculty of Medicine, University of Southampton, UK analyzed the pro- and anti- inflammatory cytokine profiles, including serum levels of IFN-γ and TNF-α, and IL-10 in patients with a primary diagnosis of GAD.

IFN-γ is crucial for the activation of the immune system against intracellular pathogens and for antitumor immunity, whereas TNF-α is a major pro-inflammatory cytokine, involved in the acute phase reaction. The type 1 or T helper (Th)1-related cytokines such as IFN-γ and TNF-α also stimulate the synthesis of nitric oxide and other inflammatory mediators that drive chronic delayed type inflammatory responses.

On the other hand, IL-10 is a potent anti-inflammatory cytokine that down-regulates Th1 responses but potentiates humural immunity and Th2 responses, directed against extracellular pathogens and involved in allergic conditions.

Hou R et al. found that patients with GAD, after controlling for age, gender, and BMI, had high levels of IFN-γ and TNF-α, but low IL-10 serum levels when compared to healthy control subjects. These differences remained statistically significant after adjustment for co-morbid depression. Thus, the authors speculate that the inflammatory response in patients with GAD is specific for this pathology.

The study demonstrates a distinct cytokine anxiety phenotype independent of the presence and degree of depression as well as an altered cytokine balance in patients with generalized anxiety disorder. The authors suggest that the pro-inflammatory state is related to altered activity of an enzyme involved in the metabolism of tryptophan, leading to degradation of serotonin in patients with GAD, with a mechanism similar to the one observed in major depression.

It appears that this is the first case-controlled study identifying altered pro- and anti-inflammatory cytokine profiles in patients with GAD. Further studies may be useful to clarify some unresolved issues, such as what is the cellular source of these cytokines, and if there are other cytokines, which may have important roles in this disease.

Additionally, better understanding of the mechanisms by which cytokines act as intermediaries between the central nervous and the immune systems, could contribute to the discovery of new biomarkers and perhaps providing the basis for the development of new therapeutic approaches for anxiety.

Source: Brain Behav Immun, 2017 Feb 1. pii: S0889-1591(17)30021-1. doi: 10.1016/j.bbi.2017.01.021.
Read more: Brain, Behavior, and Immunity

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