The concept of depression as a dysfunction of the immune system
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002174/?report=classic"Chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal axis and the immune system, acts as a trigger for anxiety and depression. Both experimental and clinical evidence shows that a rise in the concentrations of proinflammatory cytokines and glucocorticoids, as occurs in chronically stressful situations and in depression, contribute to the behavioural changes associated with depression.
A defect in serotonergic function is associated with hypercortisolaemia and the increase in proinflammatory cytokines that accompany depression. Glucocorticoids and proinflammatory cytokines enhance the conversion of tryptophan to kynurenine. In addition to the resulting decrease in the synthesis of brain serotonin, this leads to the formation of neurotoxins such as the glutamate agonist quinolinic acid and contributes to the increase in apoptosis of astrocytes, oligodendroglia and neurons.
The importance of the inflammation hypothesis of depression lies in raising the possibility that psychotropic drugs that have a central anti-inflammatory action might provide a new generation of antidepressants."
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"Until recently, the brain was considered to be an immunologically privileged organ that was protected from the peripheral immune system by the blood-brain-barrier. It is now apparent that this view is incorrect and that the brain is directly influenced by peripherally derived cytokines, chemokines, prostenoids and glucocorticoids, as well as some immune cells, that can access the brain and thereby influence those neuronal networks that appear to be malfunctioning in depression [9]. The influence of large molecules from the periphery on the brain is somewhat surprising as specific transporters for peptides such as the interleukins do not appear to be present at the blood-brain-barrier. Nevertheless, there is now experimental evidence to indicate that such molecules could access the brain a) via a leaky blood-brain-barrier that occurs in major depression, b)by activation of endothelial cells that line the cerebral vasculature and produce inflammatory mediators inside the barrier c)by binding to cytokine receptors associated with the vagus nerve and thereby signalling inflammatory changes in the brain via the nucleus tractus solitarius and hypothalamus [10,11]. Once in the brain, the proinflammatory cytokines activated both neuronal and non-neuronal (for example, the microglia, astrocytes and oligodendroglia) cells via the nuclear factor-kappa-beta (NF-kB) cascade in a similar manner to that occurring in the peripheral inflammatory response [12].
There is also evidence from clinical studies that peripherally administered cytokines can enter the brain. Thus the therapeutic administration of IFN to patients with hepatitis results in an increase in the cerebrospinal fluid (CSF) not only of IFN but also IL-6 and monocyte chemoattractant protein (MCP-1) [13]. In experimental studies it has been shown that MCP-1 activates microglia to release IL-1 and TNF [14] and as the microglia are the primary source of proinflammmatory cytokines in the brain this could be an important means whereby peripheral inflammatory mediators activate the inflammatory response in the brain. In addition, the proinflammatory cytokines modulate the release of biogenic amine neurotransmitters [15]. Recently much attention has been paid to the activation of the tryptophan-kynurenine pathway by these cytokines whereby tryptophan is shunted from the synthesis of serotonin to that of kynurenine. The importance of this pathway will be discussed in more detail later and clearly this is an important mechanism whereby serotonergic function is decreased in depression. The activity of the dopaminergic system is also reduced in response to inflammation. For example, IFN reduces the synthesis of dopamine by decreasing the concentration of the co-factor tetrahydrobiopterin (BH4), thereby reducing the synthesis of dihydroxyphenylalanine (DOPA), the immediate precursor of dopamine, from tyrosine [16]. As IFN increases the synthesis of nitric oxide by activating the BH4 dependent enzyme nitric oxide synthase in the microglia it seems likely that the reduction in dopaminergic function is linked to the increase in nitric oxide. This gaseous neurotransmitter is known to activate the glutamatergic system which, when this exceeds physiologically limits, enhances apoptosis and neurodegeneration [15,16].
Cytokines, and their signalling pathways, have been shown to enhance the re-uptake of monoamine neurotransmitters and thereby reduce their functionally important inter-synaptic concentrations in the brain [16,17]. For example,IL-1 and TNF have been shown to activate the serotonin transporter on neurons by stimulating the p38 mitogen activated protein kinase pathway [17]
In addition to the modulation of neurotransmitter function, proinflammatory cytokines contribute to the major symptoms of depression by activating the HPA axis by increasing the release of CRF, thereby contributing to hypercortisolaemia, a feature of major depression [18,19,20]. The mechanism whereby the cytokines induce hypercortisolaemia involves a decreased sensitivity of the glucocorticoid receptors thereby leading to glucocorticoid resistance; both the brain and the peripheral receptors become insensitive to glucocorticoid activation. The precise mechanism whereby the proinflammatory cytokines cause glucocorticoid receptor insensitivity is uncertain but it is known that the cytokines activate the inflammatory cascade. Thus the NF-kB, p38MAPK and the 5-STATS (signal transducer and activator of transcription 5) pathway is activated and leads to a disruption of the translocation of glucocorticoid receptors from the cytoplasm to the nucleus (21), thereby decreasing the active form of the receptor. While it would appear that glucocorticoid receptor resistance is correlated with the increase in the serum concentration of the proinflammatory cytokines, it seems unlikely that glucocorticoid resistance is directly related to the psychopathology of depression. Thus an increase in proinflammatory cytokines leading to glucocorticoid resistance also occurs in nondepressed individuals without any major change in the mood state [22]. However, such observations do throw light on the fact that many aspects of cellular and humoral immunity are not suppressed in patients with major depression despite the elevation of the plasma glucocorticoid concentration that is a common feature of the disorder."
"An important conceptual shift in the possible cause of depression has occurred recently with the discovery that inflammation plays a crucial role in the psychopathology of the disorder. However, as major depression is often accompanied by inflammatory diseases (such as irritable bowel syndrome, type 2 diabetes, arthritis and autoimmune disorders) that can activate the peripheral and central inflammatory response, it is possible that such inflammatory disorders initiate the inflammatory changes that precipitate depression. Although this is plausible, it is evident that inflammation also occurs in depressed patients who are not suffering from concurrent inflammatory disorders. Thus the increased vulnerability of depressed patients to psychosocial stress is probably the key factor that leads to the activation of the immune and endocrine axes in depression. It is known, for example, that even the relatively mild acute stress of public speaking causes an increase in NF-kB activity, a key element in the induction of the inflammatory cascade [23]. In this regard, it is also known that patients with major depression frequently show an enhanced responsiveness of IL-6 and NF-kB to an antigen challenge [24]. However, chronic stress, as experienced by caregivers or individual subject to marital discord but who are not suffering from depression also show an increase in plasma C-reactive protein, IL-6 and other inflammatory mediators [24,25]. Whatever the cause, such changes appear to be associated with activation of the microglia thereby suggestion that the inflammatory changes are also occurring in the brain [26].
The mechanism whereby psychological stress influences both the peripheral and central inflammatory cascade is co-ordinated by the autonomic nervous system. Thus the release of noradrenaline and adrenaline following the activation of the sympathetic system results in the activation of both alpha and beta adrenoceptors on immune cells thereby initiating the release of proinflammatory cytokines, via the activation of the NF-kB cascade, particularly on macrophages and monocytes in peripheral blood; antagonists of these adrenoceptors block the stress induced rise in these cytokines [27]. Conversely stimulation of the parasympathetic system has the opposite effect on the stress induced inflammatory response. Thus stimulation of the vagus nerve results in release of acetylcholine that activates the alpha-7 sub-unit on nicotinic receptors thereby reduces the activation of NF-kB [28]. It is possible that the anti-depressant-like action of vagal nerve stimulation, occasionally used to treat resistant depression, is associated with such an anti-inflammatory action.
The question arises why should inflammation occur in depressed patients despite the frequently observed increase in glucocortioids? The most parsimonious explanation is that glucocorticoid receptor resistance in the brain and periphery contribute to the lack of suppression of most types of immune cells with the possible exception of the natural killer cells. One possible explanation is that the stress induced increase in the sympathetic nervous system, combined with steroid resistance, leads to the activation of the microglia in the brain, and macrophages and monocytes in the periphery, thereby leading to the inflammatory state."
