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Depression’s influence on the immune system
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Richard Xiang
Vo l u m e 1 • N o . 1 • S p r i n g 2 0 0 7
Review Article
1 Second Year Undergraduate Student, Immunology Specialist Program, University of Toronto. Corresponding author email: [email protected].
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Abstract
Depression is a neurological disorder and can cause individuals to become more prone to diseases. This vulnerability is due to chemical
alterations in the patient’s immune system, which arise from neurological and endocrinological changes caused by depression. Immunosuppression initially results, but eventually a hyperactive immune system develops. This paper will outline the causes and effects of these
immunological alterations and their link to reducing natural killer cells, enhancing inflammation and increasing susceptibility to various
diseases. Also, the effects of an altered immune system on depressed patients and the efficacy of treating depression as a means to reestablish the immune system will be reviewed. Finally, possibilities for further research will be explored.
Introduction
A healthy individual normally possesses immune cells
such as natural killer and macrophages that are in place
before the body encounters foreign invaders such as bacteria or microbes. This is the body’s innate immune system that acts as the first line of defense against microbes
that enter the body. Cells of the innate immune system are
responsible for causing inflammation, releasing cytokines
and priming an adaptive response. Research has shown
that cells of the innate immune system are highly influenced by depression [3-5]. Depression causes patients to
show an increase in immuno-activation but a decrease in
the body’s cellular immune responses [9]. In other words,
patients suffering from depression can release hormones
that induce fever but weaken immune cells. The resulting
immune response is weak and ineffective compared to
non-depressed individuals under the same stimuli [9].
Although, the biological pathways linking depression
and immunity are not clear, research has shown that depression affects the immune system by altering the endocrinological hypothalamic-pituitary-adrenal axis (HPA)
[3, 10, 11]. The HPA is a feedback system between the hypothalamus, pituitary gland and the adrenal gland. One
role of HPA is to regulate the production of glucocorticoids (GC). The hypothalamus secretes corticotropin-releasing hormone (CRH), which causes the pituitary gland
to release adrenocorticotropic hormone (ACTH). ACTH
then travels to the adrenal gland and stimulates glucocorticoid release. Release of GC by the endocrine system can
lead to both a suppressed immune system by reducing
natural killer cell levels, or a hyperactive immune system
by inducing resistance in GC receptors [1, 9, 12]. During
depression, the number of GC receptors in the brain is
downregulated [13]. The resultant alleviation of negative
feedback reduces the brain’s ability to detect elevated levels of GC, which in turn sustains hypothalamic secretion
Journal of Undergraduate Life Sciences
of CRH. This alteration in GC production allows high levels of the glucocorticoid cortisol to be produced [13].
It is unclear how high levels of cortisol impact the immune system but one possible effect may be by decreasing the number of natural killer (NK) cells [14]. NK cells
are part of the innate immune system and induce apoptosis in virus-infected cells. Their reduction explains the immunosuppression that initially accompanies depression.
However, the decrease in NK cells was observed only in
young adults and not in older patients [15 ]. In these older
individuals, the lack of immunosuppression results when
glucocorticoid receptors become resistant to glucocorticoids [1, 2, 15]. As resistance develops, even high levels of
GC will not trigger an immune suppressing response. The
lack of immune suppression indirectly leads to a hyperactive immune system, which causes severe inflammation
and arthritis [1].
The pro-inflammatory immune response caused by a
hyperactive immune system can promote major depression by activating enzymes involved in tryptophan metabolism [8]. Tryptophan can be metabolized into glycine and
glutamate, which will bind and help open the N-methyl-Daspartate (NMDA) ion channel. The NMDA ion channel is
voltage-gated, but also requires the binding of glycine and
glutamate to open. Opening the channel allows an influx
of calcium ions into the cell, which leads to glutamatergic
hyperfunction and major depression [8]. The pro-inflammatory immune response also causes an increase in serotonin degradation [8]. The depletion of serotonin may be
caused by cytokines IL-1b, TNF-a, or IL-18 [16]. Cytokines
are proteins secreted by cells of the immune system to regulate immune responses. These specific cytokines promote
inflammation in the limbic areas of the brain, and activates
indoleamine 2,3-dioxygenase (IDO) [16]. IDO then causes
depletion of serotonin, a neurotransmitter, in paralimbic
areas (ventral lateral frontal cortex, polar temporal cortex,
Depression’s influence on the immune system
Disorders and Diseases
Immunosuppression, resulting from persistent activation of HPA and sympathetic-adrenal-medullary axes during chronic stress and short term depression, can induce
the growth of cancer by reducing the number of cytotoxic
T and natural killer cells involved in tumour surveillance
[5]. Immunosuppression is also shown to hinder responses to bacterial infections [21].
Depressed patients are more likely to become infected
with HIV because depression increases the likelihood of
high-risk sexual activities, drug abuse, and sexual abuse
[4]. Once infected, the immunological adjustments induced by depression reduce the efficiency of antiretroviral
treatments used to counter HIV [4].
Depression is also associated with chronic fatigue syndrome (CFS). While depression is a recognized symptom
of CFS, substantial biochemical evidence suggests that it
may be a cause. By altering cytokine levels, depression
leads to a reduction of omega-3 polyunsaturated fatty acids (PUFA) and elevation of monounsaturated fatty acids
(MUFA) [19]. Decreased omega-3 PUFA indirectly lowers
the ratio of omega-3 to omega-6 PUFA, which is associated
with reduced zinc levels and T cell activation. Certain viral infections are associated with CFS, because these infections will impair the biosynthesis of omega-3 and omega6 PUFA [22]. Without omega-3 and omega-6 PUFA, there
is a breakdown in cellular signaling and the synthesis of
eicosanoids [22]. Improper cell signaling and reduced eicosanoid levels explain the symptoms of CFS [22]. In addition to lowering omega-3 and omega-6 PUFA, increasing MUFA like oleic acid can lead to CFS and is often used
to measure the severity of CFS in patients [18].
Long-term depression has been found to cause a hyperactive immune system, which results in increased inflammation and arthritis [1]. There is also some evidence
that depression-altered immunity and cytokine levels contribute to vascular disease [3].
Treatments
The immune system of a depressed individual usually
reverts back to normal once the depression is treated [10].
Therefore, treatments should first target the neurological
alterations caused by depression [6, 7]. One method is to
use antagonists, which are compounds designed to bind
to receptors and prevent their activation. Using antagonists against CRH(1) receptors could prevent downstream
signaling that promotes hypothalamic secretion of CRH
(6). Another method is to lower the secretion of cytokines,
which indirectly reduces CRH production [7, 10]. Lastly,
the use of antidepressants decreases inflammatory prostaglandin in the brain [10]. Suppression of inflammation
prevents serotonin degradation and glutamatergic hyperfunction, thereby halting the propagation of depression
[7].
It must be noted, however, that antidepressants do
not prevent the lowering of omega-3 PUFA and increasing
of MUFA levels [18]. Therefore, CFS can still occur even
though a patient is being treated with antidepressants. In
order to return PUFA and MUFA levels back to normal,
treatments involving omega-3 PUFAs such as the use of
eicosapentaeonic acid and docosahexaenoic acid supplements are required [19].
Further Research
While it is clear that depression causes changes in the
immune system and vice versa, the pathways involved are
yet to be elucidated. In particular, the depression-cytokine
Journal of Undergraduate Life Sciences
Vo l u m e 1 • N o . 1 • S p r i n g 2 0 0 7
and basal ganglia) of the brain [16]. Decreased serotonin
levels will induce depression [8].
In addition, increased cytokine levels (IL-1beta, IL-2,
IL-6 and IFN) will directly induce depression [3]. Depression will then cause a further increase in cytokine levels
via CRH. This results in a positive feedback loop between
cytokine levels and emotional state that leads to a continuous propagation of depression [3, 7, 9, 17]. The cycle is
initiated when an individual experiences depression, anxiety, hunger, physical illness, and various other stresses.
Furthermore, stress causes an increase in the production
of CRH, which induces a hyper-secretion of cytokines [7].
Depression propagates the production of CRH, and the
cycle continues [7].
Recently, researchers have found that major depressed
patients have heightened levels of monounsaturated fatty
acids and lowered levels of omega-3 polyunsaturated fatty acids (PUFA) [18, 19]. Some evidence suggest that cytokine levels altered by depression may lower PUFA [19].
However the pathway linking depression and fatty acids
is still unclear.
Research shows that depressed males, who experienced stress during early life according to the Childhood
Trauma Questionnaire, have further increased CRH compared to those who did not [18]. A possible explanation
involves stress activated CRH(1) and CRH(2) receptors.
CRH(1) mediates depression behaviors and CRH production in the hypothalamus[6]. However, the purpose
of CRH(2) is currently unknown [6]. It may be possible
that CRH(1) and CRH(2) receptors retain memory of their
activation, and allow subsequent activations to be more
efficient. Therefore, when the male experiences depression during later life, the previously activated CRH(1) and
CRH(2) receptors help upregulate CRH production. Since
both depression and early life stress are capable of increasing CRH and altering the HPA, it is difficult to distinguish
their confounding effects on the immune system [5, 6]. In
other words, while depression can elicit changes in the
immune system, these alterations could be intensified by
stress in early life. The effects of early life stress on the immune system are evident because males, who suffer from
depression and experienced early life stress, were more
likely to have an overactive immune system and exhibit
enhanced inflammation compared to those who only suffered from depression [20]. The CRH(1) and CRH(2) pathways linking stress to depression require more research.
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Depression’s influence on the immune system
pathway requires the most research [23]. Very few pro-inflammatory cytokines have been examined fully, and some
depressed patients do not even show increased cytokine
levels [24]. Another pathway that requires research is the
glucocorticoid-immune (cortisol) response pathway. It is
unclear how cortisol changes the immune system; therefore, the relationship between cortisol and natural killer
cell levels requires further research [14].
Since it has been shown that alleviating depression
reverts the immune system back to normal, researchers
should investigate if correcting the immune system can
undo the neurological changes associated with depression
[7, 10]. Since depression initially causes immune suppression, studying the proteins and hormones involved in this
pathway may enable researches to improve anti-inflammatory treatments. Finally, the same MUFAs that are elevated in depressed patients are also present in olive oils
and other healthy oils. Therefore, an experiment could
test the correlation between cooking with healthy oils and
the presence of depression-altered cytokine levels. The
immune system can be a major determinant in how individuals lives their lives. Research into the links between
depression and immunity will help improve the quality of
life of depressed patients, as well as initiate a psychological approach to the treatment of diseases.
16. Spalletta, G., et al., The etiology of poststroke depression: a review of the literature
and a new hypothesis involving inflammatory cytokines. Mol Psychiatry, 2006. 11(11):
p. 984-91.
17. Chourbaji, S., et al., IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors. Neurobiol Dis, 2006. 23(3): p. 587-94.
18. Maes, M., et al., Lowered omega3 polyunsaturated fatty acids in serum phospholipids
and cholesteryl esters of depressed patients. Psychiatry Res, 1999. 85(3): p. 275-91.
19. Maes, M., I. Mihaylova, and J.C. Leunis, In chronic fatigue syndrome, the decreased
levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and
defects in T cell activation. Neuro Endocrinol Lett, 2005. 26(6): p. 745-51.
20. Pace, T.W., et al., Increased stress-induced inflammatory responses in male patients
with major depression and increased early life stress. Am J Psychiatry, 2006. 163(9): p.
1630-3.
21. Kiank, C., et al., Stress susceptibility predicts the severity of immune depression and
the failure to combat bacterial infections in chronically stressed mice. Brain Behav
Immun, 2006. 20(4): p. 359-68.
22. Puri, B.K., Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic
encephalomyelitis (chronic fatigue syndrome). J Clin Pathol, 2007. 60(2): p. 122-4.
23. Dantzer, R., Cytokine, sickness behavior, and depression. Neurol Clin, 2006. 24(3): p.
441-60.
24. de Beaurepaire, R., Questions raised by the cytokine hypothesis of depression. Brain
Behav Immun, 2002. 16(5): p. 610-7.
About the Author
Acknowledgements
Special thank you to David Yu for revising and proofreading this paper.
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Journal of Undergraduate Life Sciences
Richard Xiang is currently pursuing a Bachelor of Science at University of Toronto. He is enrolled in the immunology specialist program.
During the summer of 2006, he volunteered as a researcher in Dr.
Hu’s lab studying cystic fibrosis and will continue as a student researcher in the summer of 2007. His other research interests include
autoimmune disorders and genetic diseases.