Recent studies suggest that bipolar disorder may be linked with abnormal immune system activity. On the one hand, it is clearly strongly linked with genetic factors, with monozygotic twins exhibiting 67 percent concordance and dizygotic twins exhibiting 19 percent concordance. The heritability rate is about 80 percent. Many candidate genes have been identified, and it is possible that some of these genes may be involved in immune system regulation. “Two case-control studies reported that BD is associated with an uncommon variant with an adenine (A) at position −308 of the tumor necrosis factor alpha (TNF-) gene which is related with higher TNF- production.”
Some researchers have argued that the expression of a genetic variant of the IL-gene, the variant (-511T), was correlated with volume decrease of the gray matter, primarily in the left dorsolateral prefrontal cortex. This indicates that proinflammatory mechanisms may be at work in structural brain changes correlated with bipolar disorder.
“Two studies demonstrated that the presence of a variable number of tandem repeats (VNTR) in intron 2 of the IL-1Ra gene (IL1RN) (IL1RN2) confers susceptibility to BD [33], particularly in BD patients with a positive family history of the illness [34]. Nevertheless, a third study failed to confirm this finding [35]. Interestingly, IL1RN2 allele was associated with more prolonged and more severe proinflammatory immune response when compared with other IL1RN genotypes in humans. In vitro studies also demonstrated that the presence of the IL1RN2 allele was associated with enhanced IL-1 production and decreased production of IL-1Ra [36, 37].”
In three other studies, there was a significant association between the uncommon variant with adenine (A) at position -2581 of the CCL2 gene. This gene is associated with higher production of the chemokine CCL2/MCP-1, which is itself involved in recruiting monocytes, dendritic cells into inflammatory cites under inflammatory stimulus, and memory T cells.
When it comes to transcriptomic changes, some researchers reported that monocytes from bipolar disorder patients and their offspring exhibited over-expression of mRNA cytokines, especially TNF-, IL-1, IL-6 and CCL2. Researchers have suggested that aberrant RNA processing of cytokines in such patients might be determined by epigenetic mechanisms. These may influence both cytokine levels and neurobiology of bipolar disorder.
Only a few studies have been conducted evaluating brain abnormalities and cytokines in those with the illness simultaneously. Some researchers argued that serum levels of IL-10 was associated with the availability of serotonin transporter in the thalamus. This was especially by single-photon emission computer tomography. This association suggests that peripheral inflammation and monoamine metabolism may be linked in the brain.
Posmortem studies have been important as well:
“Postmortem studies demonstrated the presence of dendritic atrophy of neurons and the loss of oligodendroglial cells in BD, notably in the medial prefrontal cortex [46]. Only few studies have assessed immune markers in this context, revealing increased inflammatory and decreased anti-inflammatory markers in the frontal cortex of BD patients compared with controls [47, 48]. More specifically, they reported increased protein and mRNA levels of IL-1 and its receptor (IL-1R), NF-κB transcription factor subunits (p50 and p65), and astroglial and microglial markers (glial fibrillary acidic protein, inducible nitric oxide synthase, c-fos and CD11b) [47]. Conversely, BD patients showed decreased total RNA expression of transforming growth factor (TGF) in the frontal cortex [47]. Dean et al. [49] also showed that BD patients present increased transmembrane TNF- protein level in the anterior cingulate area and decreased TNF- receptor 2 protein levels in the dorsolateral prefrontal cortex in comparison with controls. Since the dorsolateral prefrontal cortex is known to be critical in executive functioning, the anterior cingulate in mood control and all these regions are implicated in BD [50]; these data suggest a role for cytokines in disease pathogenesis and also in mood and cognition modulation. Nevertheless, studies assessing whether there is any association between neuropathological findings and clinical (cognitive or psychopathological) parameters are lacking.
Taking into account that microglia is one of the major sources of cytokines in the central nervous system (CNS), these cells were investigated in BD. Postmortem studies reported decreased number and size of microglia in BD patients [51]. To conciliate these contradictory results, it was hypothesized that persistent microglia activation in early stages is associated with cellular death in the long term due to failure in the control of anabolic and catabolic cellular machineries, corroborating the view of a neurodegenerative process in BD [52].”
In 4 meta-analyses, concentrations of IL-4, sTNFR1, TNF- and sIL-2R were much higher in those with bipolar disorder than in comparison with controls. Euthymia has also been associated with a mild proinflammatory profile. This tends to be associated with higher levels of sTNFR1 levels. Tw other studies demonstrated higher CXCL10 plasma levels during euthymia. Therefore, it is possible that there is a Th1 skewed imune response in euthymia. This is because the chemokine CXCL10 is a powerful attractant of activated Th1 cells. In one study, cytokines in the cerebrospinal fluid of bipolar disorder levels were increased (more specifically, higher levels of Il-1).
“The immune changes already observed in euthymia are enhanced during mania (Table 2) and depressive state (Table 3). BD patients in mania exhibited increased circulating levels of IL-6, TNF-, sTNFR1, IL-ra, and also CXCL10, CXCL11, and IL-4. Besides the association with inflammatory molecules, mania was associated with Th1 (increased CXCL10 [58]) and Th2-type cytokines (increased CXCL11 [60] and IL-4 [48, 59, 61]). BD patients in depression had increased circulating levels of sTNFR1 and CXCL10. It is worth mentioning that the number of studies assessing peripheral cytokines in depressive BD is much lower than mania or euthymia.”
Indeed, inflammation tends to increase during mood episodes:
“BD has been associated with increased peripheral levels of proinflammatory cytokines, and this mild chronic inflammation tends to exacerbate during mood episodes. The frequency of mood episodes (mania or depression) is inversely associated with BD outcome as the higher their frequency, the worst the disease prognosis. Therefore, mood episodes seem to play a pivotal role in BD progression, and one of the putative mechanisms would be enhanced inflammatory response during mania or bipolar depression [5]. In this scenario, proinflammatory cytokines would act as major “toxic players,” contributing to psychopathological changes, cognitive impairment, and related comorbidities and could be regarded as potential biomarkers for neuroprogression in BD [74–76]. However the studies assessing stage-related cytokines changes were cross-sectional, and longitudinal or prospective evidence for this cytokine effect is lacking. For instance, Kauer-Sant’Anna et al. [77] found that the proinflammatory cytokines IL-6 and TNF- were elevated in both early- (<3 years of disease) and late-stage (>10 years of disease) BD, whereas the anti-inflammatory cytokine IL-10 was increased only in the early stage. Another study described elevated levels of proinflammatory cytokines only in patients with long-duration BD compared with short-duration disease [78]. These preliminary findings suggest that there is a tendency of enhanced inflammation with disease progression.
To date evidence of structural and neuropsychological changes derived, respectively, from neuroimaging and clinical studies supports the concept of staging in BD. Longer lifetime illness duration was related to lower total gray matter, even when controlling for age [7]. Number of manic episodes is associated with cognitive impairment, specifically deficits in executive function, episodic memory, and reduced psychomotor slowing [79].”
Thus, inflammatory mechanisms seem to be intimately involved in the progression of BPD. TNF- can act on TNFR1 and produce neuron death by means of caspses and apoptotic machinery. Such a process may contribute to volumetric reduction and hypoactivation of frontal lobes in those with the illness. This may be responsible for what disinhibits limbic structures.
“This corticolimbic dysfunction may underlie the emotional dysregulation and cognitive impairment associated with BD. In line with this, our and other groups have consistently demonstrated that there is a positive correlation between increased proinflammatory cytokines levels and cognitive impairment, particularly involving frontal lobe functions [45, 85, 86].”
While pharmaceutical treatment of bipolar disorder is based upon hypotheses concerning neurotransmitter dysregulation, antidepressants, antipsychotics and lithium also inhibit proinflammatory cytokines production. Medications associated with decrease of inflammation may help with the symptoms of bipolar disorder:
“The development of new therapeutic targets in the treatment of BD is highly needed and the immune system is a promising target. In this scenario, anti-inflammatory strategies derived from four major classes, namely, polyunsaturated fatty acids (PUFAs), cyclooxygenase (COX) inhibitors, anti-TNF, and minocycline have been tested in BD patients [95]. In a seminal study, Nery et al. [96] conducted a double blind, randomized, placebo-controlled add-on study within depressive or mixed episodes of BD patients using an COX 2 inhibitor (celecoxib). In this study the treatment with celecoxib was associated with a faster decrease in depression scores compared with placebo [96]. This study indicates a potential antidepressant effect of anti-inflammatory medications related with the inflammatory/immune imbalance in these patients [96]. New double-blind controlled studies evaluating other anti-inflammatory drugs (i.e., aspirin and minocycline) in BD patients are underway [95, 97]. However, a word of caution is necessary as the relation between BD and inflammation seems to be much more complex than a mere “pro-inflammatory status,” represented by elevated circulating levels of cytokines. This can be exemplified by the unexpected clinical observation of a series of cases of mania induced by TNF-antagonists (infliximab and etanercept) [98–100].”
