Biological changes of schizophrenia, including immunological abnormalities, were traditionally explained by these two views:
- A neurodevelopmental hypothesis suggests that a disruption of brain development during early life is responsible for later emergence of symptoms during adulthood
- A progressive hypothesis suggests that symptoms and related neurotransmitter dysregulation is responsible for immunological changes that can be observed during the course of illness.
BD was traditionally thought of as an early onset disorder that is clinically and biologically stable during the course of illness with the exception of acute relapses. The finding of a different biological profile in recent-onset versus chronic euthymic bipolars has changed this traditional vision in recent years in favor of the role of illness in determining biological changes, including immunological dysfunction.[39, 40] In addition, similarly to schizophrenia, the role of praecox stressors has been postulated in explaining prefrontal–subcortical dysfunction observed in BD.
Contribution of immune system research to the neurodevelopmental model
The neurodevelopmental model of schizophrenia/BD states that immune alterations due to several factors, including decreased vitamin D, hypoferremia and zinc deficiency, are responsible for brain development abnormalities.23 Cytokines would be the mediators between immune abnormalities and CNS development. In fact, cytokines may play an important role during neurodevelopment at all stages from the differentiation of ectoderm into neuroepithelium, to the renewal of neuroepithelial cells, which act as precursors for all neurons, microglia and adult progenitors as well as a framework for radial neuron migration. During neurogenesis, there is an overproduction of neurons and glia and cytokines act crucially to promote survival of cells, which are properly connected in the neural network, as well as to induce apoptosis of cells with impaired connections.
In other words, cytokines represent a link between altered immune system, neurotransmission dysfunction and impaired neurodevelopment, all of which contribute to the onset of schizophrenia/BD in childhood or later life. In recent years, several studies have focused on infection and subsequent activation of inflammatory pathways during neurodevelopment.[43-45]
Two major hypotheses have been postulated: one argues that individual infections increase the risk of developing schizophrenia/BD; the second suggests that different infections act through common pathways, which may alter fetal brain development and increase risk of the disorder. On the basis of clinical and preclinical findings, cytokines have been proposed as key mediators of this common mechanism.[43, 45, 46]
As mentioned above, an increase of cytokines following a maternal infection may alter the immune status of the fetal brain, causing abnormal cellular development with subsequent brain damage.[44, 45] It has been well described that maternal immune activation induces increase of cytokines in the placenta (IL-1β, IL-6, TNF-α) and amniotic fluid (IL-6, TNF- α).[47, 48] Cytokines could act on the placenta, altering transfer of nutrients, oxygen, growth factors and maternal antibodies, all of which have a crucial effect on fetal development.
However, it is not clear whether cytokines are altered in the fetal brain, even though animal models suggest that there could be a significant increase in IL-1β, IL-6, and INF-γ.[49, 50] Cytokines seem to act directly on developing neurons and cause a disruption on maturation of oligodendroglia as well as white matter abnormalities. In addition they could activate different potential mechanisms, such as stimulation of astroglia and microglia, to produce cytokines potentiating excitatory amino acids and nitric oxide, which lead to disrupted maturation of oligodendrocytes.[45, 51, 52]
Specifically, overall increase of maternal cytokines, including IL-8 and TNF-α, is correlated with several infections. Of note, IL-8 appears to be a key factor for neutrophil attraction as well as for release of lysosomal enzymes from neutrophils, leading to discharge of oxygen free radicals. TNF-α has been associated with chorioamnionitis[45, 53] and fetal infections.[45, 54]
Along with maternal infections, other factors have been considered to be involved in maternal immune activation alteration. For instance, nutritional deficits and stress have been linked with increase of inflammatory cytokines. In fact, chronic and acute stress has been associated with increased production of proinflammatory cytokines[55, 56] and decreased levels of anti-inflammatory ones.[57-59] On the other hand, life in an urban area and birth in winter–spring can enhance the risk of maternal infections with subsequent inflammatory response.[48, 60-62] However, it has not been clarified if cytokine fetal imbalance is able to induce itself an immune dysregulation in the adult brain.
Contribution of immune system research to the progressive model
As an alternative to the ‘neurodevelopmental’ hypothesis of schizophrenia/BD, the ‘neurodegenerative’ hypothesis states that immunological alterations are secondary to the onset of illness and they can be observed during the progression of illness. It has been hypothesized that immunological alterations of schizophrenia and BD may be an adaptive response to microglial activation in mature CNS. Of note, IL-6 seems to play a crucial role in both the disorders in determining biological changes observed during the course of illness. IL-6 potentiates B lymphocyte proliferation: the hyperactivation of humoral immunity stimulates the tryptophan 2,3-dioxygenase enzyme with an increase of the transformation of the amino acid tryptophan in kynurenic acid that acts as an NMDA antagonist.[65, 66] Another metabolite of tryptophan catabolism is 3-hydroxykynurenine, which is considered an endogenous oxidative stress generator, probably involved in cognitive symptoms.[67, 68] In support of this hypothesis, some studies show that a long duration of illness in schizophrenia/BD is associated with higher serum levels of IL-6.[69-71]