Evidence for the Activation of Cellular Immunity in Schizophrenia

In schizophrenia, there is evidence that the innate immune system is activated. Thus, the number of monocytes and some of the cytotoxic cells are increased [12]. In addition, the proportion of monocytes and macrophages in the CSF of patients with acute schizophrenia are increased, suggesting that immune activation occurs in the brain as well as in the periphery [13]. Of the pro-inflammatory cytokines that are raised in the CSF, interleukin 6 (IL-6) has been reported to be increased by a number of investigators [14]. IL-6 activates B cells, in addition to playing a key role in the inflammatory cytokine cascade, and therefore contributes to many of the immune changes seen in schizophrenia.

Il-6, in addition to other pro-inflammatory cytokines, is released from activated macrophages and monocytes in the periphery and from microglia and astrocytes in the brain. In vitro evidence has shown that IL-6 also stimulates the release of prolactin from the pituitary [15]. Whether this is relevant to the increase in the secretion of prolactin in patients being treated with antipsychotics is questionable as effective antipsychotic treatment usually attenuates the secretion of pro-inflammatory cytokines.

If IL-6 plays a role in the psychopathology of schizophrenia, to what extent do changes in this cytokine reflect the clinical status of the patient? It is clear that IL-6 is raised in the plasma of schizophrenic patients [15, 16] and that elevated plasma concentrations of this cytokine are related to both the duration of the disorder [17] and resistance to drug treatment [18]. In the CSF, the concentration of the soluble IL-6 receptor (sIL-6R) is also increased [18]. Il-6 has also been shown to activate both dopaminergic and serotonergic neurons in the hippocampus and the frontal cortex [19]. As these neurotransmitter changes have been implicated in the etiology of schizophrenia, it would appear that there is a close inter-relationship between the activation of the central and peripheral immune system and the changes in the monoamine neurotransmitters that are thought to be involved in the pathology of the disorder.

Although marked gliosis has seldom been detected in schizophrenic patients, microglial activation, triggered by the increase in the pro-inflammatory cytokines IL-1 and IL-6, has been detected in the frontal cortex [20]. It has also been observed that the expression of the IL-1 receptor antagonist (IL-1RA) is decreased in the prefrontal cortex of schizophrenic patients; this antagonist counteracts the overstimulation of IL-1 receptors by IL-1 [21]. As a consequence of the overactivation of IL-1, the hypothalamic-pituitary-adrenal axis is also activated; IL-1 is known to activate the anterior pituitary thereby enhancing the stress response [22]. IL-1 also decreases long-term potentiation in the hippocampus [23] thereby contributing to the disordered memory function frequently seen in patients with schizophrenia.

In addition to IL-6 and IL-1, other cytokines also appear to change in the plasma of schizophrenic patients. The changes in IL-2 and interferon-y (IFN) were reported to be decreased, at least in some large-scale studies [24]. These findings suggest that there is a decrease in the Th-1 arm of the cellular immune system in patients with schizophrenia. It must be emphasized though that there are several conflicting findings in the literature regarding this conclusion [4, 25]. In the CSF, there is evidence that the IL-2 concentrations are increased in those patients who relapsed following treatment with haloperidol; these changes were associated with the recurrence of psychotic symptoms [24]. This may suggest that there is not a direct relationship between the blood and brain compartments of the immune system regarding the role of IL-2. On balance, it would appear that some schizophrenic patients show a shift in the adaptive immune system from cellular (Th1-mediated) to humoral (Th2-mediated) immunity. This shift appears to be more prominent in patients with predominantly negative symptoms that show a poor response to antipsychotic therapy [4, 25].

Schizophrenia is frequently considered to be a neurodevelopmental disorder that may arise as a consequence of prenatal exposure to a virus. Microglia are known to migrate into the brain early in development and to be involved in neural growth (low concentrations of pro-inflammatory cytokine have neuronal growth factor potential), pruning of neurons and removal of cell debris. Microglia therefore fulfil the role of macrophages in the brain and are involved in the presentation of antigens to phagocytic cells. They also release pro-inflammatory cytokines and are known to play a crucial role in immune function in schizophrenia so that an overactivation of the microglia contributes to the increased inflammatory challenge to the brain. Conversely, the astroglial cells have a largely neuroprotective role in the brain. There is evidence that the concentration of the S100 beta protein, derived from astroglial cells, is raised in patients independently of their medication [26], which has led to the suggestion that this change is in response to the neurodegenerative impact of the inflammatory mediators produced by the activated microglia.

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