Schizophrenia is a chronic mental disorder with a complex etiopathogenesis, which involves both congenital and environmental factors. It leads to neurodegenerative changes in the central nervous system (CNS) and a significant impairment of social functioning. Its lifetime incidence has been estimated at 7.1 per 1000 people, and the male to female risk ratio is 1.4:1.
Recent research indicates that subclinical inflammation in the CNS and immune dysregulation may play a role in the etiopathogenesis of schizophrenia, which is supported by immunogenetic evidence and a higher incidence of autoimmune diseases in patients with schizophrenia relative to the general population [6,7,8]. Neuroinflammation can lead to white matter pathology, dysconnectivity, and thus to the onset of schizophrenia symptoms .
Numerous studies, including many meta-analyses, demonstrate alterations in blood cytokine levels in schizophrenia patients compared to healthy controls (HC) [12,13,14,15,16]. Additionally, they tend to manifest the increased mRNA expression of cytokine genes in lymphocytes relative to HC . This may stem from epigenetic mechanisms underlying the relationship between schizophrenia and stress in early childhood [18,19]. A known risk factor for schizophrenia, early childhood trauma is associated with poorer responses to treatment and symptom characteristics [18,20,21,22,23]. Elevated peripheral and cerebrospinal fluid (CSF) cytokine levels are hypothesized to partially result from disturbed gut microbiome composition, which were observed in patients with schizophrenia and may be caused by both maternal and developmental stress [24,25,26,27,28].
Schizophrenia research is typically conducted on a small patient population. The most extensively researched cohort is patients with first-episode psychosis (FEP), whose functioning is monitored prior to the initiation of antipsychotic treatment (first episode antipsychotics naive, FEAN). The second group consists of patients showing subsequent psychotic episodes, who receive treatment due to relapse (acute relapsed chronic, ARCh), while the third includes those in remission (stable chronic, SCh). Some other, far less studied patient populations include those with early onset psychosis (EOP) and patients at clinical high risk (CHR) or ultra-high risk (UHR) of psychosis.
A positive correlation has been found between peripheral levels of IL-10 and negative symptom severity, general psychopathological presentation, attention deficits and incidence of aggressive behaviors, and a negative correlation with cognitive deficits .
Meta-analyses of the effect of antipsychotics on IL-12 peripheral levels where no stratification by population or administered pharmacotherapy is applied seem to yield inconsistent results, suggesting their elevated [12,14,49] or unaltered values . In addition, in their meta-analysis including the largest sample, Romeo et al. described no changes in IL-12 peripheral levels in ARCh patients, and their elevated values in those treated with risperidone .
A correlation between peripheral levels of IL-18 and the severity of depressive symptoms was found in EOP, which is probably related to the increased cortisol level .
The role of immunological dysfunction in the etiopathogenesis of schizophrenia is also demonstrated by its association with disorders of known autoimmunological underpinnings . Schizophrenia has been shown to be associated with major histocompatibility complex A gene (MHC-A) polymorphisms , and with rheumatoid arthritis through major histocompatibility complex class II (MHC-II) or DRB1β chain gene (HLA-DRB1) .
Schizophrenia has also been shown to be associated with polymorphisms of numerous genes responsible for the synthesis of such cytokines as IL1A, IL1B, IL10 and IL6, which are genes for, respectively, IL-1α, IL-1β, IL-10 and IL-6 [67,68]. The polymorphism of the IL6 (-174G/C) gene does not elevate the level of IL-6 in the serum, but it has been shown to be associated with the occurrence and severity of positive symptoms in the course of schizophrenia . Polymorphisms of TGFB1, which encodes TGF-β, along with its additional overexpression  were also associated with schizophrenia . Quite remarkably, polymorphisms of the TNFR2 gene encoding the TNF-α receptor, depending on the variant, may be associated with an increased risk of schizophrenia, or may have a protective effect .
Gut microbiome dysbiosis affects behavior as well as the functioning and maturation of microglia [85,86]. Dysbiosis may also influence the activity of astrocytes with the participation of type I interferons and tryptophan metabolites . Disturbances in the composition of the intestinal microbiome are associated with an increased permeability of the intestinal epithelium for bacteria, their antigens, and pathogen-associated molecular patterns (PAMPs), e.g., LPS. Greater permeability, in turn, correlates with elevated peripheral cortisol levels and could lead to the activation of the immune system related to the secretion of pro-inflammatory cytokines, activation of the HPA axis and the creation of a positive feedback loop [88,89,90,91].
In schizophrenia, there are differences in the composition of the microbiome compared to healthy controls, both in the oropharynx and in the intestines [26,27,92]. Gut microbiome biodiversity is greater in patients with schizophrenia, and shows a negative correlation with the number of CD8+ memory T cells in the blood . The population size of individual bacterial species in the microbiome also correlates with symptom severity, and disturbances in its composition may be a marker of response to pharmacotherapy in FEP . Moreover, an altered composition of gut microbiota persists despite treatment with olanzapine, which does not appear to have a significant effect on it . Although there is no evidence of a beneficial effect of probiotic supplementation on schizophrenia symptom severity, it seems possible to use microbiome tests as an auxiliary tool in the diagnosis of the disease [27,95]. Further research is required to establish whether and to what extent dysbiosis may be responsible for the disturbances in the cytokine system present in patients with schizophrenia.
This entry is adapted from 10.3390/jcm10173849