Immune System Disturbances in Schizophrenia

Abstract

Epidemiological, genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies of schizophrenia all point to a dysregulation of both innate and adaptive immune systems in the disease, and it is likely that these immune changes actively contribute to disease symptoms. Gene expression disturbances in the brain of subjects with schizophrenia show complex, region-specific changes with consistently replicated and potentially interdependent induction of serpin peptidase inhibitor, clade A member 3 (SERPINA3) and interferon inducible transmembrane protein (IFITM) family transcripts in the prefrontal cortex. Recent data suggest that IFITM3 expression is a critical mediator of maternal immune activation. As the IFITM gene family is primarily expressed in the endothelial cells and meninges, and as the meninges play a critical role in interneuron development, we suggest that these two non-neuronal cell populations might play an important role in the disease pathophysiology. Finally, we propose that IFITM3 in particular might be a novel, appealing, knowledge-based drug target for treatment of schizophrenia. Gene*environment interactions play a critical role in the emergence of schizophrenia pathophysiology. Epidemiological, genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies of schizophrenia all point to a dysregulation of both innate and adaptive immune systems in the disease (1-3) and it is likely that these immune changes actively contribute to disease symptoms (1, 4, 5). Regardless of the abundance of data obtained to date, our understanding of the mechanism by which the immune system disturbances arise is limited: we do not have a good insight into the origin or sequence of events by which the immune dysregulation develops, and to date we have not taken full advantage of these changes as potential therapeutic targets.

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…Any disruption could offset, alter, or cease these coordinated processes with immediate, delayed, or cascading consequences on brain function and alter the trajectory of development . Depending on the timing of the insult, common disruptions could have transient effects or marked and compounding consequences that lead to chronic disability (Horvath and Mirnics, 2014a;Insel, 2010;Lewis and Levitt, 2002). Furthermore, the individual genetic makeup appears to be critical: the same insult can have minimal effect or a large effect in two different individuals, and this will largely depend on the disease-predisposing sequence variants in their genome (Horvath and Mirnics, 2014b).…”

“…However, determining causality can be difficult because of the protracted amount of time between insult and diagnosis . Immune system activation has been implicated as a risk factor for schizophrenia (Horvath and Mirnics, 2014a) and the major histocompatibility complex is the most prominent signal in GWAS studies (McAllister, 2014;Stefansson et al, 2009). MIA in rats and mice causes dysfunction of GABAergic circuitry in the hippocampus, amygdala, and cortex (Canetta and Brown, 2012;Meyer, 2014).…”

“…Interestingly, a schizophrenia-associated missense mutation in the NRG1 gene leads to increased IL-6 gene expression and protein secretion in humans (Marballi et al, 2010). Furthermore, interferon-induced transmembrane protein 3 (IFITM3) expression in astroglia appears to be involved in mediating this MIA-IL-6 response (Ibi et al, 2013), which is interesting considering IFITM3 is increased in schizophrenia and negatively correlated with GABAergic gene expression (Horvath and Mirnics, 2014a;Siegel et al, 2013). Furthermore, the delayed molecular and behavioral effects of MIA in adulthood can be revealed in at-risk genotypes as mice with mutant forms of DISC1 display additional phenotypes after in utero exposure to polyinosinic:polycytidylic acid (poly I:C), a double-stranded RNA viral mimetic and cytokine inducer (Abazyan et al, 2010;Ibi et al, 2010;Lipina et al, 2013).…”

A schizophrenia-associated HLA locus affects thalamus volume and asymmetry

“…The expression of cytokines and genes of the HLA region, critical components of the immune response, may be altered in peripheral immune cells and in glial cells of schizophrenic patients (Bernstein et al, 2015;Goudriaan et al, 2014;Miller et al, 2011;Sinkus et al, 2013). Several studies have shown a co-segregation of autoimmune diseases, chronic inflammation and maternal infection with schizophrenia (Bergink et al, 2014;Bernstein et al, 2015;Horvath and Mirnics, 2014;Knuesel et al, 2014;Stringer et al, 2014). This has led to the hypothesis that immunological disturbances are a key factor in the etiology of schizophrenia, notably through the role of microglial cells and astrocytes in the immune response in the brain (Bernstein et al, 2015;Horvath and Mirnics, 2014).…”

“…Several studies have shown a co-segregation of autoimmune diseases, chronic inflammation and maternal infection with schizophrenia (Bergink et al, 2014;Bernstein et al, 2015;Horvath and Mirnics, 2014;Knuesel et al, 2014;Stringer et al, 2014). This has led to the hypothesis that immunological disturbances are a key factor in the etiology of schizophrenia, notably through the role of microglial cells and astrocytes in the immune response in the brain (Bernstein et al, 2015;Horvath and Mirnics, 2014). While HLA proteins have been mainly studied for their roles in immunity, recent studies in rodents also point to functions in the neurons, notably of the MHC class I (MHCI) proteins (Boulanger, 2009;Elmer and McAllister, 2012;Lee et al, 2014;Shatz, 2009).…”