Recent investigation suggests a strong relationship between immunological effects and the pathophysiology of schizophrenia. Two prevalent approaches exist to this association. First, is more empirical a-priori research investigating immunological changes prevalent in schizophrenia and the second approach is more hypothesis-driven with analysis of immunological changes in schizophrenia based on known irregularities of the illness. The former approach is based upon three predominant lines of investigation including observations of a diffuse non-specific overactivation of the immunological response system, of a T-helper cell type 1 immune activation and of a T-helper cell type 2 immune activation in subgroups of schizophrenia patients. These last two theories suggest that a subgroup of patients with schizophrenia may demonstrate features of an autoimmune process, a theory supported by a growing database of investigation. The latter approach notes that many observations of immune dysregulation in schizophrenia overlap with central etiopathophysiological mechanisms as well as with clinical manifestations of the illness. Immunotherapy offers the opportunity to modify or re-balance the immune system and may become useful in management of the illness. Given that autoimmune mechanisms could interrupt neurotransmission, any process interfering with this disruption including therapeutic antibodies to involved cytokines, or with various other natural autoantibodies or immune system regulators, may become useful in the augmentative management of the illness.
"Consistent with previous findings in literature (Gilvarry et al., 1996; Muller et al., 1999; Rothermundt et al., 2001; Strous and Shoenfeld, 2006), we found that there may be an immune/autoimmune component in schizophrenia. Some of the most significant genes associated with the disease are associated with this pathway. "
"We have further found that this variant is associated with immune dysregulation, indicated by increased levels of proinflammatory cytokines and autoantibodies in carriers of the variant (Marballi et al. 2010). This is of immense importance, given the large body of studies showing dysregulation of the immune system (Potvin et al. 2008; Strous and Shoenfeld 2006), including elevated levels of proinflammatory cytokines and autoantibodies in schizophrenia. "
[Show abstract][Hide abstract] ABSTRACT: Aberrant neuregulin 1-ErbB4 signaling has been implicated in schizophrenia. We previously identified a novel schizophrenia-associated missense mutation (valine to leucine) in the NRG1 transmembrane domain. This variant inhibits formation of the NRG1 intracellular domain (ICD) and causes decreases in dendrite formation. To assess the global effects of this mutation, we used lymphoblastoid cell lines from unaffected heterozygous carriers (Val/Leu) and non-carriers (Val/Val). Transcriptome data showed 367 genes differentially expressed between the two groups (Val/Val N = 6, Val/Leu N = 5, T test, FDR (1 %), α = 0.05, -log10 p value >1.5). Ingenuity pathway (IPA) analyses showed inflammation and NRG1 signaling as the top pathways altered. Within NRG1 signaling, protein kinase C (PKC)-eta (PRKCH) and non-receptor tyrosine kinase (SRC) were down-regulated in heterozygous carriers. Novel kinome profiling (serine/threonine) was performed after stimulating cells (V/V N = 6, V/L N = 6) with ErbB4, to induce release of the NRG1 ICD, and revealed significant effects of treatment on the phosphorylation of 35 peptides. IPA showed neurite outgrowth (six peptides) as the top annotated function. Phosphorylation of these peptides was significantly decreased in ErbB4-treated Val/Val but not in Val/Leu cells. These results show that perturbing NRG1 ICD formation has major effects on cell signaling, including inflammatory and neurite formation pathways, and may contribute significantly to schizophrenia pathophysiology.
"Several mechanisms may explain the epidemiologic data [Strous and Shoenfeld, 2006]. Individuals with auto-immune diseases have elevated prevalence of antibodies directed against brain proteins or may produce antibodies that cross-react with brain proteins [Irani and Lang, 2008]; individuals with SZ can also produce antibodies against proteins in the frontal cortex [Henneberg et al., 1994], cingulate gyrus [Ganguli et al., 1987; Kelly et al., 1987; Henneberg et al., 1994], hippocampus [Ganguli et al., 1987] and against glutamate receptors [Tsutsui et al., 2012]. "
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