Immune-Related Genomic Schizophrenic Subtyping Identified in DLPFC Transcriptome

Abstract

Well-documented evidence of the physiologic, genetic, and behavioral heterogeneity of schizophrenia suggests that diagnostic subtyping may clarify the underlying pathobiology of the disorder. Recent studies have demonstrated that increased inflammation may be a prominent feature of a subset of schizophrenics. However, these findings are inconsistent, possibly due to evaluating schizophrenics as a single group. In this study, we segregated schizophrenic patients into two groups (“Type 1”, “Type 2”) by their gene expression in the dorsolateral prefrontal cortex and explored biological differences between the subgroups. The study included post-mortem tissue samples that were sequenced in multiple, publicly available gene datasets using different sequencing methods. To evaluate the role of inflammation, the expression of genes in multiple components of neuroinflammation were examined: complement cascade activation, glial cell activation, pro-inflammatory mediator secretion, blood–brain barrier (BBB) breakdown, chemokine production and peripheral immune cell infiltration. The Type 2 schizophrenics showed widespread abnormal gene expression across all the neuroinflammation components that was not observed in Type 1 schizophrenics. Our results demonstrate the importance of separating schizophrenic patients into their molecularly defined subgroups and provide supporting evidence for the involvement of the immune-related pathways in a schizophrenic subset.

Convergent impact of schizophrenia risk genes

“…For example, CMC clusters associated with SCZ (Cluster 8) compared to general affective disorders (AFF) (Cluster 12) revealed distinct convergent networks with unique node genes. Of note, the central protein-coding node gene of the cluster 12 network is ABCG2— down-regulated in a subset of SCZ cases with a neuroimmune molecular subtype (SCZ Type II) 57,58 , a biomarker associated with increased negative symptoms 59 , and associated with SCZ treatment resistance 60 .…”

A Marked Low-Grade Inflammation and a Significant Deterioration in Metabolic Status in First-Episode Schizophrenia: A Five-Year Follow-Up Study

“…Several studies, including meta-analyses, have confirmed the presence of inflammatory and immune processes dysregulations in the acute and chronic phases of the disease [ 3 , 4 , 6 , 50 ], although not in all SSD patients [ 51 , 52 , 53 ]. Uptegrove et al [ 6 ], in a meta-analysis, included 570 AP-naïve FEP patients compared to 683 CSs and identified that IL-1B, IL-6, and TNF-α were significantly elevated among the patient group and there was no significant difference in IL-2, IL-4, and IFN-γ between groups.…”

“…Thus, the current study fully agrees with the suggestion that AP treatment probably inflicts a mixture of favorable and unfavorable changes on immunologic abnormalities in SSD that may ultimately promote chronic low-grade inflammation with repeated use [ 42 ]. However, discrepancies in the research findings may result from the consideration patients with chronic psychotic disorders as a single group, although a low-grade inflammatory process has been shown to characterize a subset of patients [ 52 ]. Additionally, alterations in cytokine levels may be related to at least four different patient categories, including AP-naïve FEP patients, non-drug-naïve FEP patients, stable chronic, and chronic patients in acute relapse.…”

“…Furthermore, activation of the immune system in SSD occurs not only in the periphery but also in the brain. Activated macrophages and Th1/Th2 cells release cytokines that may increase the permeability of the blood–brain barrier and cause the overactivation of astrocytes and microglia [ 60 ], and these cytokines bind to specific receptors on neurons and adversely affect neurotransmitters [ 52 , 61 ]. They are also known to affect kynurenine pathway regulation [ 62 ].…”

Neuroimmune cortical organoids overexpressing C4A exhibit multiple schizophrenia endophenotypes

“…3a). At least one of these genes, ITGAX, was previously shown to be down-regulated in SCZ patients 19,22 . Previous comparisons of inflammatory genes associated with Alzheimer's and SCZ have shown opposite effects, where genes up-regulated in Alzheimer's were down-regulated in SCZ and vice versa 19 , suggesting specific neuroinflammation pathways for each pathology.…”