Concordance of Immune-Related Markers in Lymphocytes and Prefrontal Cortex in Schizophrenia

Abstract

Schizophrenia is a severe neuropsychiatric disorder associated with a wide array of transcriptomic and neurobiochemical changes. Genome-wide transcriptomic profiling conducted in postmortem brain have provided novel insights into the pathophysiology of this disorder, and identified biological processes including immune/inflammatory-related responses, metabolic, endocrine, and synaptic function. However, few studies have investigated whether similar changes are present in peripheral tissue. Here, we used RNA-sequencing to characterize transcriptomic profiles of lymphocytes in 18 nonpsychotic controls and 19 individuals with schizophrenia. We identified 2819 differentially expressed transcripts (Pnominal < .05) in the schizophrenia group when compared to controls. Bioinformatic analyses conducted on a subset of 293 genes (Pnominal < .01 and |log2 FC| > 0.5) highlighted immune/inflammatory responses as key biological processes in our dataset. Differentially expressed genes in lymphocytes were highly enriched in gene expression profiles associated with cortex layer 5a and immune cells. Thus, we investigated whether the changes in transcripts levels observed in lymphocytes could also be detected in the prefrontal cortex (PFC, BA10) in a second replication cohort of schizophrenia subjects. Remarkably, mRNA levels detected in the PFC and lymphocytes were in strong agreement, and measurements obtained using RNA-sequencing positively correlated with data obtained by reverse transcriptase-quantitative polymerase chain reaction analysis. Collectively, our work supports a role for immune dysfunction in the pathogenesis of schizophrenia and suggests that peripheral markers can be used as accessible surrogates to investigate putative central nervous system disruptions.

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review

“…The specific contribution mediated by the inflammation on the molecular features of the disease will be detailed in the following sections (Fig. 2) [44].…”

Immune-Related Genomic Schizophrenic Subtyping Identified in DLPFC Transcriptome

“…In contrast to these previous studies, we used brain mRNA expression to subdivide the schizophrenics and not peripheral cytokine expression. However, there has been reported concordance between the expression levels of inflammation-related genes in the periphery and in the frontal cortex [ 22 ].…”

“…Several studies have provided evidence that inflammation and the immune system may play a role in the schizophrenia pathophysiology (e.g., [ 20 , 21 , 22 , 23 , 24 ]). Building on that, multiple research groups have identified a “high inflammation” or “immuno-subtype” where a subset of schizophrenics show upregulated expressed in immune or inflammation related genes [ 7 , 9 , 10 , 11 , 12 , 25 , 26 ].…”

Associations between inflammatory marker profiles and neurocognitive functioning in people with schizophrenia and non-psychiatric comparison subjects

“…Inflammatory biomarkers were assayed in plasma as a surrogate for measuring levels directly in cerebrospinal fluid and levels of peripheral biomarkers may not reflect levels of these biomarkers in the central nervous system (CNS). In support of using peripheral biomarker levels, one study reported that CNS changes in immune/inflammatory mRNA expression are reflected in similar mRNA expression changes in lymphocytes (Gatta et al, 2021). Selection of specific biomarkers and cognitive tests were based on available literature, and we may have overlooked additional important inflammatory biomarkers as well as cognitive domains.…”