First Episode Psychosis and Schizophrenia Are Systemic Neuro-Immune Disorders Triggered by a Biotic Stimulus in Individuals with Reduced Immune Regulation and Neuroprotection

Abstract

There is evidence that schizophrenia is characterized by activation of the immune-inflammatory response (IRS) and compensatory immune-regulatory systems (CIRS) and lowered neuroprotection. Studies performed on antipsychotic-naïve first episode psychosis (AN-FEP) and schizophrenia (FES) patients are important as they may disclose the pathogenesis of FES. However, the protein–protein interaction (PPI) network of FEP/FES is not established. The aim of the current study was to delineate a) the characteristics of the PPI network of AN-FEP and its transition to FES; and b) the biological functions, pathways, and molecular patterns, which are over-represented in FEP/FES. Toward this end, we used PPI network, enrichment, and annotation analyses. FEP and FEP/FES are strongly associated with a response to a bacterium, alterations in Toll-Like Receptor-4 and nuclear factor-κB signaling, and the Janus kinases/signal transducer and activator of the transcription proteins pathway. Specific molecular complexes of the peripheral immune response are associated with microglial activation, neuroinflammation, and gliogenesis. FEP/FES is accompanied by lowered protection against inflammation, in part attributable to dysfunctional miRNA maturation, deficits in neurotrophin and Wnt/catenin signaling, and adherens junction organization. Multiple interactions between reduced brain derived neurotrophic factor, E-cadherin, and β-catenin and disrupted schizophrenia-1 (DISC1) expression increase the vulnerability to the neurotoxic effects of immune molecules, including cytokines and complement factors. In summary: FEP and FES are systemic neuro-immune disorders that are probably triggered by a bacterial stimulus which induces neuro-immune toxicity cascades that are overexpressed in people with reduced anti-inflammatory and miRNA protections, cell–cell junction organization, and neurotrophin and Wnt/catenin signaling.

Precision Nomothetic Medicine in Depression Research: A New Depression Model, and New Endophenotype Classes and Pathway Phenotypes, and A Digital Self

“…For example, this approach would allow for tailoring on-label treatments to a specific EEG profile, thereby maximizing the clinical efficacy of selective 5-HT reuptake inhibitors and not selective noradrenaline reuptake inhibitors. Nevertheless, the major problem with this approach is that a) biomarkers are found in networks of highly intercorrelated gene expression, protein–protein interactions, and multi-omics network data that interact with neurocognitive functions and the brain connectome data, making stratifying one or another biomarker or a group of biomarkers meaningless [ 52 ]. Most importantly, as explained in Section 4.2 , a correct depression model should be based on the causal links between the building blocks of an illness (see also below).…”

The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis

“…All in all, the pathogenic IL6/IL23/Th17 axis, which may be induced by microbiota, contributes to neurocognitive deficits and the phenome of schizophrenia and especially MNP, due to its key role in peripheral inflammation, gut and BBB permeability, neuroinflammation and ensuing neurotoxic effects on CNS circuits. Such effects will appear or be more prominent in subjects with CIRS deficits including lowered IL-10, magnesium, calcium, and zinc (this study), and deficits in antioxidant, miRNA and neurotrophic defenses including in brain-derived neurotrophic factor, neurotrophin/Trk, RTK and Wnt/catenin signaling (22).…”

“…First, BDNF is adversely related with IL-23 and illness severity ratings in schizophrenia (90), and a first protein-protein interaction (PPI) network created using FEP/FES genes shows that BDNF is part of the same immune PPI network as STAT3, IL-6, TNF-α, IL-1β, and IL-10 (91). Second, complement component factors that have a role in schizophrenia, such as C1q, C3, and C4 (22, 92, 93), may affect the production of IL-23 and IL-17 family members (94). Third, BBB endothelial cells express IL-17 and IL-22 receptors, and binding to IL-17 and IL-22 causes BBB permeabilization (95, 96), thereby aggravating the effects of LPS, other cytokines and tryptophan catabolites on BBB breakdown (97).…”

“…We previously addressed IL-6 and TNF-’s many neurotoxic actions, which, when coupled with other neurotoxic substances like as LPS and lipid peroxidation, may produce neurotoxicity and, hence, explain the cognitive deficits and phenome of schizophrenia (109, 110). As discussed previously, these compounds may induce a plethora of neurotoxic effects, especially on processes like neurogenesis, neuroplasticity, cerebral cortex radial glia guided migration, synapse assembly, axogenesis, axonal spreading and branching, synapse assembly and structure, pre- and post-synaptic neuronal connectivity, regulation of excitatory synaptic functions and post-synaptic protein assembly (111). By inference, the strong effects of the IL6/IL23/Th17 axis on both the cognitive detrioration and symptomatome of schizophrenia indicate that also IL-23, Th17, IL-22 and IL-21 may further contribute to the neurotoxic effects.…”

“…Key players in the CIRS are negative immunoregulatory cytokines produced by Th2 (IL-4) and T regulatory (Treg) (IL-10) cells (16). Importantly, relative deficits in the CIRS are associated with a worse outcome of FEP (21) and with increased neurocognitive impairments and the worsening in FEP and MEP (22). Moreover, increased neurotoxicity due to increased levels of toxic cytokines (e.g., IL-1β, IL-6, IL-8, TNF-α, and IFN-γ) and chemokines (e.g.…”