Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM and Paraoxonase 1 Activity

Abstract

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in schizophrenia patients with (n=40) and without (n=40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial Least Squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

Lowered Antioxidant Defenses and Increased Oxidative Toxicity Are Hallmarks of Deficit Schizophrenia: Neurocognitive and Symptom Correlates

“…on the 6 OS variables (even without FDR correction). In previous studies using the same study sample we showed that there were no significant effects of the drug state on the other biomarkers listed in table 1 [4,11]. Table 4 shows significant logistic regression models predicting deficit schizophrenia using different biomarkers sets.…”

“…TNF-α, IL-6 and CCL11 (R&D Systems, Inc, Minneapolis, MN, USA) were measured using the Bio-Plex ® 200 System (Bio-Rad Laboratories, Inc.) as described previously [9,11]. IgM levels directed to conjugated MDA were assayed using an indirect enzyme-linked immunosorbent assay as described previously [10].…”

“…While different schizophrenia subtypes (including first-episode psychosis, acute schizophrenic episodes, and chronic schizophrenia) show activated IRS and CIRS pathways, one of the subtypes, namely deficit schizophrenia, is characterized by an overwhelmingly activated IRS coupled with severe deficits in CIRS functions [7][8][9][10][11]. The latter phenotype is characterized (as compared with non-deficit schizophrenia and healthy controls) by increased neurotoxicity through elevated IL-1β, TNF-α and CCL11 levels, and signs of breakdown of gut-paracellular and vascular pathways as well as the blood-brain-barrier, increased bacterial translocation with increased IgA/IgM levels to LPS of Gram-negative bacteria, and increased IgA responses to neurotoxic TRYCATs including picolinic and xanthurenic acid [4,6,9,[11][12][13].…”

“…While different schizophrenia subtypes (including first-episode psychosis, acute schizophrenic episodes, and chronic schizophrenia) show activated IRS and CIRS pathways, one of the subtypes, namely deficit schizophrenia, is characterized by an overwhelmingly activated IRS coupled with severe deficits in CIRS functions [7][8][9][10][11]. The latter phenotype is characterized (as compared with non-deficit schizophrenia and healthy controls) by increased neurotoxicity through elevated IL-1β, TNF-α and CCL11 levels, and signs of breakdown of gut-paracellular and vascular pathways as well as the blood-brain-barrier, increased bacterial translocation with increased IgA/IgM levels to LPS of Gram-negative bacteria, and increased IgA responses to neurotoxic TRYCATs including picolinic and xanthurenic acid [4,6,9,[11][12][13]. Moreover, deficit schizophrenia is also characterized by severe deficits in the CIRS including a) lowered natural IgM-mediated responses to multiple oxidative specific epitopes (OSEs) especially malondialdehyde and azelaic acid [10], which are produced by innate-like B1 and marginal zone B cells and, as a component of the innate immune system, have anti-inflammatory, housekeeping anti-bacterial functions [10,14]; b) lowered IgM responses to TRYCATs [15], and c) lowered activity of paraoxonase 1 (PON1) activity, a strong antioxidant enzyme that is part of innate immunity and has anti-inflammatory and anti-bacterial activities [16].…”

Increased lipid peroxidation and lowered antioxidant defenses predict methamphetamine induced psychosis

“…The same disorders in LINE 1 partial methylation patterns are detected in MIP and paranoid schizophrenia and are more pronounced in the latter . Schizophrenia may result from neurotoxic processes (Maes, Sirivichayakul et al 2020) and MA usage has neurotoxic effects on cortical interneurons (Hsieh, Stein et al 2014). Activated immune-inflammatory and neuro-oxidative stress play a role not only in schizophrenia or schizophrenia phenotypes (Maes, Sirivichayakul et al 2020, Ermakov, Dmitrieva et al 2021, Cuenod, Steullet et al 2022) but also in MA dependence , Afzali, Fadaei et al 2022.…”