Association of Peripheral Inflammatory Biomarkers and Growth Factors Levels with Sex, Therapy and Other Clinical Factors in Schizophrenia and Patient Stratification Based on These Data.

Multiple lines of evidence are known to confirm the pro-inflammatory state of some patients with schizophrenia and the involvement of inflammatory mechanisms in the pathogenesis of psychosis. The concentration of peripheral biomarkers is associated with the severity of inflammation and can be used for patient stratification. Here, we analyzed changes in serum concentrations of cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-21, APRIL, BAFF, PBEF/Visfatin, IFN-α, and TNF-α) and growth/neurotrophic factors (GM-CSF, NRG1-ß1, NGF-ß, and GDNF) in patients with schizophrenia in an exacerbation phase. IL-1ß, IL-2, IL-4, IL-6, BAFF, IFN-α, GM-CSF, NRG1-ß1, and GDNF increased but TNF-α and NGF-ß decreased in schizophrenia compared to healthy individuals. Subgroup analysis revealed the effect of sex, prevalent symptoms, and type of antipsychotic therapy on biomarker levels. Females, patients with predominantly negative symptoms, and those taking atypical antipsychotics had a more pro-inflammatory phenotype. Using cluster analysis, we classified participants into "high" and "low inflammation" subgroups. However, no differences were found in the clinical data of patients in these subgroups. Nevertheless, more patients (17% to 25.5%) than healthy donors (8.6% to 14.3%) had evidence of a pro-inflammatory condition depending on the clustering approach used. Such patients may benefit from personalized anti-inflammatory therapy.

The Influence of Antipsychotic Treatment on the Activity of Abzymes Targeting Myelin and Levels of Inflammation Markers in Patients with Schizophrenia.

Catalytic antibodies, or abzymes, are capable of not only binding but also hydrolyzing various proteins. Previously, an increase in the level of myelin basic protein (MBP)-hydrolyzing activity of antibodies was shown in patients with a number of neurological and mental disorders, including schizophrenia. Furthermore, antipsychotic therapy is known to induce a change in cytokine levels in patients with schizophrenia, which affects regulation of the immune response and inflammatory status. This study investigated the influence of typical and atypical antipsychotics on catalytic antibody activity and the 10 major pro- and anti-inflammatory serum cytokine levels. The study included 40 patients with schizophrenia: 15 treated with first-generation antipsychotics and 25 treated with atypical antipsychotics for 6 weeks. It was found that treatment with atypical antipsychotics changed the levels of some pro-inflammatory cytokines. Antipsychotic therapy also caused a significant decrease in MBP-hydrolyzing activity in patients with schizophrenia (p = 0.0002), and associations of catalytic activity with interleukins were observed.

Different Directions of Effects of Polyclonal IgG Antibodies from Patients with Schizophrenia and Healthy Individuals on Cell Death In Vitro: A Pilot Study.

Numerous studies indicate the involvemen of oxidative stress in the pathogenesis of schizophrenia. It has been shown that the serum pool of antibodies in patients with schizophrenia contains catalytically active antibodies (abzymes) that have a wide range of activities, including redox properties. In the present work, the effects of IgGs-having oxidoreductase activities-isolated from the serum of patients with schizophrenia and healthy individuals were studied in vitro. The IgGs were purified by affinity chromatography followed by an SDS-PAGE analysis of homogeneity in a 4-18% gradient gel. The catalase and superoxide dismutase (SOD) activities of the IgGs were measured spectrophotometrically using a kinetic module. Human neuroblastoma SH-SY5Y cells were cultured with IgG at a final concentration of 0.2 mg/mL for 24 h. In a parallel experiment, tert-butyl hydroperoxide was used as an oxidative stressor. The number of dead cells after incubation was determined with fluorescent dyes, propidium iodide and Hoechst, by high-throughput screening on the CellInsight CX7 platform. A cytotoxic effect of the IgG from the schizophrenia patients on SH-SY5Y cells was detected after 24 h incubation. A correlation was found between the SOD activity of the IgGs and IgG-induced cell death. Under the induced oxidative stress, the cytotoxic effect of the IgG from the patients with schizophrenia on the SH-SY5Y cell line was five times stronger. Meanwhile, the IgG from the healthy individuals exerted a cytoprotective effect on the cultured cells, accompanied by high catalase activity. Thus, the observed influence on cell viability depends on the catalytic properties of the abzymes.

Multiplex Analysis of Serum Cytokine Profiles in Systemic Lupus Erythematosus and Multiple Sclerosis.

Changes in cytokine profiles and cytokine networks are known to be a hallmark of autoimmune diseases, including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). However, cytokine profiles research studies are usually based on the analysis of a small number of cytokines and give conflicting results. In this work, we analyzed cytokine profiles of 41 analytes in patients with SLE and MS compared with healthy donors using multiplex immunoassay. The SLE group included treated patients, while the MS patients were drug-free. Levels of 11 cytokines, IL-1b, IL-1RA, IL-6, IL-9, IL-10, IL-15, MCP-1/CCL2, Fractalkine/CX3CL1, MIP-1a/CCL3, MIP-1b/CCL4, and TNFa, were increased, but sCD40L, PDGF-AA, and MDC/CCL22 levels were decreased in SLE patients. Thus, changes in the cytokine profile in SLE have been associated with the dysregulation of interleukins, TNF superfamily members, and chemokines. In the case of MS, levels of 10 cytokines, sCD40L, CCL2, CCL3, CCL22, PDGF-AA, PDGF-AB/BB, EGF, IL-8, TGF-a, and VEGF, decreased significantly compared to the control group. Therefore, cytokine network dysregulation in MS is characterized by abnormal levels of growth factors and chemokines. Cross-disorder analysis of cytokine levels in MS and SLE showed significant differences between 22 cytokines. Protein interaction network analysis showed that all significantly altered cytokines in both SLE and MS are functionally interconnected. Thus, MS and SLE may be associated with impaired functional relationships in the cytokine network. A cytokine correlation networks analysis revealed changes in correlation clusters in SLE and MS. These data expand the understanding of abnormal regulatory interactions in cytokine profiles associated with autoimmune diseases.

Role of Demyelination in the Persistence of Neurological and Mental Impairments after COVID-19.

Long-term neurological and mental complications of COVID-19, the so-called post-COVID syndrome or long COVID, affect the quality of life. The most persistent manifestations of long COVID include fatigue, anosmia/hyposmia, insomnia, depression/anxiety, and memory/attention deficits. The physiological basis of neurological and psychiatric disorders is still poorly understood. This review summarizes the current knowledge of neurological sequelae in post-COVID patients and discusses brain demyelination as a possible mechanism of these complications with a focus on neuroimaging findings. Numerous reviews, experimental and theoretical studies consider brain demyelination as one of the mechanisms of the central neural system impairment. Several factors might cause demyelination, such as inflammation, direct effect of the virus on oligodendrocytes, and cerebrovascular disorders, inducing myelin damage. There is a contradiction between the solid fundamental basis underlying demyelination as the mechanism of the neurological injuries and relatively little published clinical evidence related to demyelination in COVID-19 patients. The reason for this probably lies in the fact that most clinical studies used conventional MRI techniques, which can detect only large, clearly visible demyelinating lesions. A very limited number of studies use specific methods for myelin quantification detected changes in the white matter tracts 3 and 10 months after the acute phase of COVID-19. Future research applying quantitative MRI assessment of myelin in combination with neurological and psychological studies will help in understanding the mechanisms of post-COVID complications associated with demyelination.

Catalytic Antibodies in Bipolar Disorder: Serum IgGs Hydrolyze Myelin Basic Protein.

The pathogenesis of bipolar affective disorder is associated with immunological imbalances, a general pro-inflammatory status, neuroinflammation, and impaired white matter integrity. Myelin basic protein (MBP) is one of the major proteins in the myelin sheath of brain oligodendrocytes. For the first time, we have shown that IgGs isolated from sera of bipolar patients can effectively hydrolyze human myelin basic protein (MBP), unlike other test proteins. Several stringent criteria were applied to assign the studied activity to serum IgG. The level of MBP-hydrolyzing activity of IgG from patients with bipolar disorder was statistically significantly 1.6-folds higher than that of healthy individuals. This article presents a detailed characterization of the catalytic properties of MBP-hydrolyzing antibodies in bipolar disorder, including the substrate specificity, inhibitory analysis, pH dependence of hydrolysis, and kinetic parameters of IgG-dependent MBP hydrolysis, providing the heterogeneity of polyclonal MBP-hydrolyzing IgGs and their difference from canonical proteases. The ability of serum IgG to hydrolyze MBP in bipolar disorder may become an additional link between the processes of myelin damage and inflammation.