Immunoinflammatory Profile in Patients with Episodic and Continuous Paranoid Schizophrenia

Introduction. Associations of disturbances in innate and adaptive immunity during the clinical course of schizophrenia have been found in a number of studies. Yet, the relationship of immune parameters and systemic inflammation in relation to the clinical course of the disease and its prognosis, remains poorly understood, which highlights an interesting topic for further research. The goal of this study was to research the immuno-inflammatory changes in patients with clinical continuous and episodic paranoid schizophrenia, to assess the pathogenetic significance of these changes. Methods. Thirty-six patients with paranoid schizophrenia, of which 20 had episodic symptoms and 16 had continuous symptoms, consented to participate in the study, together with 30 healthy volunteers. In the study we assessed the parameters of innate immune response (serum levels of key pro-inflammatory and anti-inflammatory cytokines, C-reactive protein) and the adaptive immune response, including humoral-mediated immunity (serum immunoglobulins IgA, IgM, IgG, circulating immune complexes), as well as the cell link of adaptive immunity (key lymphocyte subpopulations). Positive and negative symptoms were assessed with the positive and negative symptoms scale; frontal dysfunction was assessed by Frontal Assessment Battery (FAB). Results. Both patient groups had higher than normal levels of C-reactive protein and IL-8. There was a significant elevation of circulating immune complexes among patients with continuous symptoms of schizophrenia, compared to patients with episodic symptoms and healthy controls. Levels of CD45+CD3+ lymphocytes (T-cells) differed between clinical groups, with higher values identified among patients with episodic symptoms and lower values among those with continuous symptoms. In addition, patients with episodic symptoms had significantly increased levels of CD45+CD3+CD4+CD25+CD127- regulatory T-cells. Finally, the level of CD45+CD3-CD19+ B-cells was significantly higher among patients with continuous symptoms vs. patients with episodic symptoms and the control groups. Markers of activation of humoral immunity were associated with the severity of frontal disorders in these patients. Discussion. Comprehensive data on the serum level of cytokines and the parameters of adaptive immunity among individuals with continuous schizophrenia, by comparison with patients with episodic schizophrenia, are practically absent in the literature. We have shown that among those with continuous schizophrenia, there are signs of systemic inflammation and chronic activation of the adaptive humoral immune response, while among patients with episodic symptoms of the disease, there are signs of systemic inflammation and certain activation of cell-mediated immunity, without significant changes in the humoral link of adaptive immunity. Conclusion. More studies are needed, but the data obtained in this study are important for subsequent clinical studies of new treatment methods, based on various immunophenotypes of schizophrenia.


INTRODUCTION
Schizophrenia is a polymorphic mental illness, characterized by disorders of thinking, perception, impairments of memory, attention and executive functions.The prevalence of schizophrenia in Russia is around 1%, with most cases among young adults (peak incidences occur between the ages of 15 and 35).The socio-economic burden, associated with schizophrenia, is determined by a high percentage of disability and by high costs of treatment and maintenance. 1cessive activation of microglia and astrocytes, are found in schizophrenia. 2 pathogenetic mechanism in some patients. 2 series of evidence is being discussed relating of schizophrenia. 3,5-10There is a hypothesis that one of the leading components of the pathogenesis of this disease is immune dysfunction, associated with an increased risk of infections and autoimmune disorders (Figure 1).It has been shown that patients with schizophrenia have higher rates of exposure to pathogens such as toxoplasma gondii, cytomegalovirus and the human herpesvirus type 6.[13][14] The role of immune disorders in the pathogenesis of schizophrenia is supported by epidemiological and molecular biological data.Thus, according to several studies, including meta-analyses, there are signs patients with schizophrenia, including elevated levels [5][6][7][8][9] Schizophrenia is also characterized by an increase in the serum level of neutrophil activation (leukocyte elastase, a1-proteinase inhibitor), and the levels of these markers correlate with the activity of the disease. 10In patients with nonpsychotic mental disorders, changes in the level of neutrophil activation markers are much less common. 15In addition, the serum concentration of the chemokine, CCL2, which is involved in the migration of monocytes, memory T-cells and in patients with schizophrenia. 16 In the case and IL-6, however, no changes were evident with 5

Increased
8][19] According to another study, 20 In addition, a 17% decrease in the volume of the left Broca's area was observed among patients with a high level of cytokines. 20e disease, are also found in studies of the postmortal brain of patients with schizophrenia.21, 22 In the prefrontal cortex of these patients, the mRNA level of the Interferon-Induced Transmembrane Protein protein is the activation of the transcription factor 21 cortex of patients. 22[25] According to a meta-analysis of 16 works, the level of CD4 + T-helper cells, CD16 + CD56 + NK cells, naive B-cells and CXCR5 + memory T-cells, was increased among those with schizophrenia. 24,25However, according to other data, the level of T-helper cells, as well as the ratio of CD4 + / CD8 + in schizophrenia are reduced, and the patients have impairments of T-cell activation. 23,26rhaps these contradictions are associated with examined patients.
There are data that suggest that the neutrophil/ lymphocyte ratio, platelet/lymphocyte ratio and monocyte/lymphocyte ratio are higher during the relapse periods of schizophrenia, compared to the remission periods. 27tivation in schizophrenia, including excessive lymphocyte and monocyte activation, is currently independent of cardiometabolic risk factors.28 Currently, and immunomodulating agents in the treatment of schizophrenia are also of great interest.29 Thus, research data indicate that there are numerous signs of the adaptive immunity in schizophrenia.However, in terms of the perplexity of the immune response (Figure 1), there is a lack of research into multiple immune parameters in schizophrenia 30 and their relationships in terms of the clinical course of schizophrenia and its shown in Figure 1.
Both the innate and the adaptive immune system involve a cell-mediated (immune cells) and humoral-

MATERIAL AND METHODS
The study included 36 patients with paranoid schizophrenia (see Table 1) and 30 healthy volunteers

RESULTS
Table 1 shows the socio-demographic characteristics of the participants.The patients generally had fewer opportunities to progress to higher education or to be employed.
The clinical characteristics of patients are presented in Table 2.As can be seen, in the continuous course of schizophrenia compared with the episodic course, of negative symptoms and cognitive disorders.
Table 3 summarizes the data on the immune parameters of patients with episodic and continuous symptoms, and those of the healthy control group.The adaptive immunity has shown that the levels in patients course of the disease (Table 3).Both patient groups had higher than normal levels of CRP compared to the control group.

Correlations with clinical scores
Among patients with episodic symptoms, a moderate, cytokine, IL-10, with NSA-4 scale results was revealed Among patients with continuous symptoms, the level of CD45+CD3-CD19+ B cells and the level of the CIC showed a moderate, negative correlation with the of activation of humoral immunity in this subgroup of patients, was associated with more pronounced cognitive impairment.
Therefore, the patients with continuous schizophrenia had an excessive activation of humoral immunity, that was associated with the severity of cognitive disorders

DISCUSSION
In this study we found multiple signs of immunological in Figure 2    pronounced with regard to chronic symptoms of the disease. 34The results are consistent with our data on the serum levels of these cytokines.According to a metaanalysis, 5 in acute schizophrenia, the levels of IL-6, while in chronic schizophrenia, the same meta-analysis with a psychotic episode or chronic schizophrenia, activation of innate immune cells of antigens to adaptive immune cells (T-lymphocytes and B-lymphocytes).When facing an antigen, the T-lymphocytes mediate cytotoxicity against the infected or altered cells and activate B-lymphocytes to proliferate and produce immunoglobulins.The activated immune cells are orchestrated by the variety of cytokines and produce acute phase proteins.The goal of this research was to study the immunoclinical symptoms of paranoid schizophrenia (episodic and continuous) compared with healthy controls.This was conducted in order to assess the associations of immunological changes with clinical of multiple immune parameters in both episodic and continuous schizophrenia.
with no mental disorders (13 men, 17 women), interval) age of the volunteers was 27.1±1.6years, ranging from 23 to 33 years.The duration of maintenance antipsychotic therapy among patients, ranged from six before the assessment was three to four weeks.The compliance of the participants mental state at the time of the examination with the criteria for schizophrenia, informed written consent was also required to participate in the study.Patients with recurrent symptoms (Group 1) and patients with continuous symptoms of schizophrenia (n=16) (Group 2) were included in the according to DSM-5 criteria, by persistent symptoms disorder that remained throughout the duration of the illness.Subthreshold symptom periods were very brief in relation to the overall symptoms and it was impossible symptoms, the defect was stable and there were distinct psychotic episodes, with symptomatic remissions lasting more than six months.The exclusion criteria were severe somatic diseases, pregnancy, acute or exacerbated, two months preceding the examination or signs of drug or alcohol abuse.The PANSS, BFCRS, Simpson-Angus Scale (SAS), Symptom Severity Scale of the DSM5 for schizophrenia (SS-DSM5) and the FAB scale were used in clinical assessments.31We measured the parameters of humoral-mediated immunity (levels of Circulating Immune Complexes (CIC), immunoglobulins IgA, IgM, IgG), levels of signalling proteins.The parameters of the cell link of adaptive using monoclonal antibodies for the phenotyping of the CD25, CD45, CD56 and CD127 (Becton Dickinson, USA).IL-10, the markers of the humoral link of adaptive immunity CIC, the immunoglobulins (IgA, IgM, IgG) in blood serum by enzyme-linked immunosorbent assay (ELISA) and the commercial kits for ELISA by "Cytokine", "Vector Best" and "Hema" (Russia) were used.For statistical processing, Excel software (Microsoft, 2010) and STATISTICA 10 (StatSoft, 2010) were used.The Shapiro-Wilk test was used to assess the normality of distribution.The results of immunological tests were presented as medians with an interquartile range.The Kruskell-Wallis test was used to assess the hoc, pair-wise comparisons conducted using the Mann-Whitney test.The results of the clinical assessment (age, duration of education and illness, results of clinical scales) demonstrated a normal distribution and were presented as means +-standard deviations.The Student's t-test results of the clinical assessment between groups.The

Figure 1 .
Figure 1.Key mechanisms of the immune response continuous symptoms, by comparison with patients with episodic symptoms and healthy controls, whereas the Cell-mediated immunity between clinical groups, with higher values among those with episodic symptoms and lower values among those with continuous symptoms.Despite the fact that their levels in control group had intermediate the clinical groups of the controls.In addition, patients levels of CD45+CD3+CD4+CD25+CD127-regulatory T-cells.Finally, the level of CD45+CD3-CD19+ B-cells continuous symptoms vs. patients with episodic symptoms and among the control groups.
below.While the levels of CRP and IL8 were increased in schizophrenia, irrespective of clinical groups, the patients with episodic symptoms demonstrated (/CD4+) cells, and patients with continuous symptoms had increased levels of CD45+CD3-CD19, B-cells and CIC vs. the control group.Interestingly, the numbers among the clinical groups but not among the controls, were slightly increased among patients with episodic symptoms and were slightly decreased among patients with continuous symptoms.Therefore, in summary, patients with episodic symptoms of schizophrenia were characterized by changes in the humoral link immunity.Conversely, patients with continuous schizophrenia had signs of the humoral immune response.An analysis of the literature shows that the relationship 1 2 2

33 has
not been studied in detail and may be dependent on the duration of therapy and the drugs used.According to in vitro studies, conducted by Ryazantseva et al. among patients with schizophrenia, there is an imbalance in the production of Th1 and Th2 cytokines by lymphocytes and signs of inhibition of the T-cell following an examination of patients receiving outpatient treatment.It should be noted that comprehensive data on the serum level of the main cytokines and the characteristics of adaptive immunity among those with continuous symptoms of schizophrenia, by comparison with episodic symptoms, are practically absent in the to continuous schizophrenia, changes in the adaptive immune response with a predominance of activation of its humoral link are of primary importance, although do persist in patients.In particular, an increase in the content of CIC, which are formed as a result of the binding of exogenous or endogenous antigens by process with activation of the humoral link of adaptive immunity.The causes of this activation remain to be studied.It is possible that the activation of autoimmune schizophrenia (n=16) and among the controls (n=30) Consortium Psychiatricum | 2021 | Volume 2 | Issue 1 processes may take place among certain patients According to the literature (see, for example, a review 35 ), in a number of schizophrenic patients, antibodies to NMDA receptors and other central nervous system proteins are detected in the peripheral bloodstream.Based on our results, it can be assumed that patients with continuous symptoms of the disease and signs of excessive activation of humoral immunity, are a risk group for the possible presence of autoimmune diseases, and an examination may be necessary in these patients to exclude a hidden autoimmune pathology.According to our data, with regard to the episodic course of the disease, there was a pronounced complex activation of the mechanisms of systemic and endogenous.In addition, there was an increase is involved in the chemotaxis of neutrophils, monocytes reaction.There was also an increase in regulatory T-cells, which, taking into account the increased level indicate compensatory activation of immunoregulatory mechanisms.Further studies are required to determine At the same time, the activation of immunoregulatory mechanisms in certain patients may have a protective role and also requires further study.A correlation analysis showed that among patients with continuous symptoms of schizophrenia, the severity of cognitive impairment was associated with a higher level of CIC and B-cells, and among those with episodic correlated with the severity of negative symptoms changes in various types of schizophrenia, and indicate approaches to immunomodulating therapy, within the framework of the comprehensive rehabilitation of patients with schizophrenia, depending on the clinical course and immune disorders.

Figure 2 .
Figure 2. Key results of the study.