Autism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene–environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood–brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD. Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated. Claudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to controls. In the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.

https://link.springer.com/content/pdf/10.1186%2Fs13229-016-0110-z.pdf

Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders.

The inflammatory hypothesis of schizophrenia (SZ) posits that inflammatory processes and neural-immune interactions are involved in its pathogenesis, and may underpin some of its neurobiological correlates. SZ is the psychiatric disorder causing the most severe burden of illness, not just owing to its psychiatric impairment, but also owing to its significant medical comorbidity. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation worldwide. There are some conflicting results regarding the behaviour of CRP in SZ. The aims of this study were to verify whether peripheral CRP levels are indeed increased in SZ, whether different classes of antipsychotics divergently modulate CRP levels and whether its levels are correlated with positive and negative symptomatology. With that in mind, we performed a meta-analysis of all cross-sectional studies of serum and plasma CRP levels in SZ compared to healthy subjects. In addition, we evaluated longitudinal studies on CRP levels before and after antipsychotic use. Our meta-analyses of CRP in SZ included a total of 26 cross-sectional or longitudinal studies comprising 85 000 participants. CRP levels were moderately increased in persons with SZ regardless of the use of antipsychotics and did not change between the first episode of psychosis and with progression of SZ (g=0.66, 95% confidence interval (95% CI) 0.43 to 0.88, P<0.001, 24 between-group comparisons, n=82 962). The extent of the increase in peripheral CRP levels paralleled the increase in severity of positive symptoms, but was unrelated to the severity of negative symptoms. CRP levels were also aligned with an increased body mass index. Conversely, higher age correlated with a smaller difference in CRP levels between persons with SZ and controls. Furthermore, CRP levels did not increase after initiation of antipsychotic medication notwithstanding whether these were typical or atypical antipsychotics (g=0.01, 95% CI -0.20 to 0.22, P=0.803, 8 within-group comparisons, n=713). In summary, our study provides further evidence of the inflammatory hypothesis of SZ. Whether there is a causal relationship between higher CRP levels and the development of SZ and aggravation of psychotic symptoms, or whether they are solely a marker of systemic low-grade inflammation in SZ, remains to be clarified.

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications.

Discovery and development of integrative biological markers for schizophrenia

Current studies on the development autism spectrum disorders (ASD) at different ages are reviewed. The review highlights the increasing interest to this problem and converging positions of researchers from different countries, encouraged by the development of international and other classifications of mental diseases, on the terminology, classification and prevalence of ASD in children. An important feature of the present stage is to draw attention to an understudied problem of ASD in adults, including elderly, and provision of medical and social care to these patients.

[Autism spectrum disorders in children and adults: the experience of reserches from different countries].

The level hydrolysis of myelin basic protein (MBP) by IgG in patients with schizophrenia was studied depending on the clinical features and course of the disease. The patients were grouped according to type of schizophrenia and type of disease course. We found that IgGs isolated and purified from sera of schizophrenia patients' blood hydrolyses human MBP, and the level of this hydrolysis significantly exceeds that of healthy individuals. Detection of protease activity corresponding only to intact IgGs in polyacrylamide gel fragments, together with data of gel filtration of antibodies under conditions of "acid shock" (concordance of optical density profile of IgG with profile of MBP-hydrolyzing activity) and with the absence of any other proteins and bands in gradient SDS-PAGE and in PVDF membrane provides direct evidence that the IgGs from the schizophrenia patients have MBP-hydrolyzing activity. The antibodies-specific proteolytic activity of patients with acute schizophrenia (1.026 [0.205; 3.372] mg MBP/mg IgG/h) significantly exceeds the activity of IgG in patients in remission (0.656 [0.279; 0.873] mg MBP/mg IgG/h) and in healthy individuals (0.000 [0.00; 0.367] mg MBP/mg IgG/h). When comparing the specific activity in patients with different types of disease course, we have found that patients with a continuous course of paranoid schizophrenia (1.810 [0.746; 4.101 mg MBP/mg IgG/h]) had maximal activity values. It can be assumed that the increase in the activity of MBP-hydrolyzing antibodies is due to the activation of humoral immunity in acute schizophrenia.

/pdf/igg-dependent-hydrolysis-of-myelin-basic-protein-of-patients-4nensqp2xj.pdf

Igg-Dependent Hydrolysis of Myelin Basic Protein of Patients with Different Courses of Schizophrenia.

The level of antibodies (AT) to neuroantigens (nerve growth factor and basic myelin protein) has been studied in the serum of 80 patients with schizophrenia, attack-like type, (ICD-10 items F20.01-02) during the treatment with psychotropic drugs. Therapeutic effectiveness has been measured clinically and with the PANSS. It has been shown that the autoimmune component is present during the acute episode of schizophrenia in about 30% of cases. No statistically significant differences have been found in the mean values of AT before and after the treatment however the dynamics of their changes has been closely related with the results of therapy: the decrease of AT level during the therapy is a predictive factor for good therapeutical remission; on the contrary, the increase of this level may be considered as an unfavorable prognostic factor.

Changes of the level of serum antibodies to neuroantigens in patients with schizophrenia during the treatment

A state of innate and adaptive immunity (leukocyte elastase (LE) activity, alpha(1)-proteinase inhibitor (alpha(1)-PI), the level of autoantibodies to nerve growth factor (Aab-NGF) and to basic myelin protein), have been studied in the blood serum of children with schizophrenia and compared to the changes of their clinical-psychopathological state. It has been shown that the exacerbation of schizophrenic process with early onset is accompanied by the activation of some parameters of innate immunity. But the higher activity of LE and alpha(1)-PI before the treatment cannot be considered as a predictive marker of therapeutic efficacy. At the same time, the decrease of LE activity during the treatment is a significant predictor of favorable therapeutic response. The unchanged level of Aab-NGF comparing to controls is also a favorable factor associated with therapeutic efficacy.

Dynamics of immunological and clinical parameters in the treatment of childhood schizophrenia

Leukocyte elastase (LE) activity, functional activity of alpha1-proteinase inhibitor, C-reactive protein, autoantibodies to nerve growth factor and to basic myelin protein have been studied in the blood serum of children with psychotic forms of autistic disorders - children psychosis (F8402) and atypical children psychosis (F8411) The activation of innate immunity (the increase in LE activity and acute phase proteins) was seen in children psychosis The more severe mental disturbances, that are characteristic of endogenous atypical children psychosis, were accompanied by the activation of both innate and adaptive immunity ( the increase of the level of autoantibodies to neuroantigenes in the peripheral blood) Correlations between immunological and clinical parameters suggest the involvement of innate and adaptive immunity in the formation of autistic and cognitive disorders in children

[Innate and adaptive immunity in children with psychotic forms of autism-spectrum disorders].

Sixty-seven patients, aged 16-25 years, with the first episode of endogenous psychosis (ICD-10 items F20.03, F20.23, F25) have been examined. Positive, negative and general psychopathological symptoms were assessed with the PANSS. Activities of leukocyte elastase (LE) and alpha1-proteinase inhibitor were used for measuring of innate immunity and the level of autoantibodies to nerve growth factor (Aab-NGF) was used for measuring of adaptive immunity. The manifestation of endogenous psychosis was accompanied by the activation of innate immunity, the level of activation was not related with the syndrome structure of episode (the prevalence of catatonic, hallucinatory-delusional or affective-delusional symptoms). The LE activity and dynamics of Aab-NGF during the treatment may be considered as prognostic markers of treatment effectiveness: the higher LE activity during the episode and decrease of Aab-NGF in the treatment process may predict a favorable therapeutic response.

Correlations between clinical and immunological parameters in endogenous psychoses with a first episode at the juvenile age

State of innate and adaptive immunity has been assessed by the indices of activity of leukocyte elastase, alpha1-proteinase inhibitor (alpha(1)-PI), level of C-reactive protein and autoantibodies to neuroantigens (nerve growth factor and basic myelin protein) in different forms of mentalopathology: schizophrenia-spectrum disorders, mental retardation with behavioral abnormalities, organic mental disorders, affective disorders, psychogenias (adaptation disorders), early alcoholism. The increase of activity or levels of all immunological parameters was characteristic of these diseases. However within each group were patients with different levels of immunity activation. A number of patients with significant immunity activation was higher in the groups of schizophrenia-spectrum disorders, early alcoholism, organic mental disorders, mental retardation with behavioral abnormalities and affective disorders. The lowest frequency of such cases was observed for psychogenias (adaptation disorders). These results give grounds to suggest that the extent of immunity activation depends as on severity of psychopathogy as well on individual peculiarities of immunological reactivity in response to a brain pathological process.

Immunological reactions in different forms of mental disorders

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