MD Dr Sci Orlova V.A. ¹, MD PhD Mikhailova I.I. ¹, MD Dr Sci Minutko V.L.², MD Dr Sci Poletaev A.B. ³, MD Dr Sci Simonova A.V. ⁴, MD PhD Eliseeva N.A.¹, Kretova J.Y. ¹

¹«Mental Health Research Centre, Russian Academy of Medical Sciences», Moscow; ²«Mental Health» clinic; ³Medical research center «Immunculus», Mosсow; ⁴Medical center «SM-clinic»

Abnormalities in the content of serum autoantibodies to the antigens of nervous tissue in patients with schizophrenia.

Although immune component of schizophrenia pathogenesis is well established the role and involvement of pathoimmune mechanisms in the development of the disease remain unclear. Modern immune-chemical methods enable to analyze differentially deviations in the content of neurotropic autoantibodies (a-Ab), directed to the different antigens of nervous tissues. This circumstance gives the opportunity to clarify the functional condition of nervous system structures and reveal the possible immune-metabolic abnormalities typical for different nervous and mental diseases. In the field of studying schizophrenia this work was performed in respect to some a-Ab (a-Ab to nerve growth factor [1], Glutamatergic receptors [2], S100 protein [3] and others). However, monoparametric evaluation of only one-specificity serum content a-Ab without taking into account individual immunoreactivity (which can manifest as polyclonal immune activation or polyclonal immunosuppression) may be ground for incorrect clinical conclusions. So, further research should be directed to multi-component evaluation of a-Ab content which would allow to understand systematically the real clinical data.

Material and methods

To identify immune-chemical deviations in schizophrenia we have investigated 70 patients (33 males, 37 Female) (non-treated - 63) with paranoid form of the disease (F20.01 - 03 by ICD-10) in acute state and 100 healthy controls. The mean age of the studied patients was 33.8 ±11.8 years, the average age of the controls - 34.3±9.4 years.

The highly sensitive «ELI-Neurotest» method [4, 5] and corresponding kit of reagents (Medical research center «Immunculus», Moscow) were used for the establishment of the content of 12 IgG to the Nervous system structures as well as reflecting global immune system activity. As normal values we used the standard values provided by the elaborator.

Results

The deviations of the levels of different studied a-Ab by (+10%) - (-20%) from the normal values (the reaction of "internal standard" level - control serum) were revealed in the most of patients (91.4%) and only in 3.6% of controls. Elevated parameters were prevailing (77% elevated and 23% reduced ones vs. 2.5% elevated and 0.7% reduced ones in controls). Higher values indicate to the autoimmune processes in examined patients, accompanied by abnormally high production of antibodies to brain tissue.

It should be noted that examined patients had (in 72% cases) clinical evidence of immunodeficiency such as frequent and prolonged viral respiratory infections. According to immunological investigations [5,6 and others], autoimmune processes, accompanied by severe organs` destruction, are preceded by infectious and inflammatory damages, most often caused by viruses of the herpes family and lasting for decades. In the studied sample signs of infection caused by this or that Herpes virus were detected in almost all patients (99.3%). Decreasing levels of these antibodies may indicate to different phases of a pathological process in the studied patients, as well as different dysregulation influences in the a a-Ab system. In this report we focus on the analysis of the elevated rates.

The deviations of the levels of a-Ab to glial fibrillary acidic protein (GFAP), basic myelin protein (BMP) and specific axons protein NF-200 in patients were detected most frequently (in 37.2%, 37.1% and 34.3% cases correspondingly vs. 2.1.0%, 2.9%, 1.9% in controls). The elevated levels of the pointed a-Ab were also discovered frequently (in 32.9% cases for GFAP, 30% for cases BMP and 28.6% cases NF-200 in patients vs. 3.0%, 2.7%, 1.7% in controls ) and reflected inflammation as well as neurodegeneration of neurons bodies and their axons accompanied by demyelinisation and astrocyte gliosis.

The deviations of the levels of a-Ab to GABA receptors and nACh receptors (in 27% and 24.3% of patients vs. 1.6% and 1.0% of controls correspondingly), as well as the levels of a-Ab to glutamate (NMDA and AMPA),, dopamine D1 –D5, serotonin (5-Н1 - 5-Н7) receptors (non-differentiated estimation) (less frequently – in 17,1; 18,6; 20% of patients vs. 0.9, 1.0, 1.0% of controls, respectively) indicated to the changes in the corresponding neurons systems, associated with both excitative and blocking effects of antibodies to these receptors.

Abnormalities in the content of a-Ab to voltage galed Ca++ channels (VGCC) (in 25.7% cases in the patients against 2,9% in the controls) suggested the impairment of the water-electrolyte balance in nervous system and neurons energy metabolism, as well as modification of neuro-muscular contacts function. They point to the involvement of not only big hemispheres but also the cerebellum and spinal cord in the pathological processes.

13% of patients had elevated levels of a-Ab to Ca-dependent regulator of multiple cell function the S100 protein 100 (vs. 0.7% in healthy controls), reflecting the destructive changes in brain tissue and its involvement in the systemic inflammatory response often associated with a viral infection.

The elevated parameters of a-Ab to double-stranded DNA (22,9% cases in patients vs. 1,5% in the controls) and β-2-Glycoprotein (22.9% cases in patients vs. 1,1 % in the controls) demonstrated conjugation of described alterations in nervous system with non-specific immunity apoptosis activation inducing system metabolic disturbances and pathological changes in vascular network, being determined by active infection process (presumably viral). Elevation of antibodies to beta 2-glycoprotein reflects the intensification of their interactions with the protein-phospholipids complexes of cell membranes and the processes associated with damage of vascular walls ("vasculopathy") and an increase of blood clotting (anti-phospholipids syndrome). Again, we emphasize that these processes in these patients are not limited by the brain being widespread.

Discussion

Thus, the study revealed significant abnormalities in the content of a-Ab – all-pervasive molecules that normally provide the homeostatic regulation of a variety of molecular and cellular processes including those related to functional coupling between the nervous and immune systems. It is well known that abnormally excessive production of a-Ab, being a secondary phenomenon in the development of local infection and inflammatory processes, acts as a trigger of persistent self-destructive reactions, and this was shown in our work in relation to the nervous tissue. Systemic pathology revealed in a significant number of studied patients touched a generalized increase of apoptosis and the development of systemic vascular disorders and pathology of the peripheral nervous system regarding its relationship with muscle system (abnormal neuromuscular contacts).

The latter circumstance indicates that psychiatric symptoms associated with disorders of muscle tone and movements may have not only central but also peripheral genesis. Findings suggest the need to study schizophrenia as a systemic disease with not only mental but also other integrative medical approaches.

It should be noted that part of the studied patients were included in other samples which we investigated using other disciplinary approaches. Thus, our neuropsychological studies of these samples showed the pathology of white pathways between the hemispheres as well as between the hemispheres of the cerebrum and cerebellum [6, 7]. Obtained from these samples MRI angiography data confirmed other presented results of the immunochemical study in the aspect of patients having complex of cerebral vascular disorders [9] and conjugation of these vascular disorders (including dilated perivascular spaces, venous collectors abnormalities and venous discirculation in general ) with a level of antibodies to the Herpes viruses[10].

Prospects for further immunochemical studies of autoantibodies in schizophrenia should include a wider range of markers, dynamic monitoring during treatment, study of interactions between established pathology and clinical symptoms. However, at this stage of our knowledge of the pathogenesis of schizophrenia it is necessary to develop complex therapeutic interventions that taking into account the identified etiopathogenetic factors of the disease.

Conclusions.

The study carried showed:1. Deviations of neurotropic autoantibodies content in the majority of examined patients with paranoid schizophrenia that indicate to link of pathology of cerebral structures with immunochemical disorders. 2. Processes of neurodegeneration accompanied by demielinisation and astrocyte gliosis. 3. Abnormalities in neural network of the brain. 4. Metabolism and water- electrolyte balance disturbances in the central nervous system. 5. Abnormalities in neuromuscular contacts. 6. Non-specific immune activation and immunochemical signs of anti-phospholipide syndrome. 7. Evidence for connection of local brain pathology and the generalized one with infectious and inflammatory processes which have predominantly viral etiology.

References.

1. Kozlovskaya G.V., Klushnik T.P.Goryunova A.V., Turkova I.L. et al. Autoantibodies to nerve growth factor in children with different forms of psychic dysontogenesis and from schizophrenia high risk group.//J neuropathology and psychiatry. – 2000. - N3. – P. 50 -52.

2. Steiner J., Walter M., Glanz W., Sarnyai Z., Bernstein H.G. et al. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N- N-methyl-D-aspartate glutamate receptor encephalitis.//JAMA Psychiatry.- 2013.-N3 (70). – P. 271 – 278.

3. Vartanyan M. Immunological components of mental diseases pathogenesis. In: Biological psychiatry. Moscow: «PM Vesti», 1999. -P. 152 – 160.

4. Poletaev A., Osipenko L. General network of natural autoantibodies as Immunological Homunculus (Immunculus). //Autoimmunity Review – 2003.- V. 2. - N5. –P. 264 -271.

5. Poletaev A.V. Physiologic Autoimmunity and Preventive Medicine - Bentham Science Publishers. 2013. – 235P. http://www.immunculus.ru/

6. Simonova A.V., Lebedeva I.S. Innovational methods of diagnostics and treatment of secondary immunodeficiency states.//Treating physician. - 2012.- N4. – P.16 – 19.

7. Orlova, V. A. Tsherbakova N. P., Korsakova N. K., Savina T. D., Yermakov I. L., Sudakov S. A. Neuropsychologicai Characteristics of Cortical and Subcortical Zones of the Human Brain as Multidimensional Genetic Risk Factors of Schizophrenia.// Human physiology. – 2004.-V.30.- N 3.- P.268 – 273.

8 .Gerasimova O.V., Orechov I.N., Mikhailova I.I., Orlova V.A., Minutkо V.L., Savina T.D. Neuropsychological symptoms connected with cerebellum pathology in schizophrenia. Theoretical and applied problems of medical (clinical) psychology. М. 2013. – P.183 – 184.

9. Mikhailova I.I., Orlova V.A., Berezovskaya T.P., Shavladze N.Z., Minutkо V.L. MRI- parameters of brain abnormality in attack-like schizophrenia: new data with angiography using.//Vestnik (Herald) of the Russian Scientific Center of Roentgen Radiology. – 2013.- № 13. № N1. http://vestnik.rncrr.ru/vestnik/v13/papers/michail_v13.htm

10. Mikhailova I., Orlova V., Minutko V. Berezovskaya T.P., Shavladze N.Z., et al. Clinical-immunological correlations in patients with gravely forms of attack-like schizophrenia and their connectivity with MRI signs of the brain abnormalities.// In press.