Laboratory for the Mosaic of Autoimmunity

Scientific results:

1. Using a multiple sclerosis model in mice, we have refined a scheme for its experimental therapy. Introducing tuftsin-phosphorylcholine decelerates the development of the disease and alleviates it. The efficiency of experimental therapy depends on the dose and the scheme of administration of the drug, the drug reduces the degree of lymphoid infiltration and demyelination in lesions. For the first time, we have demonstrated the efficiency of this method with respect to autoimmune diseases of the CNS.
2. Studies of the properties of the immune complexes of patients with sarcoidosis have demonstrated that in the case of this disease blood plasma forms in vitro complexes with antigens of homologous tissues affected by granulomatous inflammation and does not form those with marker antibodies of tuberculosis mycobacteria. By studying the spectrum of autoimmunity, we have demonstrated that for 33% of sarcoidosis patients there is a characteristic increase of the titer of citrullinated vimentin autoantibodies. The relationships between the onset of sarcoidosis and some anamnestic risk factors of its development, including adjuvant-like, turn out to be accurate, which connects sarcoidosis with autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA). In the case of sarcoidosis, we have demonstrated the existence of manifestations of polyneuropathies of thin neural fibers, which is characteristic of autoimmunopathies. We found features of the spectrum of autoimmunity and subpopulations of blood lymphocytes in sarcoidosis and tuberculosis, which is similar to it. We produced a formula that allows to make the differential diagnostics of these diseases with higher resolution. In sarcoidosis we have for the first time found hyperprocalcitonemia, which can be interpreted as a confirmation of the role of infection in its etymology.
3. In a research of the relationship between Hashimoto’s autoimmune thyroiditis (AIT) and psychoses we established the influence of the levels of prolactin, free thyroxine, autoantibodies to thyroglobulin on the rate and extent of onset of psychiatric disorders. We found cases of autoimmune limbic encephalitis with antineuroreceptor autoantibodies, which imitate Hashimoto’s encephalopathy. For the first time we obtained an experimental model of Hashimoto’s encephalopathy in mice with intracisternal administration of IgG from ill mice, reproduced some of its behavioral symptoms. In mentally ill patients with AIT we found hyperprolactinemia unrelated to drug treatment. We did not observe a significant connection between mental disorders and titers of thyroid peroxidase antibodies. At the same time, in mentally ill patients with AIT an increased concentration of autoantibodies to alpha-enolase is three times more frequent than in mentally healthy individuals with AIT. The level of the latter in mentally ill individuals with AIT correlated with laboratory signs of hypothyroidism and some psychoneurological symptoms, as well as with the concentrations of the proinflammatory cytokine — IL-1b and the key cytokine of Th17-dependent immune reactions — IL-21. A correlation was found between a number of symptoms of mental disorders in cases of AIT and the concentrations of antiinflammatory cytokines and cytokines amplifying autoimmune processes. We found regularly developing hyperprolactinemia as well as a high incidence of prolactinomas and an inhomogoenous echostructure the pituitary gland during MRI scans in individuals with AIT and patients suffering from obesity with pink striae (Simpson–Page syndrome). We substantiated a new concept on the organic nature of the latter, which was previously viewed as a functional disease, and its role as a risk factor with prolactinomas. A world novelty is data obtained by us concerning the subpopulation composition of Т lymphocytes in peripheral blood in AIT (a decrease of the share of Th1 lymphocytes and double-negaive (CCR4–CXCR3–) Тh17, an increase of the share of double-positive (CCR4+CXCR3+) Th17, changes in the Tfh subpopulations). For the first time in world literature we have characterized the ferritin exchange in AIT, found an increase of its concentration in patients with COVID-19 comorbid with AIT and a decrease of the level of AIT marker autoantibodies against this background.
4. In a reproductological research we obtained an experimental model of autoimmune infertility by administering IgG of women who lost their reproductive potential due to AIT to experimental female mice. IgG of diseased individuals (but not of healthy donors) caused a pregnancy loss, hypostatura and fetal resorption, a loss of the volume and weight of the placenta, a disruption of its structure, a decrease in the number of conceptions. We found pathomorphological and pathophysiological mechanisms of these disorders (decrease in annexin V expression and changes in the structural and functional characteristics of trophoblastic cells). In a clinical pathophysiological study we have confirmed a similar connection between AIT in women with a loss or adverse outcome of a pregnancy or who underwent in vitro fertilization. Therefore we proved the pathogenic role of IgG in disruptions of pregnancy, placenta formation and fetogenesis in AIT patients.
5. In a study of the pathogenesis of various forms of autoimmune dysautonomia we obtained new high-priority data testifying to the fact that different forms of clinical chronic fatigue syndrome (CFS) meeting the criteria for myalgic encephalomyelitis —  chronic fatigue syndrome (ME/CFS), are characterized by differences in the spectrum and the intensity of autoimmunity depending on the etiology. An increased level of autoantibodies to beta-2 glycoprotein 1 turned out to be the most characteristic feature of all the etiological variants of ME/CFS. Autoimmunity to nervous tissue antigens and non-organ-specific antigens was strengthened more significantly than to organ-specific autoantigens, which indicates the secondary, dysautonomuc nature of visceral complaints of CFS patients. We found autoantibodies both correlating and discorrelating  with the diagnosis of ME/CFS. For the first time we demonstrated that, compared to control groups of women who underwent breast surgery without the use of silicone, after its silicone endoprosthesis over one year there is a significant increase in the concentration of autoantibodies to TSH receptors up to a pathological level. Before a planned and more or less long-anticipated breast surgery, regardless of its type, preoperative transient hyperprolactinemia can be observed, which is probably of psychogenic origin, that is compensated within 3 to 6 months after the surgery. Over the first year after a breast surgery the number of women with positive ASIA criteria increased. ASIA symptoms correlated with increased concentrations of some non-organ-specific autoantibodies, which, however, did not exceed normal values over this period. In women who have had silicone breasts implants for a long period (from 3 to 15 years), a number of manifestations of ASIA was observed that are similar to the clinical picture of ME/CFS. At the same time in women with long-term silicone breast implants (compared to healthy women without implants) we found a highly significant decrease in concentrations of autoantibodies to several G protein-coupled receptors of vegetation bioregulators in serum, while the levels of such autoantibodies is negatively correlated with manifestations of dysautonomia and depression symptoms. It was determined that dysautonomia in individuals with silicone implants is not a purely nervous disease but a neuroimmune one and that a certain level of autoantibodies to autonomic nervous system receptors is inherent to healthy individuals and is necessary for adequate vegetation regulation. It is not autoimmunity by itself but solely an inadequate (increased or decreased) number of autoantibodies as regulators leads to dysfunction and diseases. In the light of this fact, we proposed a new interpretation of ASIA as a prenosological  condition caused by prolonged excess stress imposed on immune neuroendocrine regulation.
6. Our oncoimmunological research has demonstrate that inhibitors of cause ASIA syndromes regardless of the presence or absence of previous autoimmune diseases and of various types of anamnestic trigger impacts. This characterizes the degree of immune stimulation caused by these drugs that leads to autoimmune manifestations even in individuals without predisposing factors in the anamnesis. On a large cohort of AIT patent we found a susceptibility to lymphocytosis and a high incidence of lymphoproliferative neoplastic diseases in AIT.
7. In geoepidemiological study we found the extreme unevenness of the regional distribution of cases of autoimmunopathies (type 1 diabetes, rheumatoid arthritis, Graves–Basedow disease) in Russia and a growth trend for the number of cases of these diseases over the investigated period. We found a statistically significant relationship between the unevenness of the distribution of autoimmune diabetes cases (both in adults and in children) in Russian and the anthropogenic factors of the automotive activities, in children it was also related to the intense pollution of the surface water sources in the region. We found a relationship between the regional numbers of cases of autoimmune and the concentrations of some microelements (mercury, iodine, aluminum) in the hair of the inhabitants of the regions. Using the Jaccard similarity measures, we  have studied the likeness of the distribution of the incidence of the main autoimmune diseases across Russian regions. The medicogeographic distribution of nosologically distinct autoimmunopathies were mutually correlated.
8. In 2022, we described a new clinical phenotype of the post-COVID syndrome, tested a new method of the diagnostics of autoimmune diseases and the post-COVID syndrome, obtained a patent for a method of diagnostics relying on in vivo confocal microscopy, for the first time we demonstrated the differences in the profile and spectrum of autoimmune reactions in various forms of chronic fatigue. As a result of the study of autoimmune consequences of silicone mammoplasty, we clarified contraindications and medical examination protocols. 

Implemented results of research:

We have modernized a methodology for coloring of histological cross-sections for the comparative analysis of methods of infiltration of human tissue and skin» and implemented it at the Resource Center for the Development of Molecular and Cell Technologies of the Saint Petersburg State University Research Park. It is applicable and important for problems of diagnostics, taking into account a significant time saving benefit (over 10 hours).

«Handbook of autoimmune diseases for general practitioners» by Yehuda Shoenfeld, Pier Luigi Meroni and Leonid P. Churilov, is used in the education process as compulsory reading. It is used at Saint Petersburg State University. The handbook is officially approved for the training discipline «Autoimmunology 1»   «Autoimmunology 2»  as part of the curriculum.

The monograph by Yuriy A. Fesenko, Leonid P. Churilov, Vladimir A. Khudik et al. based on the results of our research «Neuroses and stress» was implemented into the education process at the Research Institute of Phthisiopulmonology of the Ministry of Health of Russia,.

«Reproductively significant autoimmune diseases in ART» and «Autoimmune diseases and pregnancy programming» have been implemented in the education process (main residency  education program «Obstetrics and gynecology» for students majoring in Obstetrics and Gynecology) at the Department of Obstetrics, Gynecology and Reproductology of Saint Petersburg State University and the D. O. Ott Research Institute of Obstetrics and Gynecology and Reproductology.

Using the obtained patent «Method of forecasting of the onset of tuberculosis in healthy individuals», the method has been implemented into the practice of Research Institute of Phthisiopulmonology. The results of the study of the immunoendocrine parameters of reactivity after silicone breast prosthesis allowed to clarify the indications and contraindications, amend the pre-surgery examination scheme and implemented into the practice of plastic surgery clinics in Saint Petersburg and Krasnodar.

We have developed a method of the diagnostics of neuropathies of small fibers with the use of confocal microscopy. 

Education and career development:

The Laboratory has developed and received approval for two electronic education programs in autoimmunology for Saint Petersburg State University. They were introduced to the study plan starting from the academic year 2018–2019. In 2017–2019, the leading scientist gave lectures to undergraduate and postgraduate students of Saint Petersburg State University and conducted seminars with them totaling up to 50 academic hours each year. 

A textbook on experimental and clinical pathology for students majoring in Medical care and Dentistry is used in the education process and is available to all students. 3rd edition, corrected and amended. Edited by Leonid P. Churilov, Saint Petersburg, Spetslit, 2017, 599 p.

Employees of the Laboratory have completed internships at a specialized center and completed advanced training, participated in Russian and international forums.

Employees of the Laboratory and Saint Petersburg State University students  have received training from leading autoimmunologists and pathologists of the world in the program «Academy of autoimmunity» (Lisbon, 14–16 May 2018). Over the 4,5 years of the functioning of the Laboratory, our employees have received more than 150 certificates of advanced training.

In 2020, we created new education courses and implemented them into the education process: «Reproductively significant autoimmune diseases in ART», «Autoimmune diseases and pregnancy programming» (Dariko Niauri).

Since 2017, in the domain of the project 7 graduate qualification works, 5 specialist degree theses, 3 residency theses have been prepared and defended, as well as 3 Candidate of Sciences in Medicine dissertations.

We have published two textbooks and two study guides and introduced them into the education process.  

At academic events our employees delivered 48 invited presentations, 37 oral presentations and 33 poster presentations.

Since 2017 and to this day, we have delivered 70 invited, 120 oral and 56 poster presentations. Employees of the Laboratory participated in the 13^th International Congress on Autoimmunity in Athens (2022). On the grounds of Saint Petersburg State University we successfully staged the annual International Medical and Biological Conference for Young Researchers «Fundamental science and clinical medicine» that featured presentations and publications on the topic of the grant, such as: «Natural killers as a link between autoimmune thyroiditis and thyroid cancer», Alexandra A. Ivanchak, in the book: «Fundamental science and clinical medicine — human and his health». Proceedings of the 25^th International Medical and Biological Conference for Young Researchers. 2022. p. 26−27.

Professor Yehuda Shoenfeld continues close collaboration with the team of the Laboratory for the Mosaic of Autoimmunity of Saint Petersburg State University and contributes to the results of the conducted research. The Laboratory s team regularly (every week) participates in joint seminars and presents research at international online symposiums conducted by Professor Shoenfeld.  

Infrastructure transformations:

The work of the Laboratory and the leading scientist has been enjoying complete support from Saint Petersburg State University since 2017. At the same time, over the course of the work on this project, new branches of the three main research direction emerge and are implemented, for instance, «Immunological aspects of plastic surgery», «Research of the role of adjuvants in autoimmune diseases and studying geographic peculiarities of autoimmune diseases on the territory of Russia».

Apart from the laboratory premises allocated by Saint Petersburg State University (with an overall area of 111,7 square meters), equipped for the preliminary processing of blood samples, storage of biological materials, with work places of the leading scientist and the employees of the Laboratory and a conference hall,  we are also actively using rooms of the Saint Petersburg State University Research Park : 1) the Resource Center for the Development of Molecular and Cell Technologies, 2) the GLP compliant Vivarium of the Institute of Translational Biomedicine of Saint Petersburg State University, 3) the Pirogov Clinic of High Medical Technologies of Saint Petersburg State University. The Saint Petersburg State University Research Park has all the equipment necessary for conducting scientific research within the project. The Laboratory has mastered the equipment of the Saint Petersburg State University  Research Park necessary to achieve all the planned objectives of the project. Moreover, we purchased additional equipment necessary to ensure optimal logistics for biological material processing (a Liebherr refrigerator (Austria) for plasma and serum sample storage, an ELMI CM-6M laboratory centrifuge (Latvia), electronic analytical weighing scales (CSJC «MASSA–К», Russia) for preliminary processing of blood samples). We have purchased, installed and are operating an analyzer robot.

Clinical and pathophysiological examinations of patients and a part of laboratory research was conducted by employees of the Laboratory at clinical, scientific and educational organizations — the Research Institute of Phthisiopulmonology of the Ministry of Health of Russia, Kashchenko Moscow Psychiatric Hospital No. 1, the Institute of Experimental Medicine. Pursuant to a contract for service provision, a part of standard clinical laboratory tests of patients was conducted at the Laboratory for Diagnostics of Autoimmune Diseases of the Pavlov First State Medical University of Saint Petersburg, the Research Institute of Experimental Medicine and the Research Institute of Phthisiopulmonology, the Leningrad Oblast Oncological Hospital and the «Baltimed» clinic;. Pursuant to an agreement of scientific cooperation, we used collections of biological materials of the Saint Petersburg Pathological-anatomical Bureau.

We have opened the Center for the Study of Autoimmune Diseases and the Effects of the New Coronavirus Disease, which was named after Prof. Yehuda Shoenfeld. The center works on the grounds of the Pirogov Clinic of High Medical Technologies of Saint Petersburg State University. Employees of the Center are Russian and Israeli scientists and doctors, who also work for the Laboratory. 

Other results:

• Employees of the Laboratory have organized and staged the largest international congress in autoimmunity in the history of this domain in Russia  «A bridge between the East and the West» at Saint Petersburg State University with the participation of more than 50 leading autoimmunity researchers of the world and more than 600 Russian and foreign undergraduate and postgraduate students, medical doctors and scientists. As a result of the congress Russian scientists, including employees of the Laboratory, obtained advanced training certificates in the system of continuing medical education.

• The Laboratory won a Russian Foundation for Basic Research grant to conduct the 4^th Academy of Immunity in 2019. 

• Ariel University, Israel. The current president of Ariel University is Yehud a Shoenfeld. Internships of employees, joint research work, joint publications.
• Zabludowicz Center for Autoimmune Diseases: joint research in the domain of the grant (experimental therapy of multiple sclerosis on models), joint scientific events (seminars of researchers from this Center – Yehuda Shoenfeld, Boris Gilburd, Miri Blank, Howard Amital — at the Laboratory for the Mosaic of Autoimmunity, internships of employees  of the Laboratory at the Zabludowicz Center). Joint publications.
• Laboratory for Diagnostics of Autoimmune Diseases of the Pavlov First State Medical University of Saint Petersburg (Russia): joint research (in the directions «Immunopathological lung diseases» and «Autoimmune thyroid diseases»), joint scientific events (employees of the First Pavlov State Medical University of Saint Petersburg participated in Yehuda Shoenfeld’s seminars at the Laboratory).
• Department of General Pathology and Pathological Physiology of the Institute of Experimental Medicine (Russia): joint research, joint scientific events (employees of the  Laboratory participated in the 6th International Symposium «Interaction of the nervous and immune systems in the norm and in pathology» organized by the Institute of Experimental Medicine (Yelena A. Korneva, Yehuda Shoenfeld, Leonid P. Churilov, Yuriy I. Stroyev), employees of the Institute took part in seminars organized by Yehuda Shoenfeld at our Laboratory).
• Saint Petersburg Research Institute of Phthisiopulmonology (Russia): joint research (employees combine clinical work at the institute and research work at Saint Petersburg State University, the direction of cooperation is «Immunological lung diseases») joint scientific events (employees of the Laboratory – Leonid P. Churilov, Yehuda Shoenfeld – delivered scientific presentations at meetings of the Academic Council of the Institute   of Phthisiopulmonology).
• Institute of Translational Biomedicine of Saint Petersburg State University (Russia): joint research (modeling of autoimmunopathies on animals), joint scientific events, publications and presentations at conferences.
• D. O. Ott Research Institute of Obstetrics and Gynecology and Reproductology (Russia):  technological and methodological consulting on mastering techniques of the morphometric analysis of biological material obtained in the experimental model of the autoimmune mechanisms of the pathogenesis of infertility.
• Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences (joint research ).
• «Medical research center „IMMUKULUS”» Ltd., Moscow (joint research).
• Institute of Cytology of the Russian Academy of Sciences (joint research).
• Small Innovative Enterprise «Pharmatitan–SPbSU» — joint patented developments.