The Role of Interleukin-33 in Pathogenesis of Bronchial Asthma. New Experimental Data.

Interleukin-33 (IL-33) belongs to the IL-1 cytokine family and plays an important role in modulating immune system by inducing Th2 immune response via the ST2 membrane receptor. Epithelial cells are the major producers of IL-33. However, IL-33 is also secreted by other cells, e.g., bone marrow cells, dendritic cells, macrophages, and mast cells. IL-33 targets a broad range of cell types bearing the ST2 surface receptor. Many ST2-positive cells, such as Th2 cells, mast cells, basophils, and eosinophils, are involved in the development of allergic bronchial asthma (BA). This suggests that IL-33 directly participates in BA pathogenesis. Currently, the role of IL-33 in pathogenesis of inflammatory disorders, including BA, has been extensively investigated using clinical samples collected from patients, as well as asthma animal models. In particular, numerous studies on blocking IL-33 and its receptor by monoclonal antibodies in asthma mouse model have been performed over the last several years; IL-33- and ST2-deficient transgenic mice have also been generated. In this review, we summarized and analyzed the data on the role of IL-33 in BA pathogenesis and the prospects for creating new treatments for BA.

The TLR4 Agonist Immunomax Affects the Phenotype of Mouse Lung Macrophages during Respiratory Syncytial Virus Infection.

In the study, the effect of the TLR4 agonist Immunomax was investigated in vitro and in vivo. In particular, Immunomax was shown to polarize mouse bone marrow macrophages from the M0 and M2 states into the M1 state (ARG1 and iNOS mRNA expression levels were used to identify the mouse M1 and M2 phenotypes). Next, we investigated the prophylactic antiviral effect of Immunomax in both a model of mouse respiratory syncytial virus (RSV) infection and a model of RSV-induced bronchial asthma (BA) exacerbation. In the experiment with RSV-induced BA exacerbation, Immunomax-treated mice were characterized by a significant decrease of the viral load in lung homogenates, an increased amount of M1 macrophages in the lung, a tendency toward Th2-dependent ovalbumin-specific IgG1 antibodies decrease in blood serum, a significant increase in RSV-activated CD4+ T cells secreting IFNγ (Th1 cells), and a simultaneous significant decrease in the amount of CD4+ cells secreting IL-4 (Th2 cells) in the mouse spleen, which were detected by ELISPOT 1.5 months after experiment. These findings suggest that treatment with the TLR4 agonist Immunomax polarizes the immune response towards antiviral Th1 and may be used for short-term antiviral prophylaxis to prevent acute respiratory viral infections in asthmatics.

Regulation of the target protein (transgene) expression in the adenovirus vector using agonists of toll-like receptors.

Replication-defective adenoviral vectors are effective molecular tools for both gene therapy and gene vaccination. Using such vectors one can deliver and express target genes in different epithelial, liver, hematopoietic and immune system cells of animal and human origin. The success of gene therapy and gene vaccination depends on the production intensity of the target protein encoded by the transgene. In this work, we studied influence of Toll-like receptors (TLR) agonists on transduction and expression efficacy of adenoviral vectors in animal and human antigen-presenting cells. We found that agonists of TLR2, 4, 5, 7, 8 and 9 significantly enhance a production of the target protein in cells transduced with adenoviral vector having the target gene insert. The enhancement was observed in dendritic cells and macrophages expressing cytoplasmic (GFP), membrane (HA) or secretory (SEAP) proteins encoded by the respective rAd-vectors. Experiments in mice showed that enhancement of the transgene expression can be achieved in the organism of animals using a pharmaceutical-grade TLR4-agonist. In contrast to other TLR-agonists, the agonist of TLR3 substantially suppressed the expression of transgene in cells transduced with adenoviral vectors having insert of GFP or SEAP target genes. We propose that the enhancement of transgene expression is linked to the activation of MyD88→ NF-kB, while the inhibition of transgene expression depends on TRIF→ IRF signaling pathways. Both of these pathways jointly exploited by TLR4-agonists lead to the enhancement of transgene expression due to the dominant role of the MyD88→ NF-kB signaling.

[Immunogenetics of type 1 diabetes mellitus--from fundamental ideas to medical practice].

The review of studies of Russian researchers on theoretical and practical aspects of genetic predisposition to type 1 diabetes associated with immunity: HLA and not HLA genes. Most important for practical public health outcomes are evidence that HLA-genetic predisposition to type 1 diabetes is associated with the DRB1-genotype, consisting entirely of variants DRB1-genes associated with the development of T1D. It was also established that CTLA4 gene has an independent predictive value for T1D.

[Immune response genes products in human physiology].

Current data on physiological role of human immune response genes' proteomic products (antigens) are discussed. The antigens are specified by a very high level of diversity that mediates a wide specter ofphysiological functions. They actually provide integrity and biological stability of human as species. These data reveal new ideas on many pathological processes as well as drafts new approaches for prophylaxis and treatment.

[Regulatory role of the immune system in the organism].

The paper presents modern idea of regulatory role of the human immune system in performing a number of physiological functions including intercellular interactions, reproductive process, and forming of protection against external and internal aggression. Significance of the immune system is considered and substantiated, that of genes of the human immune response in particular in provision of human survival as a biological species.

[Prospects for development of immunoprophylaxis up to 2020 - 2030].

Analytic materials on perspectives of immunization up to 2020 - 2030 are presented. Middle-term and long-term prognoses are proposed, perspectives of development of distinct aspects of immunization are considered including increase of number of infections controlled in framework of national immunization schedule, routine immunization of middle-aged and elderly persons, keeping of routine mass vaccination during epidemiological welfare, development and implementation of alternative methods of immunization as well as using new technologies of vaccine manufacturing. It was concluded that to 2020 - 2030 synchronous use of vaccines in national immunization schedules framework will result in elimination of several anthroponoses, decreased incidence of widespread childhood infections down to sporadic cases and significant increase of life-span of patients with chronic diseases.

[The physiological role of the HLA system and the population aspects].

Identification of HLA genes and further identification of their biological role were among major achievements of medical-biological science in XX century. Several Nobel Prizes awarded in that field of science proved their importance. The end of XX Century and beginning of the XXI century were marked by introduction of molecular genetic methods in research. The contributed to development and revision of current ideas of physiological role of HLA supporting genetic homeostasis and human survival as species. Moreover they prompted to review the existing concepts of inter- and intra-populational polymorphism among HLA-frequencies.

[The use of achievements in human molecular immunogenetics in the management of type 1 diabetes mellitus].

New original data are presented on the use of achievements in human molecular immunogenetics in the management of type 1 diabetes mellitus. They include materials allowing for the prediction of the development of the disease at the population, family, and individual levels along with novel approaches to its radical treatment by the reconstitution of the lost glucose tolerance. The reported data may find wide application in current clinical practice. They open up new prospects for the enhancement of efficacy of prognosis, diagnosis, and treatment of type 1 diabetes mellitus and other autoimmune diseases.

[Significance of the functional activity of toll-like receptors and other receptors of the innate immune system of the kidney physiology].

The kidney needs to defend against microbial pathogens in order to maintain normal structure and function. This is achieved through innate and adaptive components of the immune system. For a long time, immunologists were concentrating on the adaptive immune system, which, as a result, was studied in detail; at the same time, the significance of the innate immune system was underestimated. This gap was partly filled in the recently, when the key role of the innate immune system in fighting microorganisms and in activating and regulating the adaptive immune system was convincingly established. In the first part of the present article, the sense apparatus of the innate immune system (the so-called pattern-recognition receptors) will be reviewed; particular attention will be paid to the toll-like receptors (TLRs), which bear the main burden of microorganism recognition. Signalling pathways that are activated by TLRs and result in the activation of effector mechanisms will also be reviewed. In the second part of the review, we will analyse available data on how these mechanisms of the innate immune system secure defence and normal functioning of the kidney.

[New possibilities of genotypic in the prediction of the likelihood of autoimmune diseases].

The purpose of the study was to estimate the incidence of thyroid dysfunction and cardiovascular diseases in perimenopausal females. The cross-sectional study covered 554 females (mean age 52.6±6.1 years). The levels of thyroid-stimulating hormone (TSH), total cholesterol (TC), high-density lipoproteins (HDL), low-density lipoproteins (LDL), and very low-density lipoproteins (VLDL), the incidence of arterial hypertension (AH), coronary heart disease, chronic heart failure, myocardial infarction, cerebral circulatory disorders, and the severity of menopausal syndrome (MS) were determined. The study detected euthyroldism in 381 (68.8%) patients, hypothyroidism in 168 (30.3%), out of them 35 (20.8%) patients having primary hypothyroidism, and hyperthyroidism in 5 (0.9%) females. Out of the 133 patients receiving L-thyroxine therapy, hypothyroidism was compensated. In 78(58.7%) cases, the dose of L-thyroxine was inadequate. The level of LDL was significantly higher in hypothyroidism; the median of TC was higher than the normal levels in both groups. There were no differences in the incidence of vascular disease between the groups. In both groups, AH was encountered In more than 60% of cases. The females with hypothyroidism had a more severe course of MS. With the adequate dose of L-thyroxine, the level of HDL was significantly higher and that of triglycerides and VLDL was lower than in hypothyroidism. It is expedient to include the measurement of TSH levels into the algorithm of examination of patients with severe MS.

[Physiology of innate immunity].

The mechanisms of innate immunity functioning--the first row of counteraction (resistance) to infectious agents are reviewed. A concept of pathogen associated molecular patterns--the unique prokaryotic conservative structures--as well as a concept of pattern-recognizing receptors of innate immunity cell recognizing the given bacterial patterns, are discussed. The data on molecular and genetic structures of both Toll-like- and NOD-receptors: the important compounds of pattern-recognizing receptors, the main signaling pathways from receptor to cell genome activation as well as the principles of immune cell activation by pathogen associated molecular patterns are submitted.

[The physiological activation and inhibition features of immunity cell functions. Receptor structures and intracellular signal ways of macrophages and natural killer cells].

The receptor structures of activating and inhibiting types of innate immunity central cells (macrophages and natural killer cells) participating in supporting genetic homeostasis and providing organism protection from extracellular and intracellular microbes and other alien cells, have been considered. The molecular physiological formation mechanisms of intracellular signal ways providing macrophage activation under interaction influence of Toll-like phagocyte receptors with one of its ligands: lipopolysaccharide that is the main component of gram-negative bacterium membrane have been analysed.

[New ideas of the physiological role of the genes' HLA in reproductive process].

The data presented in this paper shows the role of HLA genes and their products HLA-antigens in reproduction. The study is concentrated on new ideas of the role and mechanisms underlyin the functions of both classical and newly determined HLA genes and their products: New data and hypotheses on HLA-molecules' role in "physiological" pregnancy are discussed.

[Multiple cerebral abscess caused by Nocardia brasilientis].

Streptococcus aureus, streptococci, and enterobacteria were major causative agents of abscesses of the brain. At present, associated infection is responsible for 60% of cerebral abscesses. When systemic and specific immunities are diminished, a risk for cerebral abscesses caused by fungi increases. Among them, there are the most common fungi Candida species or Aspergillus species. The paper gives an example of successful complex treatment of multiple cerebral abscesses caused by an association of Nocardia brasiliensis and Staphylococcus epidermidis. The specific feature of the observation was the correct diagnosis before intraoperative verification of cerebral abscesses. The disease developed in the presence of diminished systemic immunity and in the absence of specific immunity to Nocardia. Immunodeficiency could be caused by prior herpetic infection, Epstein-Barr disease, a wasp bite. The pathogen that was able to cause microstrokes played an indubitable role in the pathogenesis of the disease, which predisposed to the development of cerebral abscesses in patients with immunodeficiency. Impaired blood circulation in the occipital region could be also induced by wasp venom.

[Physiology of immune response genes]. / Fiziologiia genov immunnogo otveta.

In addition to performing its major physiological function--a control of the immune response, the major gene complex: HLA system, also maintains a human genetic diversity. The latter provides optimal conditions for survival of human being as species. We submit modern data on genome and proteome mechanisms which are principal for maintenance of these functions.

[Epidemiological and economic effectiveness of immunization of adult and children against influenza and acute respiratory viral infections with the vaccine Grippol]. / Epidemiologicheskaia i ékonomicheskaia éffektivnost' immunizatsii vaktsinoi Grippol pri grippe i ORVI u vzroslykh i detei.

Materials on the characterization of the vaccine Grippol, indications for its use and the results of mass use are presented. Analysis of the morbidity level in influenza and acute respiratory viral infections (ARVI) among the vaccinated persons are indicative of considerably decreased level. The coefficient of the epidemiological effectiveness of Grippol in the immunization of children has proved to be 75-95%. The conclusion has been made that the vaccine Grippol is sufficiently effective and safe for use by Russian public health service.

[Conjugated polymer-subunit immunogens and vaccines]. / Kon"iugirovannye polimer-sub"edinichnye immunogeny i vaktsiny.

A study of fundamental mechanisms regulating the immune response resulted in producing a theory explaining the mechanism of immunostimulating properties of polyelectrolytes, as well as in working out the principles for creating the synthetic immunomodulators and, on the basis of them, polymer-subunit immunogens and vaccines. The above theory produced a basis for creating polyoxidonium, a new polymer polyelectrolyte, which was used to synthesize the conjugated polymer-subunit "Grippol" vaccine that, after its commissioning into production, has been widely used.