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The purpose of research - to establish features of heat shock proteins (HSPs) levels change, chemokines and collagen degradation marker in the blood of patients with osteoarthritis in the age aspect. The results of the study shown, HSPs participate in the pathogenesis of osteoarthritis is complex and multi-layered process. HSP70 acts as an immunologic adjuvant reactions involving chemokine CXCL17, under the influence of external risk factors. Low levels of HSPs not allow them to act as autoimmune factor interaction with Toll-like receptors of immune cells, but obviously it contributes for CXCL17-dependent activation of dendritic cells and macrophages, which initiate local inflammation involving key cytokines, including TNF-α. Chondrocytes and osteoblasts, subjected cytokine attack, are not able to reply fully enhanced expression of HSP70 and HSP27 for whatever reason. With aging, the pathophysiology of osteoarthritis enters the phase of the local tissue reaction, where significant role have processes hypertrophic differentiation of chondrocytes and osteo-like cells of subchondral bone.

Aim: Study innate and adaptive immunity in patients with migrating erythema, clinical effectiveness ofcombined therapy using Immunovac vaccine and dynamics of immunologic parame- ters as a result of the therapy., Materials and Methods: 37 adult patients with migrating erythema were examined. The patients were divided into 2 groups: 1st gr. (14 individuals) - Immunovac by intranasal-subcutaneous method against the background of basic therapy; 2nd gr. (23 individuals) - 200 mg/day doxycycline therapy for 21 days. Phagocytic activity of blood neutrophils; TLRs expression on mononuclear leukocytes of peripheral blood (PBML) and skin cells in foci by flow cytometry with mAT against TLR2, 3, 4, 5, 6, 7, 8, 9 using flow cytometer FC-500; subpopulation composition of peripheral blood lymphocytes; levels of pro-, anti-inflammation and regulatory cytokines in blood sera by EIA method; IgG, 1gM, IgA in blood sera were studied in patients before treatment and 1 month after therapy., Results: A high level of TLR2, 4, 7, 8 on skin cells in foci, TLR2, 4 - on blood cells; low content of CD95+ and CD25+, high-level of serum IL-lb, IL-2 and IL-4, an increase of general IgE level was detected in patients'with migrating erythema. Immunovac facilitated an increase of CD95+ and CD25+, IFN-y synthesis, reduced the level of general IgE in a more pronounced way than basic therapy., Conclusion: Inclusion of Immunovac into therapy of patients With migrating erythema facilitates increase of clinical effectiveness and correlates with correction of immunologic disorders.

Purine receptors are located on immune and somatic cells of animal and human organisms. Summation of signals from purine and TOLL-like receptors takes place on the level of inflammasome formation and results in summation of the first and second signals of innate immunity. The first signal--from PAMPs (pathogen associated molecular patterns), the second--from DAMPs (danger associated molecular patterns). Adenosine triphosphate (ATP) is the most studied DAMP. ATP connects with purine receptors which include P2 (P2X7 receptors are the best described), that results in opening of channels of these receptors and transit of ATP into the cell. In parallel exit of K⁺ from cells and entrance of Ca²⁺ and Na⁺ into the cells is observed, that is associated with activation of the immune competent cell. Damaged cells dying via necrosis or apoptosis are the source of extracellular ATP, as well as activated immunocytes. Signals from P2 and TOLL-like receptors are summarized in effectors of immune response, and activation of P2 receptors in lymphocytes makes a contribution into activation of cells, mediated by T-cell receptor. Negative side of purine receptor activation is a stimulating effect on proliferation and metastasis of malignant cells. The practical output of knowledge on functioning of purine receptors for clinical immunology is the application of agonists and antagonists of purine receptors, as well as explanation of effect of immune modulators from the position of launch of K⁺/Na⁺-pump; resulting in prolonged activation of immune competent cells.

This review considers the role of innate immunity in mechanisms of transplant tolerance and rejection, analyse the role of innate immunity cells (dendritic cells-DC, NK, must and other cells) in these processes, and the pathes of creation of tolerogenic DC for transplant rejection therapy and tolerance.

This paper content analytical review of literature on commensal microflora and endogenous inductors of pathophysiological reactions of innate immunity. The important role of participation in the homeostasis of the intestinal microflora, the repair of tissue damage, maintaining the innate immune system in a state of physiological tone by interacting with receptors pattern recognition receptors. Effects of the interaction of components commensal flora and innate immune receptors play an important role in physiological processes of microorganism in maintaining the balance of the synthesis of pro-inflammatory and anti-inflammatory cytokines and antimicrobial substances.

Studies of Toll-like receptors (TLR) in 20 cosmonauts-members of long-duration (124-199-day) missions to the International space station evidenced changes in relative and absolute counts of peripheral blood monocytes with TLR2, TLR4 and TLR6 on the surface, expression of TLR2 and TLR6 genes, and genes of molecules involved in the TLR signaling pathway and TLR-related NF-KB-, JNK/p38- and IRF pathways on the day of return to Earth. The observed changes displayed individual variability.

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease developing as a result of the interaction between genetic predisposition and environmental factors. Considerable role in allergic diseases development is played by polymorphisms of genes of pattern-recognition receptors (PRR) which are capable of recognizing conservative standard molecular structures (patterns) unique for large pathogen groups. In this study polymorphic variants of PRR genes--Toll-like receptors (TLR1, TLR2, TLR4, TLR5, TLR6, TLR9, TLR10), NOD-like receptors (NOD1, NOD2), lipopolysaccharide receptor CD14 gene, and C11orf30 and LRRC32 genes, located in 11q13.5 region, have been investigated in AD patients and control subjects from the Republic of Bashkortostan. An association of TLR1 (rs5743571 and rs5743604), TLR6 (rs5743794) and TLR10 (rs11466617) with AD was found. Our results confirm an important role of the innate immune system in the pathogenesis of AD and the significance of polymorphisms within the Toll-like receptor 2 subfamily genes in AD development.

The article reports survey data on 23 patients with erythemas, including 19 patients with herpes-associated erythema multiforme (HAEM) and 4 patients with Darier's erythema annulare centrifugum (DEAC). Patients in the initial state (baseline) and after two weeks of therapy with proteflazid were characterized by measuring the levels of Toll-like receptor (TLR) expression in peripheral blood mononuclear cells (PBMC) and in epithelial cells of the throat and the skin. The TLR expression in PBMC and skin was assessed by flow cytometry with monoclonal antibodies (ICA) (Caltag Laboratories, USA; Hycult Biotech, Netherlands) against relevant antigens. In addition, patients were also characterized by the content of subpopulations of lymphocytes expressing surface markers CD3, CD4, CD8, CD16, CD21, CD23, CD72, CD25, and HLA-DR in the peripheral blood, which was measured by flow cytometry. The therapy with proteflazid in patients with both HAEM and DEAC led to normalization of the level of both T-cell and B-cell immunity, which was manifested by an increase in the total number of lymphocytes, CD3+, CD4+, CD21+, and CD72+. Measurements of the dynamics of TLR expression in the course of immunotherapy showed an increase in the number of TLR 2, 3, 4, 7, 8, and 9 in PBMC (which was especially pronounced for TLR2) and in epithelium of the pharyngeal mucosa and skin (increased expression of TLR3, 7, and 9).

Aim: Confirmation of immunostimulating effect of an original low molecular weight germanium organic compound (LMW-GOC) during immunization of mice with Vaxigrip vaccine., Materials and Methods: The experiments were carried out in CBA mice divided into 4 groups: control, those that received Vaxigrip influenza vaccine intraperitoneally, those that received LMW-GOC intraperitoneally and those that received both preparations at once. Effect of the preparations administered was evaluated by flow cytofluorometry based on changes of CD3, CD4, CD5, CD8, CD19, CD25, Foxp3, NK1.1, gammadelta T, MHC II, TLR2, TLR4, TLR9 expressing cell content in mice spleens. The content of the colored cells was determined at normal, 24 hours and 7 days after the administration of the preparations. Statistical treatment of the data was carried out by using Win MD 128 program package., Results: LMW-GOC can enhance the effect of Vaxigrip vaccine that is expressed by an increase of content in spleen of some lymphocyte subpopulations 24 hours and 7 days after the intraperitoneal administration. In some cases LMW-GOC increases the content of some lymphocyte subpopulations in mice spleen after administration as a monopreparation, i.e. without the vaccine. LMW-GOC suppressed stimulating effect of the vaccine on the spleen content of various lymphocyte subpopulations in none of the observations., Conclusion: By using cytofluorometry method it is possible to form an understanding of an elevated role of various types of cells in the development of immune response to the vaccine as well as regarding additional enhancement of this response during administration of LMW-GOC to mice. The effect of the preparation is manifested for a few days after its administration. The preparation manifests adjuvant properties and after further studies may be suggested for use as an adjuvant.

The article is dedicated to examination and analysis of materials on translocation of microflora and its products from intestine to the internal environment of the macroorganism and persistence of biologically active substances of microflora in the bloodstream. High frequency of translocation and persistence of intestine microflora and its components in system bloodstream is shown. Persistent biologically active substances of endogenous microorganisms take part in human physiology and pathology.

Contemporary data on the interaction of commensal microflora and Toll-like pattern recognition receptors are presented. These receptors recognize normal intestine microflora in physiological conditions, and this interaction is necessary for the maintenance of homeostasis and damage reparation of the intestine, for the induction of heat shock cytoprotective proteins. As a side effect in disruption of immunologic tolerance and misbalance of protective immunological mechanisms, multiorgan pathologic changes of organs and tissues may develop, including chronic inflammation processes of various localization.

In the study concerning morphology and pathogenesis of psoriasis a number of Langerghans's cells (CD1a+) and an expression of toll-like receptors (TLR2, TLR4, TLR9) in psoriatic and normal skin has been estimated. A statistically significant increase of Langerghans's cells as well as the expression of TLR2 and TLR4 in psoriatic lesions has been founded out. The importance of observation in the pathogenesis of psoriasis has been discussed.

Aim: Proof of therapeutic efficacy of a novel type of vaccine with a combination of natural Toll like receptor agonists (TLR) 1/2, 4, 5/6, 9 in infectious and noninfectious human pathology., Materials and Methods: Immunovac-VP-4 vaccine, containing antigens of opportunistic microorganisms that are TLR 1/2, 4, 5/6, 9 ligands, was used for experiments and clinical trials., Results: Immunovac-VP-4 activates innate immunity by inducing maturation of dendritic cells with expression of costimulating molecules on their membrane (CD40+, CD80+, CD86+), terminal differentiation molecules--CD83+ and antigen-presenting molecules (MHC class I and II); activates proinflammatory (TNFalpha, IL-6) and regulatory (IL-12, INFgamma) cytokine synthesis that programs T-lymphocyte differentiation by Th1 pathway; increases cytotoxic activity of natural killer cells, inhibits melanoma B16 growth and Lewis lung carcinoma metastasis. Therapeutic effect of Immunovac-VP-4 was evident regardless of pathology by a significant decrease of quantity and severity of recidives, improvement of all clinical parameters, reduction of quantity of administered pharmaceutical preparations including antibiotics and glucocorticosteroids. The rate of intercurrent acute respiratory viral illnesses and their bacterial complications decreased. Immunovac-VP-4 therapy modified course of illness from severe into milder forms. Positive therapeutic effect was 69.2 - 100%., Conclusion: High therapeutic effect of vaccine therapy is based on innate immunity activation by combining TLR agonists. Immunovac-VP-4 contains an optimal combination of natural TLR agonists that ensure high therapeutic effect in various nosological forms of infectious and noninfectious human pathology.

The system of congenital immunity was studied in 12 essentially healthy males 18 to 26 years of age subjected to 5-day dry immersion without use of countermeasures. Peripheral blood was analyzed for monocytes, granulocytes and lymphocytes expressing the TLR2+, TLR4+, TLR6+, CD11b+, CD14+, CD16+, CD18+, CD24+, CD36+, CD54+, CD56+ and CD206+ receptors. Expression of early activation marker CD69 on lymphocytes-natural killers was studied in unstimulated and interleukin-2 activated mononuclear cell cultures. The negative shifts in the congenital immunity system in some volunteers at the end of immersion and during recovery can be considered as warnings about depletion of the system reserve and increase of the risk of infectious diseases such as caused by normal microflora which typically does not provoke pathological reactions of the host.

Despite the numerous ways the host defended viral infections, which mediated through reactions of innate and adaptive immunity, viruses escape from immune surveillance by interacting with receptor molecules of immune system for penetration into a cell and activation of synthetic processes in it for realization of early stages of viral replication. Recently, data about signaling receptors of innate immunity--Toll-like receptors (TLRs), which participate in recognition of conservative molecules of pathogenic microorganisms including viruses, were published. In this review several variants of effects of viruses (paramyxovirus, cytomegalovirus, smallpox virus, measles virus, and others) on TLR-mediated mechanisms of innate immunity are presented. Obtained data can be used for development of new antiviral drugs as well as vaccines.

Aim: To study the Toll-like receptor (TLR)-mediated functional activity of peripheral blood mononuclear cells (PBMC) from children with different forms of neutropenia., Materials and Methods: TLR-mediated functional activity of PBMC was evaluated by production of proinflammatory cytokines--TNF alpha and IFN alpha. Ligands for TLR1/2, TLR 2/6, TLR4, TLR5, and TLR9 were used to stimulate TNF alpha production by PBMC from healthy children and children with neutropenia. Ligands for TLR3, TLR4, TLR7, TLR7/8, TLR8, and TLR9 were used to induce production of IFN alpha. Levels of TNF alpha and IFN alpha were measured in PBMC supernatants by ELISA. The group of patients with neutropenia included 9 children with immune neutropenia and 3 children with congenital neutropenia. Control group consisted of 12 healthy children of the same age range., Results: It was revealed that TLR2, TLR4, and TLR5 ligands have enhanced stimulating effect on TNF alpha production by PBMC of children with congenital neutropenia and had no effect on PBMC of children with immune neutropenia. Children with immune neutropenia are characterized by significantly increased IFN alpha production induced by ligands of TLR3, TLR8, and TLR9., Conclusion: Revealed changes of TLR-mediated functional activity of PBMC from children with various forms of neutropenia may play significant role in development and course of infections in these patients.

Innate immunity is the first line of host defense against infection including those caused by herpesviruses. Toll-like receptors (TLRs) are the main pathogen-recognizing receptors. TLR2 binds to glycoproteins of herpesvirus virion; intracellular TLR9 recognizes nonmethylated CpG repeats of herpesvirus' DNA, which lead to activation of receptor signaling pathways and synthesis of proinflammatory cytokines, chemokines, antimicrobial peptides and other molecules, which participate in induction of innate immunity mechanisms. Many viruses (measles virus, cytomegalovirus etc.) activate expression of TLRs for more effective replication of the virus in cells.

Cellular and molecular mechanisms of congenital immunity at different levels are discussed including single cell expression patterns and intracellular localization of individual TLR, the use of adapter molecules for generation of activation signals in response to microbial and non-microbial pathogens, soluble trap receptors, and intracellular negative regulators.

Ideas of I.I Mechnikov stated in biologic theory of inflammation and, specifically, about leading role of phagocytic cells are getting more and more prevalent. Special attention is paid to study of Toll-like receptors (TLRs) and cytokines roles in initiation of inflammatory reaction. TLRs are present not only on immune system's cells but virtually on all cells of an organism. On the basis of these data we proposed the hypothesis designated as "one receptor-many cells" and "one receptor-one cell". In the former case the leading role in recognition of antigen belongs to TLRs then followed by other organism's cells, which is characteristic for innate immunity. In the latter case recognition is realized through T- and B-cell receptor presented only on lymphocytes, which is characteristic for adaptive immunity. New class of lipid mediators (rezlovins, protectins etc.) involved in stage of inflammation resolve is revealed. This means that drugs with antiinflammatory activity can act according to principle "go-stop". Complex of natural cytokines and cationic antimicrobial peptides (Superlymph) possesses such effect.

Increasing interest to heat shock proteins (HSP) from biologists and medics is connected to widespread distribution of HSP in live nature and reflects their key role in support of life functions which is based on the unique polyfunctionality of these biomolecules. Together with main function, which is defense of biologic systems from stress effects, some HSP in the process of evolution acquired the ability to incorporate in the reactions of the immune system. The in vestmen of this protein in practical reactions of innate immunity system are described. Analysis of mechanisms underlying the adjuvant effect of pro- and eukaryotic HSP in innate immunity system is presented. HSP receptor structures on target cells as well as triggered intracellular signaling pathways are described.

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.

Production of citokines of tumor-necrosis factor (TNF)-alpha and interferon (IFN)-alpha by peripheral blood mononuclear cells (PBMC) from healthy men and from patients with common variable immunodeficiency (CVID) after stimulation with zymosan, lypopolysaccharides, flagellin and CpG, which are ligands of TLR 2/6, TLR 4, TLR 5, TLR 9 respectively, was studied in vitro. In healthy men production of TNF-alpha varied between individuals, whereas synthesis of IFN-alpha was similar. Spontaneous production of TNF-alpha by PBMC in patients with CVID was increased and accompanied by decrease in TNF-alpha production stimulated by each analyzed ligands except CpG. Observed changes in TLR-dependent TNF-alpha production can play important role in pathogenesis of CVID.

Regulatory T-cells CD4+CD25+Foxp3 (Treg) present a small subpopulation of CD4+ T lymphocytes, which develop in the thymus and are disseminated into peripheral lymphoid organs on the 3rd or the 4th day of the neonatal period. Treg play a decisive role in the pathogenesis of autoimmune diseases and the development of tolerance to transplantation antigens, regulate the immune response to allergens, and suppress antimicrobial immunity. Treg suppress proliferation as well as the cytotoxic effect and the secretion of Th1 and Th2 cytokines by effectory T lymphocytes, thus limiting the strength of the immune response of effectory T-cells, which makes them impossible to adequately control viral and bacterial infections. Recognition via antigen-presenting cells and the subsequent induction of the proliferation of antigen-reactive T and B lymphocytes, directed towards infectious agent elimination, is accompanied by the activation of regulatory T cells as well, which leads to immune response suppression; repeated microbial infections are not only able to strengthen T-cell immunity by generating memory T-cells, but can also strengthen the suppressive activity of endogenous T regulators CD4+CD25+. Moreover, T reg are capable of the direct recognition of a microbial product; these cells selectively express Toll-like receptors (TLR)-2, -4, -5, -7, and -8. Under normal conditions T reg are anergic, but are capable of direct proliferation in response to stimulation by TLR ligands, expressed on microbes and parasites. Treg removal enforces protective immune response to contagious microorganisms, including bacteria, viruses, and fungi, which leads to the elimination of pathogens from the host organism. The removal of Treg population will help to accomplish infectious pathogen elimination and diminish inflammation within a short period of time.