The theory of polyetiological tumorigenesis is one of the most important theories of carcinogenesis. A great place in this theory is given to the role of inflammatory component, which is implemented via the factors of innate immunity. I.e., toll-like receptors (TLRs), chemokines and their receptors are related to innate immunity. Activation of TLRs may lead to regress or progression of cancer process. It is known that TLR3, TLR5, TLR7, TLR9 have the greatest anti-tumor effect due to the dendritic cells (DCs)-mediated activation of type I T helpers, activation of M1-type macrophages and Treg inhibition. Stimulation of TLR2 and TLR4 exerts an activating effect upon the tumor, by the MyD88 hyperactivation and secretion of IL-6 and TNFα, but exact mechanisms are not fully understood. In addition to TLRs, chemokines and their receptors have a great influence on the cancer development. It is shown that CCL2, CCL4, CCL17, CCL22 and CXCL12, which are secreted by cancer microenviroment, activate chemotaxis of tumor cells. It is also known that the chemokines activate CXCR4 and CCR7 (expressed by tumor cells) thus leading to metastasis.

It is shown that there is an association between some gene polymorphisms of TLRs’, chemokines and their receptors, and development of cancer.

Thus, we may conclude that the role of TLRs and chemokines is important in oncogenesis. Further study of innate immunity factors influencing tumorigenesis are important for finding new approaches to cancer therapy and new potential vaccines against cancer. 

Over last decade, the importance of immune mechanisms for development of psoriasis has expanded considerably. This review describes biological properties of the cytokines from the interleukin-36 (IL-36) family, and their role in pathogenesis of plaque psoriasis, generalized pustular psoriasis and psoriatic arthritis. Keratinocytes and dendritic cells (DC) are the main sources of IL-36 in the skin. Production of this cytokine is greatly enhanced by inflammation. The studies have shown that, in affected skin of psoriatic patients, an increased expression of IL-36α and IL-36γ is observed. IL-36γ can be considered a specific marker of psoriasis, which is not found in other inflammatory skin diseases (neurodermatitis, lichen planus, eczema). The levels of this cytokine correlate with severity of psoriasis and decreases after anti-TNFα therapy. High level of IL-36 cytokines in the areas of psoriatic eruptions correlates with increased concentrations of pro-inflammatory TNFα, IL-17, IL-22 and IFNγ in the skin. We present literature data on the role of IL-36RN mutation which encodes the IL-36ra receptor antagonist, playing a role in the development of generalized pustular psoriasis (GPP). Excessive activity of IL-36 agonists leading to accumulation of neutrophilic granulocytes in epidermis may be a key event in the GPP pathogenesis. The article deals with modern ideas about the role of neutrophilic granulocytes in development of chronic inflammatory processes underlying pathogenesis of psoriasis. Proteases of neutrophils (cathepsin G, elastase and proteinase-3) are potent IL-36 activating enzymes that increase activity of IL-36 cytokines up to 500 times. In this review, a new mechanism (netosis) is suggested for the role of neutrophils in immune response. During the netosis, a large number of cytokines, antimicrobial peptides, intracellular components, serine proteases are released into the extracellular space. Thus, they may be involved into initiation and maintenance of a chronic inflammatory process in psoriasis.

The present information concerning a role of new IL-36 family cytokines as one of the main psoriasis mediators has opened new therapeutic goals for the treatment of this disease and development of new methods of targeted therapy. Specific blocking of IL-36R signaling, or inhibition of neutrophil proteases of cathepsin G, neutrophil elastase that activate members of the IL-36 family, is likely to be a successful strategy in the therapy of psoriasis. 

Traumatic brain injury (TBI) commonly proceeds as a severe disease with high morbidity that can lead to neurological disorders in some of these patients. TBI is associated by multidirectional abnormalities of immune system, which affect quantity and functions of T-, B-, and NK-lymphocytes leading to infectious complications or autosensibilization. Restoration of the disturbances in neuroimmune interactions after TBI may be achieved by means of immunomodulators that have neuroprotective properties and may potentially initiate regenerative CNS activity. IL-2 is a cytokine that possesses neurooperative and neuroprotective properties. In immune system, IL-2 is produced by T-cells in response to antigen stimuli; in CNS, by brain cells. Lack of IL-2 production by both T-lymphocytes and brain cells increases a possibility of autoimmune and inflammatory pathologies. The objective of present study was to evaluate possible effects of human recombinant IL-2 (rIL-2, Roncoleukin®, Biothech Ltd., Russia) upon state and correction of immune and neuro-endocrine TBI consequences. The study was performed in adult Wistar rats. Mechanical TBI was produced by the dropping load model. 72 hours after inflicting the TBI, r-IL-2, at dose 30 mg/kg was injected once a day for three times. The animals from control group received 0.15M NaCl solution over the same period. The results have shown that, within first hours and days after TBI, corticosterone levels showed a sharp increase, whereas testosterone concentrations were decreased.In parallel, an increase in cytotoxic and proliferative activity of splenocytes was revealed, as well as increased number of splenocytes at their late apoptotic stage. Three daily injections of rIL-2 resulted into a significant increase in corticosterone and testosterone levels in injured animals on the day 7 after TBI. The animals treated with rIL-2 have exhibited more rapid normalization of cytotoxic and proliferative activity of splenocytes and return to normal ratio of proliferating splenocytes vs. apoptotic cells. Therefore, usage of rIL-2 may correct neuro-endocrine and immune interaction disturbances after TBI and decrease risk of chronic neurological disorders in TBI patients.

This work concerned a comparative study of potentiating effects produced by some drugs of natural origin, as well as metformin, upon antitumor activity of doxorubicin. An increased therapeutic efficacy of doxorubicin used in combination with echinochrome A, oxycarotenoids, ginsenoside Rh2, and metformin was tested in the in vivo Ehrlich ascites carcinoma model. The negative effect of luteolin disulfate (10 mg/kg body weight) upon efficacy of antitumor therapy was revealed. When studying the effect of these substances on the level of intracellular ROS in primary cultures of murine spleen cells, using a selective fluorescent indicator (2’,7’-dichlorofluorescein-diacetate), we did not find a positive correlation between induction of excessive ROS synthesis and potentiation of doxorubicin action with the compounds studied. Some of the studied agents showed a positive correlation between interferon-inducing activity, as well as a negative correlation between increased IL-1 content, and higher antitumor effect of doxorubicin. The obtained results suggest expedience of further studies of antitumor effect potentiation using preparations of echinochrome, ginsenoside Rh2, a mixture of oxygenated carotenoids and metformin.

Previous studies have revealed associations of antibodies, specific to chemical carcinogens and steroid hormones with lung cancer in men. However, the mechanisms of their formation and action were remained unclear. In particular, the relationships between antibodies and gene polymorphisms of cytokines were un- known. The purpose of this study was to identify possible associations between occurrence of A class antibodies, specific to benzo[a]pyrene, estradiol and progesterone (IgA-Bp, IgA-Es and IgA-Pg), and frequency of genetic polymorphisms of IL1RN VNTR, IL1В (rs1143634, rs16944), IL4 VNTR, IL6 (rs1800795), IL10 (rs1800896), TNFA (rs1800629, rs361525) genes in healthy male smokers and lung cancer patients.

We have examined 381 men with non-small cell lung cancer and 158 apparently healthy donors without respiratory diseases. A non-competitive solid phase immunoassay of antibodies was performed. Analysis of polymorphic loci of IL1RN (VNTR, intron 2), IL4 (VNTR, intron 3) was performed by means of conventional PCR; IL1В (rs1143634, rs16944), IL6 (rs1800795) SNPs were detected by RFLP, and IL10 (rs1800896), TNFA (rs1800629, rs361525) genotyping was carried out with TaqMan Real-time PCR. Results of the study have shown that the proportion of cases with high level of IgA-Pg and low levels of both IgA-Bp and IgA-Es among the lung cancer patients was lower than in healthy men (OR = 0.31, p < 0.0001). Vice versa, the ratio of cases with high levels of both IgA-Bp and IgA-Es and low levels of IgA-Pg was higher in lung cancer patients (OR = 3.6, p < 0.0001). No relationships were revealed between the levels of antibodies, and rates of genetic polymorphisms for the studied cytokines in both groups of men. At the same time, the detected associations of IgA-Bp, IgA-Es and IgA-Pg with lung cancer proved to be significant only in carriers of certain cytokine genotypes, e.g., in AG IL10 heterozygotes (OR = 5.1, p < 0.0001).

In conclusion, these results provide indirect evidence that IgA-Bp and IgA-Es could stimulate initiation and promotion of lung carcinogenesis. On the contrary, IgA-Pg could inhibit the promotion of carcinogenesis. Immunoassay of these antibodies combined with molecular biology studies of IL10 gene variants are recommended for the lung cancer risk assessment.

Treatment efficiency of chronic infertility does not exceed 40% when using in vitro fertilization (IVF) programs. Therefore, sufficient attention should be given to studies of pathogenetic mechanisms, identification and correction of the factors that adversely affect onset and outcomes of pregnancy. It is known that hypersecretion of cytokines interferes with implantation, but their relationship with immunoregulatory proteins is poorly understood for various types of infertility. The aim of present study was to investigate changes in cytokine contents (IL-8, IL-6, TNFα, IFNγ), lactoferrin and α2-macroglobulin concentration in follicular fluid and venous blood of women with infertility of various genesis, and to evaluate their effects upon results of the IVF programs.

The studied proteins were determined in the samples obtained on the day of transvaginal puncture of follicles in 28 infertile women with external genital endometriosis, 38 cases of chronic endometritis, 31 women with polycystic ovary syndrome, 25 patients with adenomyosis, and in 37 women with pure tubal infertility factor (comparison group). According to IVF outcomes, the patients were retrospectively divided into those who became gravid, and women with pregnancy failure. In cases of external genital endometriosis, we have found reduced contents of chemoattractant IL-8 in follicular fluid and blood, as well decreased levels of lactoferrin, which modulates its synthesis and shows antiproliferative activity. In blood of non-pregnant women with tubal infertility associated with chronic endometritis, increased concentrations of pro-inflammatory TNFα and lactoferrin were revealed, thus suggesting presence of latent inflammation. Among women with polycystic ovary syndrome, the TNFα concentration in follicular fluid and blood was reduced, along with increased content of IFNγ. In cases of adenomyosis, the IFNγ levels in follicular fluid were increased, accompanied by reduced content of regulatory-transport α2-macroglobulin in blood samples.

The revealed changes in cytokine concentrations and proteins which regulate their synthesis, in biological samples from infertile women may explain the ineffectiveness of IVF programs in a number of cases. Such an imbalance has a negative impact upon development of oocytes, growth of embryos, and their ability for implantation. It is important to continue further investigations of such pathogenetic factors in order to improve approaches providing better efficiency of IVF in chronic infertility treatment.

The aim of the study was to investigate the phenotypic features of dendritic cell (DCs) differentiated from peripheral blood monocytes in patients with kidney cancer (KC). The study involved 28 patients with KC (Т3N0М0, clear cell type) before surgical treatment at the age of 40-55 years and 31 healthy age-matched people. Immature DCs (IDCs) were generated from blood monocytes by culturing for 5 days with GM-CSF and IFNα. Activation of the DCs (MDCs) was induced by incubation with tumor cell lysate and TNFα followed by incubation for 48 hours. Phenotyping of DCs at different maturity degrees was carried out by the method of flow cytometry. It was found that the monocytes differentiated into IDCs formed a cellular pool with a high level of costimulatory activity in patients with KC, by increasing number of cells with a high level of CD80 and CD86 receptor expression. In this case, a significant amount of undifferentiated monocytes and cells with an intermediate phenotype (CD14+CD83+) remained in the cell culture. In KC patients, the cell culture formed an increased number of IDCs with the CD83+CD80highCD86highHLA-DR+ phenotype (in comparison with the control values). However, expression level of the HLA-DR receptor on CD83+CD80highCD86high-IDCs in patients with KC was reduced. Therefore, this type of DCs has a high costimulatory and weak antigen-presenting activity. Maturation (activation) of DCs from patients with KC was accompanied by retained amounts of undifferentiated monocytes in cell culture associated with decreased contents of cells with CD14+CD83+ phenotype. Presumably, a part of cells with the CD14+CD83+ phenotype and additional antigenic and cytokine load matured to the level of MDCs. Mature DCs in patients with KC are characterized by weak costimulatory and antigen presenting activity, due to decreased expression of CD83 and CD86 markers. Upon maturation, the amount of DCs with different levels of CD80 expression in cell culture in healthy people and in patients with RP is equalized, but the MDCs with a highly active phenotype (CD83+CD80highCD86high и CD83+CD80highCD86highHLA-DR+) are formed with KC cells to lesser degree. Moreover, MDCs with CD83+CD80highCD86high phenotype in tumor patients show weaker expression of receptors providing costimulatory and antigen-presenting activity. The differences in the IDCs and MDCs phenotype between healthy people and KC patients may be determined by different features of phenotype and functional activity in blood monocyte populations as well as immunosuppressive factors synthesized by the tumor.

Cytotoxic T lymphocytes (CD3+CD8+, Tcyt) play a major role in protective immunity against intracellular pathogens and can eradicate malignant cells. As based on CD45RA and CD62L expression, the peripheral CD3+CD8+ blood lymphocytes were divided into "na ve" (N) cells, central memory (CM) and effector memory (EM), as well as "terminally-differentiated" CD45RA-positive effector cells (TEMRA). Using multicolor flow cytometry, a co-expression of effector (perforin, granzyme B and CD57) and regulatory (CD27, CD28, CD244 (2B4), CD279 (PD-1) and KLRG1) molecules was studied on all these subsets. CD57 was expressed in 2.39±0.31% “na ve” and 5.45±0.91% of central memory Tcyt. Meanwhile, within EM and TEMRA Tcyt subset, its expression was identified on the cell membranes of 26.53±2.20% and 51.43±2.55% of cells, respectively. Cytolytic effector molecules (granzyme B and perforin) were detected in cytoplasmic granules of 4.22±0.36% and 5.30±0.43% of na ve Tcyt, respectively. For CM cells, these values were 10.09±1.17% and 24.90±3.10%, respectively. Dramatic increases of granzyme B and perforin expression were observed in the “EM → TEMRA” cell lineage, when the relative number of granzyme B-positive cells increased to 41.05±2.63% and 66.73±3.29%, respectively, while perforin was detected in 59.33±4.26% and 75.08±3.12% of cells, respectively. For regulatory molecules, CD244 and KLRG1, the similar dynamics were observed, their expression increased from “na ve” to late maturation stages, while the expression of two main costimulatory molecules – CD27 and CD28, decreased in the lineage N → CM → EM → TEMRA cells. The highest level of CD279 was observed in EM cells. It was shown that CD57-positive cells contain perforin and granzyme B in their cytoplasmic granules and lack CD28 expression. Furthermore, CD57 can be used as a surrogate marker for multicolor immunophenotyping to identify most mature effector cells containing cytolytic enzymes. Our results on the co-expression of all the beforementioned molecules suggest that the most mature CD45RA+CD62L– effector peripheral blood cytotoxic T cells express CD244 and CD57, lack costimulation molecules CD27 and of CD28, as well as inhibitory receptors KLRG1 and CD279.

In view of increasing epidemic danger potential of some natural plague foci and performing measures to provide specific prevention of this infection, it becomes necessary to carefully monitor the state of immunity in vaccinated (revaccinated) individuals. The aim of the study was to assess humoral and cellular immunity levels in the persons after repeated anti-plague revaccination performed for appropriate epidemiological indications. Evaluation of immune responses to anti-plague revaccination was carried out according to studies of blood samples from 20 people aged 24 to 53 years living in the Caspian sandy natural plague focus located at the territory in Kalmykia Republic. Specific antibody titers to the F1 antigen of plague microbe were assessed in blood serum by immunoassay testing using an “ELISA-AT-F1 YERSINIA PESTIS” test system (Russian Research Anti-Plague Institute “Microbe”, Russia), along with spontaneous and concanavalin A-induced production of different cytokines, i.e., IFNγ, TNFα, IL-4, IL-10 (Vector-Best, Russia), IL-17A (Bender Medsystems, Austria). The studies were performed before vaccination, and 1, 6, 12 month after the booster vaccination.

The results of the study indicate that immunological reconstitution after revaccination with live plague vaccine occurs occurred mostly according to mixed Th1/Th2 type. Detection of antibodies to the F1 specific plague microbe antigen before and 1 month after revaccination (65 and 85%, respectively) was indicative of development of humoral response. The most informative cytokine markers (IFNγ and TNFα) for evaluation of an anti-plague cellular immune response have been identified. The threefold increase in IFNγ induced production before revaccination indicates to initial immunological competence of all the examined individuals. A high correlation between TNFα and other cytokine levels was determined. The fact of high correlation for the studied cytokines (TNFα, IFNγ, IL-10) indicated to a synchronism in the immunocompetent T helper cell reaction. By measuring the levels of spontaneous and induced cytokine production levels, one may indirectly judge on degree of anti-plague cell immunity in humans.

As a result of activation and/or apoptosis, the cells can form microvesicles (MV) from 100 nm up to 1000 nm in size. Nowadays, the attention is being increasingly focused on dynamic detection and evaluation of leukocyte-derived microvesicles by their contents. In this regard, determination of microvesicles formed by NK cells is of utmost interest. The main function of these population is to induce apoptosis of virus-infected and tumor cells. At the present time, there is no direct evidence of the NK cells ability to produce microvesicles. This investigation was performed in order to estimate contents of NK cell-derived microvesicles using highprecision flow cytometric approach. It has been shown that the high-precision flow cytometry allows to detect microvesicles formed by NK cells, ranging from 200 to 1000 nm in size. It was demonstrated that incubation of NK cells in the presence of TNFα did not affect the relative value of microvesicles, however, being associated with increased intensity of CD95 expression on microvesicles. Hence, the high-precision flow cytometry can be used to detect microvesicles and to determine their phenotype. 

Defects in programmed death of peripheral blood lymphocytes may result into autotolerance and chronic persistence of inflammatory reaction in rheumatoid arthritis. According to recent data, apoptosis is not an autonomous process, i.e., an excessive accumulation of cells in conjunction with a depleted medium leads to cellular excess, thus causing effect of cells already committed to apoptosis upon surrounding cells, by morphogenetic damage due to mechanical forces. Such effects are called compensatory proliferation or apoptosis-induced proliferation. Extracellular vesicles (ectosomes and apoptotic bodies) also have a negative effect on cultured cells, triggering their programmed apoptotic death. In turn, apoptosis can also be controlled by neighboring cells in non-autonomous manner.

We conducted studies that allowed us to optimize methods aimed at the initiation of apoptotic cell death and to investigate the effects of apoptotic environment upon autologous cells under physiological conditions. The selected conditions in combination with a fluorescent labeling of lymphocytes and subsequent separate flow cytometric analysis allowed us to evaluate parameters of early apoptosis in subpopulations of peripheral blood T-lymphocytes in rheumatoid arthritis. In vitro studies of cells from the patients with rheumatoid arthritis allowed us to reveal a pronounced readiness of primary (CFSE) and secondary (CFSE+)-induced T lymphocytes for early apoptosis after stimulation with anti-CD3 antibodies. It was observed both against initial level of apoptosis, and when compared to cells induced for apoptosis. The obtained data suggest that stimulation of T lymphocytes with antibodies against CD3, and, as a result, an in vitro rise in cell proliferation rate leading to increased levels of early apoptosis not only among the cells directly receiving a proliferative stimulus, but also to increased effect of cellular and humoral components from anti-CD3-stimulated cultures upon normally proliferating lymphocytes.

The transfer of an autologous apoptotic “aCD3” and dexamethasone-stimulated cultures, which were initially induced under conditions of cell overcrowding and medium exhaustion, was shown to activate the process of early apoptosis among normally proliferating cells. Glucocorticoids are known to serve as agents of cell death induced by activation. At pharmacological concentrations, glucocorticoids and their synthetic analogues stimulate endonucleases in activated lymphocytes. These enzymes destroy DNA in the internucleosomal regions thus resulting into cell apoptosis. The results obtained in present study suggest an opportunity of an in vitro early-stage apoptosis induction in T lymphocytes from the patients with rheumatoid arthritis, by means of cells subjected to activation-induced apoptosis. 

This article presents a detailed description of shifts in subsets of blood lymphocyte subpopulations associated with development of the corneal ulcerative lesions as well as during penetrating keratoplasty.

We have revealed some general changes typical for patients with corneal ulcer and patients with keratoplasty, reflecting inflammatory activity, i.e., a significant increase in the numbers of lymphocytes (CD45+), relative and absolute contents of the T-cell population (CD3+), CD3+ CD4+ subpopulation, and B-lymphocytes (CD19+), as compared with the control group. A statistically significant increase in natural killer cells (СD16+СD56+) proved to be a distinctive feature of the group with keratoplasty.

When analyzing mean values of CD4+/CD8+ cells from the patients with corneal ulcer, there was no statistically significant difference between the clinical groups studied. However, individual comparison of nature and frequency of CD4+/CD8+ shifts among the patients with «high» index allowed qualitative separation of the third group (severe corneal ulcer): a severe imbalance of main T-cell subpopulations was detected 2.4 times significantly more often than in the group of patients with mild forms of corneal ulcers.

The obtained data are important for understanding pathogenesis of centrally localized corneal ulcer, and should be taken into account when predicting and developing a differentiated approach to the treatment of the disease. 

Already about one hundred years BCG remains the only widely used tuberculosis (TB) vaccine. It is known that intensity of the BCG-induced Th1 immune response decreases over time and comes to naught within 10-15 years. It significantly distinguishes BCG from the vaccines providing a lifelong protection such as vaccines against poliomyelitis or measles, and can be bound to natural restriction of duration of a persistence of the BCG-induced CD4+ T-cells. Data on insufficient ability of BCG to stimulate life-long immunological memory is accumulating. Earlier in our lab on the model of rather resistant to TB C57BL/6 mice infection with the virulent laboratory strain of Mycobacterium tuberculosis (Mtb) H37Rv protective activity (comparable to that of BCG Russia) of 3 subunit vaccine variants was demonstrated as assessed by lung and spleen CFU counts and life span of animals after infection. The aim of this study was to study the characteristics and duration of the immune response induced by the most effective variant of these vaccines. Groups of C57BL/6 mice were vaccinated intramuscularly twice with two-week intervals with 10 μg protein conjugated to 200 μl of an aluminum hydroxide emulsion. Immune response (production of specific antibodies, vaccine proteinstimulated production of interferon gamma and proliferation in vitro) was monitored during 10 months after vaccination. We have shown that the test vaccine induces in mice the formation of long-term immunological memory to a bacterial antigen. Moreover, in the presence of glutoxim the immunological memory spectrum shifts to a "protective" type, i.e. the predominance of the cellular component of the immune response over the antibody response is stimulated. The next step will be the investigation of vaccine effectiveness for revaccination after primary BCG immunization. 

To date, pathogenetic events underlying coronary heart disease and hypertensive syndrome should be regarded as complex reactions of neuroimmune interactions characterized by activation of proinflammatory cytokines, opiate receptors and endogenous opioid peptides. These changes are mediated by high activity of basic regulatory systems that increase myocardial resistance to acute and chronic ischemic damage. However, there is lack of data concerning severity of these changes in the course of complicated coronary heart disease and hypertension, which occur in the background of anxiety-depressive disorders.

The aim of present study was to assess regulatory disturbances at the level of neuropeptide-cytokine pool in the patients with polymorbid cardiovascular disease accomplished by anxiety and depressive conditions. Clinical examination of 85 patients (males) aged 35 to 45 years, with complicated cardiovascular disease (coronary heart disease combined with essential hypertension stage II) associated with anxiety and depressive disorders. To address these issues, we have formed a group of patients with anxiety and depressive disorders (group 1, n = 40), patients with coronary artery disease and stage II hypertension; group 2 (n = 20) included patients with coronary artery disease; group 3 (n = 25) included patients with hypertension stage II; group 4 (n = 30) represented controls (healthy person). In order to study dysfunction of regulatory neuropeptides at the level of cytokine-mediated immunity in these groups, we have studied diagnostic markers of the suprasegmentary autonomous nervous condition, and cytokine pool of immune system. Immune testing was used to determine β-endorphin, cytokines of pro-inflammatory (TNFα, IL-1β, IL-6) and anti-inflammatory (IL-4, IL-10) spectra in blood serum of patients.

In the course of clinical and laboratory examination, the authors found that the patients with polymorbid cardiovascular pathology exhibit regulatory dysfunctions at the level of neuropeptide-cytokine links of immunity characterized by 1.5-2-fold decrease of β-endorphin levels, increase in pro-inflammatory cytokines (TNFα, IL-1β, IL-6) and decrease in anti-inflammatory (IL-4, IL-10) cytokines.