REVIEWS
Increasing amounts of literature data suggest the leading role of indoleamine 2,3-deoxygenase (IDO) enzyme in regulation of immunosuppressive mechanisms. IDO is produced, mostly, by dendritic cells, being induced, e.g., under IFNγ involvement. Its function is to provide catabolism of tryptophan, an essential amino acid. Any reduction of tryptophan levels in extracellular environment was shown to cause functional suppression of certain immune cells, and induction of T regulatory cells. Accumulation of different tryptophan catabolites may exacerbate the immunosuppressive status induced by increased IDO expression. It is assumed that the interactions between IDO, tryptophan and its catabolites largely determine a development of hypersuppressor state in tumor growth and a hypo- (or lack of) suppressor status in autoimmune and allergic diseases. This implies some novel tasks for the therapy, including a treatment aimed for reduction of the IDO activity since the latter is involved in suppressor cell induction during tumor growth. Respectively, stimulation of IDO activity may augment suppressor activity of the regulatory cells.
Development of atherosclerosis and its clinical manifestations, i.e. unstable angina, myocardial infarction, and ischemic stroke, is largely determined by a genetic inheritance, particularly inherited variation of the genes encoding Toll-like receptors (TLRs), a major effector of innate immune system. Polymorphisms of the TLR genes may affect vascular inflammation, as well as plaque formation and its stability. Miriades of immune cells and bioactive substances are involved into pathogenesis of atherosclerosis. They exert different effects upon vascular wall and participate in development of universal inflammatory response. Local inflammatory reaction underlyes atherosclerotic plaque destabilization and endothelial dysfunction. This response is associated with TLR activation and induced synthesis of proinflammatory cytokines. Here we review the literature on the role of inherited variations within the TLR genes in the development and progression of atherosclerosis and its complications. Moreoxer, we conclude that a search for genomic markers of atherosclerosis, e.g., TLR gene polymorphisms, may be applied in personalized cardiovascular medicine, in order to predict clinical course and evolution of the disorder, like as to perform prophylactic measures aimed for prevention of the disease progression.
ORIGINAL ARTICLES
Dendritic cells (DCs) play an important role in pathogenesis of rheumatoid arthritis (RA) and are considered a novel target for immune therapy. Under inflammatory conditions, local dendritic cells of non-lymphoid organs are thought to be differentiated from monocytes. Moreover, DCs differentiation and activation in RA may be largely controlled by interferon-alpha. The aim of the present study was to investigate phenotypic and functional properties of monocyte-derived DCs generated in the presence of interferonalpha (IFN-DCs) in RA patients, and to specify, whether IFN-DCs are sensitive to a tolerogenic effect of dexamethasone. Fourteen RA patients with moderate-to-high disease activity treated with disease-modifying drugs have been included into the study. Twenty sex- and age-related healthy donors were used as a control. IFN-DCs were generated from monocytes by culturing adherent fraction of mononuclear cells for 5 days with GM-CSF and IFNα in the absence or presence of dexamethasone (10-6 M). IFN-DCs from RA patients were characterized by increased numbers of CD14+CD83- and lower amounts of CD14- CD83+ cells, thus presuming a delayed maturation. Furthermore, IFN-DCs from patients were characterized by higher expression of B7-H1 and TLR2. The phenotypic changes did not significantly influence specific functional activities of DCs, in particular, the capacity of DCs to produce TNFα, IL-10, IL-6, to stimulate proliferation of allogeneic T-cells and to activate T-cells for Th1 and Th2 cytokine production. Generation of patients’ DCs in presence of dexamethasone caused a decrease in CD83 and CD86 expression, reduced TNFα production, and suppressed allostimulatory activity of the DCs. Moreover, dexamethasone inhibited the ability of DC to stimulate Th1 response, along with shifting the balance towards Th2-stimulating activity. The data obtained provide an evidence that IFN-DCs from RA patients remain sensitive to the tolerogenic effects of dexamethasone. Furthermore, the revealed variations in sensitivity of patient’s DCs to dexamethasone-mediated inhibitory effect may be of interest for prediction of therapeutic response to glucocorticoid therapy. Our results also provide an evidence for possible implementation of IFN-DCs as a new cell platform for obtaining tolerogenic DCs.
Toll-like receptor (TLR) are responsible for recognizing various molecular patterns associated with pathogens. Their expression have been detected in skin cells such as keratinocytes and melanocytes. Numerous experimental studies demonstrate the key role of TLRs in the pathogenesis of immune diseases, including psoriasis. The objective of this study is to analyze the associations of polymorphisms in TLR7 gene and the risk of psoriasis development. DNA samples were collected from 138 patients with psoriasis and 317 healthy controls. Genotyping of rs179003, rs179008, rs179020, rs850632, rs12013728 polymorphic loci in TLR7 gene was performed using the SNPlex™method (AB, USA). SNP in the TLR7 gene rs179008 (Gln11Leu) was associated with psoriasis in entire psoriasis, late onset and sporadic subgroups (Рс = 0.0065, OR = 1.95; Рс = 0.0004, OR = 2.50; Рс = 0.0078, OR = 2.2, respectively). In conclusion, this study is the first to identify genetic variants of the TLR7 gene significantly associated with psoriasis.
Immune status of healthy people, patients with secondary immunodeficiency and allergic diseases is assessed. To reduce the number of characteristics of immunity (23 indicators) to a number of the generalizing factors the multivariate analysis is used (principal component method). This method consistently reveals the principal components – independent functional complexes of interacting factors, with the characteristic of force of their interrelation. The principal components reflect communications between separate indicators and are located in size of their contribution to the total amount of information. The method is applied to structuring immunological indicators and a possibility of detection of features (distinctions) of the immune status of patients with secondary immunodeficiency and allergic diseases. The method of principal components when it is applied to the assessment of immune status creates welldefined pattern of a functional condition of the immune system, accentuating main types of the reacting immunocompetent cells, their combinations and interaction. In the general immune status of healthy people (blood donors) the T cell compartment (the first and second the principal components) plays the major role. The second in importance components reflect the humoral immunity status. The indicators describing the response of the innate immunity (natural killer cells, the system phagocytic cells), follow them. Mathematical modeling reveals hierarchy of responses of innate and adaptive immunity, which is in agreement with established mechanisms of immune response. Differences of individual indicators of principal components of donors blood (norm), the patients with secondary immunodeficiency and allergic diseases built in the first, second and fourth to the principal components are detected. They group and display the status of 40% of the total amount (dispersion) of immunological information taken in the analysis accentuating quantity and a functionality of T cells subpopulations and to a lesser extent – the level of B cells. In case of secondary immunodeficiency the major part of distribution of values principal individual components is in a zone of negative values, and in case of allergic diseases – in a zone of positive values, indicators of the norm are in the intermediate position. Distribution of the principal component, reflecting immunoregulatory index is similar. The principal component value describing the activation of T cells, exceeded the norm, in case of secondary immunodeficiency, and in case of allergies. Multivariate mathematical analysis of immune status demonstrates its usefulness for differential diagnosis of secondary immunodeficiency and an allergic diseases.
Trophoblast cells actively interact with endothelial cells participating in the process of vasculogenesis in the uterus/placenta contact area and remodeling of uterine spiral arteries. Cytokine production by the placental cells is subject to gradual changes from the 1st to 3rd trimester of physiological pregnancy. It is also changed in cases of obstetric disorders, e.g., in pre-eclampsia. At present time, there are lacking data on effects of cytokines and placenta-derived factors upon local interactions between endothelium and trophoblast cells. Hence, the aim of our study was to assess the influence of placental factors upon formation of tube-like structures by endothelial cells in presence of trophoblastic cells. We performed co-cultures of Ea.Hy926 endothelial cell line and Jeg-3 trophoblastic cells in a 3-D collagen matrix («Matrigel», BD, USA) with secretable factors from placentas of healthy pregnant women at 9-11 weeks of gestation (n = 15), healthy pregnant women at 38-39 weeks of gestation (n = 15), or the women with preeclampsia at 38-39 weeks of gestation (n = 14). We have shown that the trophoblastic cells may modify the ability of endothelial cells to form tube-like structures only with placental factors from health pregnant women. In pre-eclampsia condition, the trophoblast cells are not able to correct the behavior of endothelial cells, and to promote physiological growth of blood vessels.
Pathogenesis studies in thyroid autoimmune diseases take a specific place among endocrine disorders, due to high prevalence of these pathologies, thus representing an urgent problem of the modern medicine. Their triggering mechanisms of their are still unknown. Changes of thyroid status in cases of nonthyroid pathology, e.g., during development of «nonthyroidal syndrome», may launch synthesis of some functionally opposite cytokines by immunocytes, with subsequent loss of tolerance to thyroid autoantigens. One may suggest that mast cells may potentially influence secretory activity of thyrocytes via Toll-like receptors, and, therefore, induce synthesis of opposite cytokines, with subsequent loss of auto-tolerance. The mast cells found in thyroid gland affected by an autoimmune disorder may also regulate functional activity of immunocytes and hormone-secreting cells due to molecular effects of secretable substances. The mechanisms prevailing in autoimmune thyroid disease are, however, widely unknown. These effects may involve either primary activation of mast cells by thyroid hormones, or secondary changes of thyroid status. To address these issues, we studied some features of mast cells response and production of functionally opposite cytokines (IL-1β, IL-10, IFNγ, TNFα) in experimental thyrotoxicosis and hypothyroidism. To boost the immune response, a subgroup of experimental animals with thyrotoxicosis was treated with recombinant interleukin-2. Specific changes of IFNγ/IL-10 ratio depending on thyroid status confirmed a role of opposite cytokine balance for development of different pathological variants. A significant increase in the Th1-marker cytokines revealed at the organ level in cases of thyrotoxicosis argued for direct involvement of thyroid hormones into the immune regulation, as confirmed by a focal infiltration of a thyroid gland with mast cells, along with significant increase in pro-inflammatory cytokines at systemic and organ levels. A hypothesis on possible reception of thyroid hormones by immune cells is in accordance with intensive correlations between the levels of opposite cytokines in target organ and contents of thyroid hormones in peripheral blood. A regulatory role of interleukin-2 was suggested as a factor of keeping balance for opposite cytokines and changing vector of immune response in case of altered thyroid status. The results of our study presume an important role of mast cells and balance of opposite cytokines in pathogenesis of thyroid dysfunction. Further studies are required, in order to clarify the mechanisms of interaction between thyroid hormones and immune cells.
Serum concentrations of cytokines (IL-2, IL-6, IL-8, IL-10, GM-CSF, IFNγ, TNFα) were determined in blood serum of pregnant women with different types of metabolic disorders, i.e., gestational diabetes, obesity, and a combination of those disorders. The study was performed by means of flow fluorimetry, using a multiplex test system. Changes of cytokine profiles in pregnant women with overweight or obesity, and pregnant women with gestational diabetes showed some similarities. In pregnant women with overweight or obesity we have found an increase in blood concentrations of IL-2, IL-6, IL-10, IFNγ, and TNFa. Meanwhile, an increase in blood levels of IL-2, IL-6, IL-10 and TNFα was revealed in pregnant women with gestational diabetes. The changes in cytokine profile were most pronounced in cases of pregnancy complicated with gestational diabetes and obesity. In these women, increased IL-6, TNFα, GM-CSF and IFNg concentrations were revealed in blood, along with low contents of IL-2 and IL-10. Potential causes and consequences of suggested subclinical inflammation in pregnant women are discussed. We conclude that pregnant women with metabolic disorders may develop a subclinical inflammation at the early stages of obesity, or metabolic disturbances.
SHORT COMMUNICATIONS
Prevalence of hypertension in patients with osteoarthritis is rather high. According to published data, a combination of osteoarthritis and hypertension is registered in 45 to 80% of the patients, dependent on the age group. Pathogenesis of arterial hypertension developing in patients with osteoarthritis is of sufficient interest to the clinicians. We studied systolic and diastolic blood pressure, levels of some cytokines (IL-1β, IL-6, IL-18, TNFα) and markers of endothelial function (EDN1, vWF activity) in 83 patients (mean age 45.7±6.3 years) with osteoarthritis of knee and hip joints (radiographic stage II-III) accompanied by chronic pain. Local pain intensity over last month was evaluated by means of a visual analogue scale. According to the data obtained, the patients were divided into three groups. Group 1 consisted of 27 patients with mild pain (the pain index ≤ 3 points), the 2nd group included 34 persons with moderate pain (3 to 7 points), and the 3rd group consisted of 22 people with highest pain ratings (pain index ≥ 7). Increased pain intensity correlated with elevation of systolic and diastolic blood pressure. Meanwhile, higher levels of proinflammatory cytokines, and increased activity of EDN1 and vWF were observed in patients with moderate osteoarthritis and severe pain syndrome. Minimal values of cytokines were observed in patients with mild pain, whereas maximal levels, in the patients with severe pain and arterial hypertension. Inflammatory mediators are able to induce activation and injury of endothelium causing its dysfunction. vWF activity and EDN1 contents increased in all the studied groups, along with increased pain intensity. Higher EDN1 concentration and vWF activity may be considered objective signs of endotheliosis in the osteoarthritis patients. In turn, endothelial dysfunction is among major pathophysiological mechanisms of arterial hypertension. This may suggest a sufficient contribution of pain to occurrence and development of artherial hypertension in this group of patients. Chronic pain is likely to be a factor of early development of cardiovascular complications in the patients with osteoarthritis.
Thirty-five patients with non-allergic bronchial asthma (NABA), 22 patients with NABA and diabetes mellitus type 2 (DT2), 23 subjects with DT2, and 31 healthy controls were enrolled into the study. ELISA assays for IL-4, IL-10, IL-6, IFNγ were performed by means of a standardized protocol using immunoassay kits purchased from VectorBest, and Cytokine. In asthma patients complicated by DT2, the pattern of bronchial asthma was ascribed to NABA. This finding may be consistent with a theory of specific insulin-receptor interactions in asthma. The NABA patients with type 2 diabetes mellitus exhibited a significant increase in IL-6, IFNγ, and decrease of IL-4, as compared with healthy controls and NABA. Moreover, we have revealed an increase of IL-4, IL-6, IFNγ, when compared with DT2. Hence, the patients with coexistence of non-allergic bronchial asthma and DT2 were characterized by a specific cytokine profile of pro- and anti-inflammatory cytokines, which may correlate with increased glycation and deterioration of lung function.
ISSN 2313-741X (Online)