Vol 27, No 1 (2024)
- Year: 2024
- Published: 06.08.2024
- Articles: 11
- URL: https://rusimmun.ru/jour/issue/view/32
Full Issue
ORIGINAL ARTICLES
Role of opioid receptors in phagocytosis regulation and production of Th1/Th2 cytokines under acute cold stress in non-immune mice
Abstract
Endogenous opioid system plays an important role in the regulation of body functions under stress, providing stress-protective, analgesic and immunoregulatory effects. The aim of this work was to assess the effect of acute cold stress on the in vivo production of adaptive immunity cytokines IL-2, IL-4, IFNγ, phagocytosis, and production of reactive oxygen species in non-immunized mice with induced blockage of opioid receptors. The object of the study were male white mice subjected to acute cold stress at -20 °C for 10 or 60 minutes. To block opioid receptors, naloxone hydrochloride was used, which was administered subcutaneously at a dose of 0.2 mg/kg 20 min before inducing the stress. After the cold exposure, spleen and peritoneal lavage were obtained from the animals. The cytokine concentrations were determined using ELISA technique. The absorption activity of CD11+ cells of the peritoneal cavity was assessed using FITC-stained St.cohnii with a flow cytometer; the production of reactive oxygen species was assessed using the reaction of luminol-dependent chemiluminescence.
It was found that the both cold stress regimens caused naloxone-independent inhibition of spontaneous IFNγ production. In stimulated cultures, an inhibitory effect on IFNγ secretion was registered in animals subjected to stress for only 60 min, being also independent on the opioid receptor blockade. IL-2 production decreased in stimulated cultures against the background of 60 min stress naloxone independently. Both variants of cold stress had no effect on IL-4 production. Stress for 60 min inhibited absorption activity of CD11+ cells from the peritoneal lavage and activated production of oxygen radicals, being, however, canceled by naloxone administration. Hence, acute cold stress led to naloxone-independent inhibition of Th1 cytokine production by splenocytes, naloxone-dependent inhibition of phagocytosis and activation of the microbicidal potential of peritoneal cavity cells.
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Spontaneous cytokine production by the cells from peripheral blood, lymph nodes, spleen, thymus and skin in a murine model of acute psoriasis-like dermatitis
Abstract
Imiquimod-induced model of psoriasis in mice is used for the studies in psoriasis. Imiquimod administered as skin application triggers a complex multi-stage process simulating psoriatic inflammation of the skin, accompanied by changes in production of cytokines. The aim of this work was a comprehensive study of their contents in cell supernatants isolated from skin, blood, from central and peripheral lymphoid organs and the effect of imiquimod on these parameters. Forty-six C57BL/6 mice were divided into two groups: (1) control (n = 22), and (2) experimental (n = 24). Development of experimental pathology was evaluated by van de Fits et al. The mice from experimental group were treated with a cream containing 5% imiquimod (62.5 mg/ cm2/ day/mouse) for 7 days. On the 7th day of experiment, the animals were subject to blood sampling, extraction of spleen, lymph nodes, thymus, and skin biopsies were also made. To obtain cell suspensions, the tissues of spleen, lymph nodes, and thymus were crushed in a homogenizer, and then passed through cell filters (50 mcm pore size). The method of spontaneous migration was used to isolate skin cells. The cultures of blood, spleen, lymph nodes, thymus, and skin cells were incubated for 24 hours in RPMI-1640 followed by assessment of spontaneous cytokine production in supernatants. The cytokine level (IFNγ, IL-1β, IL-5, IL-6, IL-10, IL- 17, TNFα, IL-10) was determined using the murine Th1/Th2/Th17 Panel test system. Our study revealed that the cells isolated from blood and lymphoid organs synthesize increased amounts of pro-inflammatory cytokines: IL-1 and IL-17. The most pronounced changes in the cytokine profile are observed in cell supernatants from blood, skin and spleen cultures.
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Mapping of IgE cross-reactivity of Gly m 4, Gly m 5 and Gly m 6 soybean allergens in patients with atopic diseases
Abstract
Currently, a significant portion of the food consists of multiple different ingredients. Soybean proteins have been widely used for production of these combined foodstuffs. Meanwhile, soy proteins may contain a wide range of allergens, and even, if present in small amounts, they can cause severe allergic reactions due to cross-reactivity. The aims of our study were to evaluate the prevalence of sensitization to soybean allergen components Gly m 4, Gly m 5 and Gly m 6, and to map their IgE cross-reactivity with homologous proteins of Bet v1-like proteins and cupin proteins in patients with atopic disorders. We have studied IgE’s to 112 allergenic components of plant and animal origin in blood sera from 54 patients with history of allergy, using the ImmunoCap ISAC method. The results were analyzed by means of MS Excel program using parametric statistical criteria. Results: In patients with atopic diseases, we have detected serum IgE to the rGly m 4 allergic component (5 patients out of 29; 17.24%). Frequency of sIgE detection to rGly m 5 (3 patients of 29; 10.24%) and rGly m 6 (1 patient of 29; 3.44%) was less pronounced. Cross-reactive sIgE was detected only to allergens of the Bet v1 superfamily. The strongest relationship was found between sIgE level to rGly m 4 and rBet v1 (R = 0.68; p = 0.001). Another IgE cross-reaction was found between soybean rGly m 4 and alder pollen rAln g1 (R = 0.681; p = 0.000). IgE antibodies to rGly m 4 may also cross-react with kiwi rAct d8 (R = 0.59; p = 0.001). We have also found a weak correlation between sIgE to soybean rGly m 4 and two hazelnut rCor a1 isoforms: rCor a 1.01 (R = 0.42; p = 0.023), and rCor a 1.04 (R = 0.39; p = 0.036). The IgE cross-reactivity profile of the soy allergens revealed in this study is important for improvement of testing strategy for the presence of causally significant allergens. This finding will help to avoid the development of hidden cross-reactions that trigger both oral and respiratory allergic processes in subjects with allergic pathology. Moreover, this will enable administration of optimal diets and develop technologies for development of hypoallergenic food products.
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Immuno-hormonal regulation of tumor proliferation in breast cancer patients
Abstract
It is well known that tumor cells proliferation is regulated by sex steroid hormones, estradiol and progesterone (E2 and Pg) in breast cancer patients (BCP). Moreover, specific auto-antibodies to estrogen receptor (ERα) were detected in blood serum of BCP. Their levels positively correlated with the percentage of Ki-67 expressing breast cancer cells. We proposed that antiidiotypic auto-antibodies to E2 and Pg (IgG2-E2 and IgG2-Pg) could act as antibodies against membrane ER and progesterone receptor (PR). Our study aimed for research of IgG2-E2 and IgG2-Pg according to E2 and Pg serum levels in association with Ki-67 positive tumors in BCP. Antiidiotypic antibodies were studied in ER-positive patients with breast cancer (stage I, n = 374, and stage II-IV, n = 379,) using ELISA technique with monoclonal antibodies against E2 and Pg as adsorbed antigens. Blood serum concentrations of E2 and Pg were measured using “ImmunoEA-Estradiol” and “ImmunoEA-Progesterone” test-systems (“Immunotech”, Russia). Tumor Ki-67 was studied by standard immunohistochemical technique at the Kemerovo Oncological Hospital. Higher percentage of Ki-67 positive breast cancer cells (Ki-67 > 30) was increased in BCP II-IV stages compared with stage I patients (50.7% vs 29.8%, p < 0,001). Such increased values were detected for the BCP with low levels of both IgG2-E2 and IgG2-Pg antibodies in the following subgroups: 1) at low serum E2 concentration of ≤ 200 pmol/L (50.9% vs 21.3%, р < 0.001); 2) at the E2 exceeding 200 pmol/L (74.2% vs 34.1%, р = 0.003); 3) at the Pg levels under 600 pmol/L (60.6% vs 22.2%, р < 0.001); 4) at Pg values exceeding 600 pmol/L (58.5% vs 30.8%, р = 0.02). Similar differences were not revealed between stage II-IV and stage I BCP with low levels of both IgG2-E2 and IgG2-Pg. Corresponding Ki-67 > 30 indices were as follows: 1) 36.9% vs 22.0% (р = 0.14); 2) 48.4% vs 34.5% (р = 0.08); 3) 34.0% vs 27.7% (р = 0.75). Significant differences were detected in BCP with Pg > 600 pmol/L and high IgG2-E2 and IgG2-Pg levels only: 48.1% vs 26.6%, (р = 0.01). Hence, antiidiotypic auto-antibodies to steroid hormones may participate in regulation of tumor proliferation in BCP. Immunoassay of IgG2-E2 and IgG2-Pg may be used for prognosis of tumor proliferation upon breast cancer progression.
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Determination of the immune response type in measles patients of different ages from a high-incidence area
Abstract
According to the WHO data, the incidence of measles is now in the cyclic increase phase. The non-vaccinated subjects, like as persons who have previously received one or two doses of measles vaccine are involved in the epidemic process. The purpose of our study was to determine the immunological pattern in the groups of measles patients of different age in areas with high incidence of infection. To determine the immune response type in measles patients, qualitative and quantitative indices of IgM and IgG were used, detected by the following ELISA test-systems: VectoMeasles-IgM (JSC “Vector-Best”, Russia); Anti-Measles Viruses ELISA (IgG) and Avidity Anti-Measles Viruses ELISA IgG (Euroimmun, Germany). The serological study of 1893 patient allowed to determine the primary and secondary types of immune response. In 72.64% of the patients with primary immune response, the serum samples contained low-avidity IgG at a concentration of 0.45 (0.22- 0.74) IU/mL. In the group with a secondary immune response, high-avidity antibodies were detected at a concentration of 24.28 (21.59-27.4) IU/mL. The antibody levels in secondary type of response was 54-fold higher than IgG values in the first group (p < 0.05). In the group with primary immune response, the ratio of children (< 1 to 14 years) and adults (18 to 70 years old) was almost the same (49.6% and 47.56%). Appropriate values for children and adult cohorts with a secondary immune response were 2.12% and 96.53%, respectively (p < 0.05). Among 46 teenagers (15-17 years old), 84.8% responded with a primary immune response to the measles virus. Thus, in the area with high-incidence of measles among patients of different age, the primary-type immune response was determined in 72.64%, and secondary-type, in 27.36%. We have found that in the patients with a secondary type of immune response group, the proportion of children and teenagers was 27.8 times lower than among adults, thus indicating to high efficiency of vaccination in pediatric population. At the same time, the results of studies among measles patients with primary-type immune response, both children and adults, suggest some “gaps” in the vaccine prevention program.
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Features of the neutrophil granulocyte phenotype in children with infectious mononucleosis
Abstract
The course of infectious diseases caused by viruses, and their common outcome is determined by the activity of the inflammatory reaction which occurs both at the local and systemic levels. However, the features of neutrophil functions during inflammatory reaction are virtually unknown in the patients with infectious mononucleosis (IM), caused by Epstein–Barr virus (EBV). Hence, the aim of our study was to evaluate some characteristics of phenotypic spectrum of blood neutrophils in children with IM. Patients and methods. We examined 84 children aged 3 to 11 years with EBV infection with moderate or severe clinical course of the disease. All patients exhibited a positive test for EBV DNA in blood lymphocytes and appropriate serological markers of acute EBV infection. The control group consisted of 40 conditionally healthy children at the similar age range. The study of neutrophil phenotype was carried out by flow cytometry using direct immunofluorescence of whole peripheral blood samples.
A study of the neutrophil phenotype with a combination of two functional antigens (CD64 and CD32) has revealed that in children with IM, regardless of age, the main fraction of blood neutrophils are double-negative cells, whereas in healthy children it consists of CD64-CD32+ neutrophils. The main fraction of neutrophils in the paired combination of CD64 and CD11b antigens in sick children aged 3-6 and 7-11 years was similar to the healthy controls (CD64-CD11b+), but with a change in the content of minor cell fractions. The number of CD64-CD15+ neutrophils (main fraction of cells in healthy children) proved to be significantly reduced in the IM patients of both age groups. However, we have revealed a marked increase in the level of double-negative cells for the CD64 and CD15 antigens. At the same time, the content of double-negative neutrophils for these markers was also increased in IM children of both age groups. The cells with CD11b-CD15+ and CD11b+CD15+ phenotypes comprised the main fractions in IM, as studied by a paired combination of CD11b and CD15 antigens; in healthy children – only CD11b+CD15+ neutrophils are detected.
The phenotypic changes of neutrophils during IM suggest a decreased migratory ability of cells with high activity of proinflammatory functions. The established ontogenetic features of the neutrophil phenotype are significantly changed in the children with IM, probably, due to specific immunopathogenesis of the viral infection. The detected changes in phenotypic composition of neutrophils associated with IM may be caused both by the features of protective reaction of innate immune cells and pathogenic effects of the virus itself upon blood neutrophils.
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Isolation of donor gamma globulin obtained from multiparous women and its effects upon expression of HLA-G and HLA-DR molecules on lymphocytes from mothers of children with septal congenital heart defects
Abstract
A common pathogenetic mechanism of reproductive losses and congenital heart disease (CHD) is associated with immune inflammation in the “mother-embryo” system which affects differentiation and proliferation of cardiovascular progenitor cells. It is hypothesized that this link may be blocked by regulatory auto- and alloimmune antibodies to HLA-G and HLA-DR molecules. Moreover, these antibodies may be present at sufficient amounts in donor immunoglobulins, especially those obtained from the blood of multiparous women. Based on this suggestion, the aim of our study was to obtain enriched gamma globulin fraction from the blood of multiparous women and evaluate its functional effects towards HLA-DR and HLA-G molecules.
Isolation of the gammaglobulin fraction (GGF) from the blood plasma of multiparous women was performed using affinity chromatography in several sessions. Purity grade of the resulting protein was analyzed by immunoelectrophoresis, electrophoretic separation of the protein fraction of blood serum and electrophoresis in 4.12% polyacrylamide gel with the addition of SDS (PAGE electrophoresis). PAAG electrophoresis showed that this GGF did not differ from commercial therapeutic intravenous immunoglobulin (IVIG).
Assessment of the functional activity of GGF upon HLA-DR and HLA-G molecules was performed in the main group of women and their children with congenital heart disease (n = 38), and control group of women who gave birth to conditionally healthy children (n = 21). To determine the specificity of GGF with respect to HLA-G, HLA-DR molecules, as well as to compare its effect with autologous and allogeneic sera and IVIG, we developed an immunological testing protocol using flow cytometry. The protocol was arranged on the basis of the methodology of “cross-match” approach and Russian patent “Method for determining antibodies to HLA-G”. It was found that the blocking activity of female serum towards autologous (intrinsic) and allogeneic (embryo/fetus/child) HLA-G and HLA-DR molecules may determine the protective effect on development of congenital heart defects in the next generation. Donor human immunoglobulin showed a similar blocking effects to these molecules, possibly due to the presence of alloimmune antibodies to HLA classes I and II. The gammaglobulin fraction obtained from the donor blood of multiparous women has a more pronounced blocking effect on the HLA-G and HLA-DR expression. Hence, this immunobiological preparation can be considered a prototype of therapeutic and prophylactic agent blocking the genesis of congenital heart defects.
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Immunotherapy for children with malignant brain tumors
Abstract
The incidence of high-grade malignant gliomas (MG) ranges from 35 to 46% of all central nervous system tumors. Despite combined therapy including surgery, radiation treatment and chemotherapy, overall five-year survival does not exceed 10%. The advent of novel immunotherapeutic strategies has promoted a renewed hopes for the treatment of MG. The aim of the present study was to improve the survival rates of glioma patients.
Our study included 5 pediatric patients at the median age of 7.6 years (2-16). Three pts had anaplastic astrocytoma (AA) (1st relapse, 1 pt; 2nd relapse, in 2 pts), One patient was diagnosed with glioblastoma multiforme (GBM) (3rd recurrence), and 1 child had diffuse brainstem glioma (BSG). The median time to the first relapse was 12 months (4 to 16), the second relapse occurred at a median of 5 months (1 to 8). The protocol of immunotherapy included combined administration of autologous dendritic cell-based vaccine (DV) and repeated intrathecal/intraventricular injections of donor allogeneic immunocompetent cells (alloIC) for at least 2 years.
Two of 3 pts with AA experienced a progression-free interval of 67 and 71 months. One patient with 3rd GBM relapse is alive without any treatment for 13.3 years after starting the immunotherapy. The median time of follow-up was 67 months, with the 2-year overall survival rate of 58%. Two pts died from the disease progression within 6 and 7 months from the beginning of immunotherapy. Over the period of treatment, the patients received a median of 20 alloIC injections (8 to 60), and 18 DV administrations (8 to 44). No serious side-effects were observed.
Immunotherapy could be an promising option for treating patients with high-grade malignant gliomas refractory to conventional therapy and, therefore, deserves further investigations.
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SHORT COMMUNICATIONS
High-altitude speleotherapy in the treatment of bronchial asthma
Abstract
The present study concerns clinical effects of speleotherapy in bronchial asthma. The aim of our work was to study the efficiency of speleotherapy in a group of patients with bronchial asthma. We observed a group of 51 patients with bronchial asthma (BA) aged 18 to 50 years, who received a course of treatment at the private center “Solevik” (Yakutsk City), carried out at the Department of Allergology and Immunology. All the examined patients were diagnosed with atopic bronchial asthma, of moderate severity. Basic therapy in all cases included Symbicort and Seretide treatment. The patients were managed and monitored before and after the course of treatment by a therapist, pulmonologist and allergologist-immunologist at the outpatient center. Laboratory parameters included general blood tests and the levels of total serum IgE. Examination of patients after a course of speleotherapy revealed disappearance and reduction of asthma attacks (up to 1 attack per month) in 80% of the examined. General blood testing before and after speleotherapy showed decreased levels of blood eosinophils after the course of treatment. I.e., the average initial level of blood eosinophils before treatment was 12±0.4%, being decreased after the course of speleotherapy to 5.5±0.2%. Measurements of total IgE before and after speleotherapy revealed the following results: in patients before therapy, the average level of this index was 500±0.8 units/mL. After a course of speleotherapy, this parameter decreased to 80±0.3 units/ mL.
Speleotherapy shows a positive effect on the clinical course of the patients with bronchial asthma and significantly increases the efficiency of treatment.
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Relationship between biomarkers and platelet aggregation activity in presence of hydrogen sulfide in patients with coronary heart disease
Abstract
Biological significance of hydrogen sulfide (H2S) in regulation of platelet functions and in development of thrombosis is being studied, but there is no consensus on the role of H2S in these physiological processes. The platelets are very sensitive to various mediators released from blood vessels and blood cells. Multiple pro-inflammatory molecules may exert direct effects on the state of cardiovascular system. Thus, an imbalance in the production of pro-inflammatory and anti-inflammatory cytokines increases the risk of thrombosis, and it can lead to endothelial dysfunction, instability and rupture of atherosclerotic plaques. The aim of our study was to determine concentrations and identify the relationships between certain biomarkers (LIGHT, PlGF, IFNá2, TNFáâ, IL-3, IL-5, IL-6, IL-8, IL-15, IL-17F, MIP-1á, CXCL16) and collagen-induced platelet aggregation in presence of hydrogen sulfide exposure in patients with coronary heart disease. We performed a simple one-step comparative study which included 22 patients with coronary artery disease (CHD). The level of biomarkers was determined by multiplex analysis (xMAP technology). Platelet aggregation activity was studied by the turbidimetric assay. All samples were examined against the background of a 30-min pre-incubation with hydrogen sulfide, with the addition of an aggregation inducer (collagen, 2 mmol/L). Sodium hydrosulfide at a concentration of 10-6 M was used as a hydrogen sulfide donor. The results of comparative and correlation analysis were considered reliable at a statistical significance level of p < 0.05. The patients were divided into two groups, i.e., group 1 (n = 10) showed a reduced aggregation or a decreased size of aggregates against the background of preincubation with H2S. In group 2 (n = 12), preincubation with H2S was followed by increased degree or size of platelet aggregates. The concentrations of tumor necrosis factor ligand (LIGHT), interferon IFNá2, interleukins IL-3, IL-8, IL-15, IL-17F, chemokine CCL3/MIP-1a were significantly increased in group 2 patients, where collagen-induced platelet aggregation increased upon preincubation H2S, as compared with patients in group 1. The correlation analysis revealed positive correlations found that in the 1st group of patients between the concentrations of MIP-1a (Rs = 0.56, p = 0.03; Rs = 0.69, p = 0.01), IL-5 (Rs = 0.83, p = 0.01; Rs = 0.73, p = 0.01), and IL-8 (Rs = 0.60, p = 0.02; Rs = 0.95, p = 0.01), respectively, and with both size of aggregates and the index of the platelet aggregation degree. Moreover, distinct correlations between the aggregate size and the concentration of IL-6 (Rs = 0.53, p = 0.04) were revealed. In the 2nd group of patients, correlations were found with the size of aggregates and PIGF (Rs = 0.59, p = 0.04), and between CXCL16 values and the size of aggregates (Rs = 0.58, p = 0.04), like as with the degree of aggregation (Rs = 0.65, p = 0.04). Thus, we have found that, in 2 groups of patients with coronary heart disease with increased collagen-induced platelet aggregation, preincubated with H2S, higher concentrations of inflammatory biomarkers (IFNá2, IL-3, IL-8, IL-15, IL-17F, MIP-1á) were detected. One may suggest that the more pronounced proinflammatory state in this group of patients may cause platelet resistance to inhibitory effect of hydrogen sulfide. In the 1st group of patients, we revealed multiple correlations of aggregation parameters with values of inflammatory markers (IL-5, IL-6, IL-8, MIP- 1a), which may be a pre-requisite for different corrective therapies for the patients of these groups.
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Changes in serum levels of pro- and anti-inflammatory cytokines in women with papillomavirus infection before and after therapy”
Abstract
Papillomavirus infections (PVI) are among the most common sexually transmitted diseases in the young population. A long, sluggish inflammatory process sufficiently worsens adequate preparation for normal pregnancy. Herpesvirus and Chlamydia infections are the most frequent associations with papillomavirus infection. Many authors believe that PVI may cause dysregulation of pro- and anti-inflammatory cytokines revealed in blood serum. Currently, there are no uniform standards for management and treatment of women with papillomavirus infection without pronounced clinical manifestations, in order to prevent morphofunctional disorders of genitourinary system leading to reproductive disorders. However, most authors believe that antiviral and immunomodulatory drugs are the main tool of therapy against expansion of pathogens in the body. The aim of our study was to compare changes in the levels of IL-17, IL-12 p70, IL-12 p40, IL-13 and TGF-p1 in blood serum of women with papillomavirus infection before and after therapy with Inosine pranobex (IP) and Solanum tuberosum (ST).
We conducted a survey of 137 patients with papillomavirus infection treated with drugs containing Inosine pranobex and Solanum tuberosum as active substances. The levels of IL-17, IL-12 p70, IL-12 p40, IL-13, and TGF-p1 in blood serum were determined using specific reagents from R&D Diagnostics Inc. (USA).
Changes in pro- and anti-inflammatory cytokines before therapy were as follows: decreased levels were found for IL-12 p70, p40; increased values were revealed for IL-13, IL-17, and TGF-p1. After the courses of therapy, we have registered the following changes in PVI-infected patients treated with synthetic drug Inosine pranobex (IP): the levels of IL-12 p70, IL-12 p40 were increased, along with decrease in IL-13 and TGF-p1. Meanwhile, ST therapy was associated with increase in IL-12 p70, IL-12 p40, and a decrease in IL-13 and TGF-p 1. With IP therapy, patients with combined HPV + HV infection showed an increase in IL-12 p70, IL-12 p40 and a decrease in IL-13, while TGF-p1 did not change. Following ST therapy, these patients exhibited higher IL-12 p70, IL-12 p40, decreased IL-13, whereas TGF-p 1 remained unchanged. In the group of women with HPV + Chlamydia infection, an increase in IL-12 p70, IL-12 p40 and a decrease in IL-13 and TGF-p1 was associated with IP therapy. An increase in IL-12 p70, IL-12 p40 and a decrease in IL-13 and TGF-p 1 were shown after ST therapy. In all groups of patients, IL-17 remained at high levels after therapy without significant differences between the mentioned subgroups. In the groups of patients treated with IP. we have recorded a general normalization of immune disorders.
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