Vol 23, No 1 (2020)

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ANNIVERSARY

РОССИЙСКОЕ НАУЧНОЕ ОБЩЕСТВО ИММУНОЛОГОВ С ГЛУБОЧАЙШИМ ПОЧТЕНИЕМ И БЛАГОДАРНОСТЬЮ ОТ ИМЕНИ ВСЕХ ИММУНОЛОГОВ РОССИИ И СТРАН БЫВШЕГО СОВЕТСКОГО СОЮЗА ПОЗДРАВЛЯЕТ ОСНОВОПОЛОЖНИКА ИММУНОЛОГИИ В НАШИХ СТРАНАХ РЭМА ВИКТОРОВИЧА ПЕТРОВА, БЕССМЕННОГО ПОЧЕТНОГО ПРЕЗИДЕНТА РНОИ, С ЗАМЕЧАТЕЛЬНЫМ 90-ЛЕТНИМ ЮБИЛЕЕМ!

Abstract

Рэм Викторович Петров является одним из ведущих в мире специалистов в области фундаментальной и прикладной иммунологии.
Russian Journal of Immunology. 2020;23(1):7-8
pages 7-8 views

REVIEWS

TYPE 2 DIABETES MELLITUS – AN AUTOIMMUNE DISEASE?

Asfandiyarova N.S.

Abstract

In recent years, the association of type 2 diabetes mellitus (DM) to autoimmune diseases has been discussed. Participation of innate immunity in the development of inflammation in obesity and insulin resistance, which determine the development of type 2 DM is well known. These changes, along with gluco- and lipotoxicity, lead to the destruction of the pancreatic β cells, emergence of autoantigens and development both humoral and cell type autoimmune reactions. The effectiveness of drugs used in the treatment of autoimmune diseases also leads some authors to the conclusion that type 2 diabetes can be referred to autoimmune diseases. However, most researchers believe that the presence of an autoimmune component is a side effect of inflammation and do not consider type 2 diabetes as an autoimmune disease.

Alternatively, autoimmune reactions may take part in the pathogenesis of type 2 diabetes because: a viral infection contributes to the development of antiviral immunity, however, in the presence of insulin-cross-reactive antigens, an autoimmune reaction is observed. Most patients with uncompromised immune system, the clone of auto-aggressive cells sensitized to insulin is destroyed. In a small percentage of patients with impaired immune system, insulin-sensitized lymphocytes do not die that leads to destruction of pancreatic islet cells and development of type 1 diabetes. In other patients, on the one hand, the immune system is also unable to remove the cell clone exerting signs of autoaggression, but it tries to suppress this effect by blocking insulin receptors on immunocompetent cells. This maneuver succeeds, and suppression is reversible. However, insulin receptors are abundant not only on sensitized lymphocytes, but also on liver cells, muscles, and adipose tissue. The effect of blocking insulin receptors in insulin-sensitive tissues contributes to the development of primary insulin resistance, which precedes and contributes to the development of obesity. Subsequently, excessive intake of dietary fats results in obesity progression, so that the entire cascade of inflammatory reactions is involved in the pathological process. This, in turn, contributes to the formation of secondary insulin resistance, which accounts for the development of type 2 diabetes and cardiovascular diseases and so on.

Type 2 diabetes does not belong to autoimmune diseases, but suppressed autoimmune reactions with respect to insulin play a role in the development of insulin resistance.

Russian Journal of Immunology. 2020;23(1):9-18
pages 9-18 views

PATHOGENETIC MECHANISM OF ACNE-COUPLED INFLAMMATION

Rumyantsev A.G., Demina O.M., Raikina E.V.

Abstract

Acne (Ac) represents a widespread dermatosis most commonly found in adolescents and adults covering 6-85% total cases. It has been traditionally believed that Propionibacterium acnes (P. acnes) colonizes ducts of the sebaceous hair follicles (SHFs), activates innate immune response and triggers transition of non-inflammatory erosions (comedones) into inflammatory lesions such as papules, pustules and nodules. Moreover, it was also shown that inflammatory reaction develops at late Ac stage and its severe course. Today, it has been evidenced that Ac-coupled inflammation develops at all stages of dermatosis, perhaps in a subclinical manner, even prior to emergence of comedones.

It is commonly accepted that acne targets SHFs displaying location-related marked morphological, microbiological and metabolic diversity. For instance, SHFs is profoundly affected by altered hormone and immunological properties as well as environmental cues.

Comparative studies examining efficacy nd medicated therapy with anti-inflammatgory potential evidence about early inflammatory reaction related to acne.

The data obtained confirm that P. acnes elicits inflammatory reaction in acne that additionally maintains P. acnes proliferation. It was found that P. acnes initiates TLR2-mediated innate immune reaction both at early and late stages of developing dermatosis. Such reaction results in upregulated immune genes including those encoding cytokines and chemokines recruiting immune cells.

Today, owing to clinical, immunological, histology and immunohistochemistry data there has been accumulated evidence confirming significance of ongoing inflammation as a pathophysiological basis for emerging acne.

Upon that, pathophysiological mechanisms triggering inflammatory reaction in acne are complex and poorly investigated, thereby underlying a need to conduct further studies.

Russian Journal of Immunology. 2020;23(1):19-26
pages 19-26 views

ORIGINAL ARTICLES

NEW STRAIN OF MUTANT MICE CHARACTERIZED BY SELECTIVE RESISTANCE TO ONE OF TWO SEPTIC SHOCK PROTOCOLS

Astrakhantseva I.V., Gladkova L.S., Vasilenko E.A., Tarabykin V.S., Drutskaya M.S., Nedospasov S.A.

Abstract

More than 40 years ago ethyl nitrosoеurea was identified as a powerful mutagen for mammalian germ cells resulting in random point mutations in gamete DNA. This feature allowed the use of this mutagen for genetic studies on the mechanisms of various pathological and physiological processes in model organisms. In our study genome-wide mutagenesis in C3H mice by ethyl nitrosourea followed in generation F3 by selection of animals resistant to acute lethal hepatotoxicity caused by a combination of E. coli lipopolysaccharide (LPS) and D-galactosamine (D-gal). Tumor necrosis factor (TNF) is known to be a critical mediator of this pathology. Exposure to D-galactosamine increases sensitivity of hepatocytes to TNF leading to their necrosis and/or apoptosis. After double LPS/D-gal screening in F3 several mice resistant to LPS/D-gal-induced hepatotoxicity were identified, and became the founders of the corresponding “mutant” families. Using outcrossing to C57BL6 background followed by intercrossing, generations F5 and F7 were obtained. Among families of mutant animals only one family showed the resistance to the combination of LPS and D-gal, but sensitivity to TNF-D-galactosamine. This phenotype showed approximately Mendelian inheritance consistent with the recessive mutation hypothesis. This latter fact was confirmed by the sensitivity of mice from “heterozygous generations” (F4 and F6) to lethal LPS/Dgal hepatotoxicity. Primary bone marrow macrophages obtained from half of the mutant mice showed significantly reduced levels of TNF after LPS stimulation in vitro. At the same time, the serum TNF levels 1 hour after the administration of a non-lethal LPS dose did not differ in the mutant family mice and wild-type mice. These results implicate a recessive mutation either in innate TLR4-mediated signaling pathway, including proteins associated with LPS transfer, adapter molecules, components of kinase signaling cascades, transcription factors, or in enzymes involved in regulation of TLR4 cascades, such as components of the ubiquitin cycle, or in genomic regulatory sequences that control the expression of one of these genes, including the tnf gene.
Russian Journal of Immunology. 2020;23(1):27-34
pages 27-34 views

STUDY OF Na/K-ATPhase α-SUBUNIT DISTRIBUTION IN RAT CEREBRAL STRUCTURES IN PARKINSON-LIKE SYNDROME MODEL AND AFTER THYMUS HORMONE CORRECTION

Korolev A.G., Novoseletskaya A.V., Kiseleva N.M.

Abstract

Here we examined distribution of Na/K-ATPhase α-subunit in rat cerebral structures, which activity changes in Parkinson-like syndrome. The study was aimed at analyzing quantitative change in diverse different isoforms of Na/K-ATPhase α-subunit in model of Parkinson-like syndrome as well as after refining it by using thymus hormone thymulin. The study was performed on 42 sixweek-old Wistar rats males by dividing animals into 3 groups: 2 experimental and 1 control group. To simulate Parkinson-like syndrome, a solution of 1-methyl 4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) was administered intranasally. 10 days after MPTP inoculation, thymus hormone thymulin was abdominally administered to animals in one experimental group for 5 days. It was demonstrated that level of tissue-specific isoforms of Na/K-ATPhase α-subunit was peaked in hypothalamus, amygdaloid body and striatum, the minimal level was observed in medial prefrontal and prefrontal cortex. It was estimated that in MPTP-stimulated model of Parkinson’s disease, the level of Na/K-ATPhase α1-subunit was significantly higher in striatum, amount of α2-subunits was decreased in the hippocampus, whereas the level of α3-subunit was elevated in the cerebellum compared to control group. Administration of thymus hormone thymulin corrected changes in level of α1, α2 and α3-subunits observed after exposure to neurotoxin.
Russian Journal of Immunology. 2020;23(1):35-40
pages 35-40 views

INFLUENCE OF POLYOXIDONIUM, Poly(I:C), DALARGIN ON THE PROTECTIVE EFFICACY OF YERSINIA PESTIS VACCINE STRAIN EV LINE NIIEG IN EXPERIMENTAL PLAGUE

Shchukovskaya T.N., Kurylina A.F., Shavina N.Y., Bugorkova S.A.

Abstract

In this study, the use of immunoadjuvants polyoxidonium (azoximer bromide), Poly (I:C) as a synthetic analog of double-stranded RNA (TLR3 ligand), and synthetic analog of leu-enkephalin dalargin (DA) was experimentally investigated for their potential to minimize ImD50 Yersinia pestis vaccine strain EV line NIIEG co-administrated via invasive (subcutaneous) and noninvasive (intranasal) routes in lethal bubonic and pneumonic models of plague followed by challenge with virulent Y. pestis strains of the main and non-main subspecies from various natural plague foci. The data showed that in all cases immunoadjuvants significantly increased protective efficacy of Y. pestis vaccine strain EV line NIIEG co-administrated to BALB/c inbreed mice in case of lethal challenge with virulent Y. pestis strains in spite of varying magnitude of humoral immune response. Y. pestis vaccine strain EV line NIIEG formulated with polyoxidonium provided more effective protection against lethal challenge with wild-type high virulent strain Y. pestis in pneumonic model of plague. Polyoxidonium introduced into vaccine formula resulted in four-fold rise in total survival in animals with pneumonic plaque. Feasibility of using immunoadjuvants for regimen of specific and urgent plaque prevention is justified.
Russian Journal of Immunology. 2020;23(1):41-50
pages 41-50 views

GENDER-RELATED IMMUNE STATUS IN ISCHEMIC STROKE

Maslyakov V.V., Pavlova O.N., Fedotova N.N., Abakumova Y.V.

Abstract

Research objective – to reveal gender-related features of changes in immune status during acute ischemic stroke.

There were enrolled 160 subjects including 100 (50 males and 50 females) apparently healthy (no complaints, no check-ups and no diagnoses). On admission, 60 (30 males and 30 females) were diagnosed with ischemic stroke, who were examined for changes in immune status by assessing the following parameters such as T and B-cell subsets: peripheral blood CD3+ (mature T lymphocytes); CD4+ (T helper); CD8+ (cytotoxic T cells) T cells; CD16+ (natural killers); CD20+ (B cells) cells as well as CD4/CD8 ratio. Total amount of IgG, M, A antibodies was measured by simple radial immunodiffusion by Mancini et al., whereas IgE level – by ELISA. Level of serum C3-, C4-complement components, TNFα, IL-1β, IL-2, IL-6, IL-8, INFγ, IL-4, IL-10 was measured by ELISA.

Our study revealed that in peripheral blood count of total leukocytes, band neutrophils and lymphocytes was significantly increased in acute ischemic stroke vs healthy subjects in sex-independent manner. Moreover, no pronounced differences between females vs males were observed. Rise in such parameters may be due to host inflammatory response. While examining humoral immunity, it was shown that activity the complement system and cytokine level in patients with acute ischemic stroke had gender-related increase in pro-inflammatory cytokines IL-1β, IL-6, IL-8, IL-2 that paralleled with decreased anti-inflammatory IL-10, IL-4 and IFNγ. In addition, subjects in both groups demonstrated significantly increased amount of IgG, IgM, IgE, total complement and its С3- and C4 fractions, C1-inhibitor, CIC, factor H, FI, FH, NBT-sp., NBI-st. hence, based on this it may be concluded that patients with ischemic stroke exert signs of marked inflammation. Similar to cellular immune arm, the above parameters revealed gender-related differences so that all immune parameters were significantly increased in males vs females.

Russian Journal of Immunology. 2020;23(1):51-60
pages 51-60 views

IMMUNOLOGICAL PHENOTYPE AND HORMONAL BALANCE IN POSTMENOPAUSAL WOMEN

Glushkov A.N., Polenok E.G., Mun S.A., Gordeeva L.A., Kostyanko M.V., Lutsenko V.A., Kolpinskiy G.I., Brezhneva E.V., Vafin I.A.

Abstract

Serum concentrations of estradiol (Es) and progesterone (Pg), Es, Pg and benzo[a]pyrene-specific IgA and IgG antibodies were studied in 227 postmenopausal healthy women (HW) and 639 breast cancer patients (BCP). The high individual Pg/Es ratio (> 5.0) was revealed in HW (54.6%) and BCP (26.4%, p < 0.0001, OR = 0.3) marked as “hormonal balance”. The low Pg/Es (≤ 5.0) ratio was detected more frequently in BCP (OR = 3.3) marked as “hormonal imbalance”. The high Pg/Es ratio was more common in HW with protective immunological phenotype (IgA-Bp/IgA-Pg ≤ 1 and IgA-Es/IgA-Pg ≤ 1) than with procarcinogenic immunological phenotype (IgA-Bp/IgA-Pg > 1 and IgA-IgA-Es/IgA-Pg > 1): 78.8 vs 47.4%, p = 0.005. The same parameters for IgG-immunological phenotypes in HW were 73.3 and 48.6%, p = 0.002. The differences between IgA-immunological phenotypes were lowered (41.6 vs 24.4%, p < 0.007), whereas between IgG-phenotypes it was absent in BCP. Thus, for the first time it was revealed the influence of immunological phenotypes based on antibodies specific to the environmental chemical carcinogens and endogenous steroid hormones on the hormonal balance in HW and its reduced effects in BCP.
Russian Journal of Immunology. 2020;23(1):61-68
pages 61-68 views

ANTIBODIES SPECIFIC TO CHEMICAL CARCINOGENS AND SEX STEROIDS AS WELL AS SERUM ESTRADIOL AND PROGESTERONE LEVELS IN FEMALES WITH BREAST CANCER AND LUNG CANCER MALES

Glushkov A.N., Polenok E.G., Mun S.A., Gordeeva L.A., Kostyanko M.V., Kolpinsky G.I., Lutsenko V.A., Antonov A.V., Titov V.A., Vafin I.A.

Abstract

Previous studies found some associations between immunoglobulin class A antibodies specific to benzo[a]pyrene (IgA-Bp), estradiol (IgA-Es) and progesterone (IgA-Pg) as well as breast cancer (BC) in females and lung cancer (LC) in males. It was suggested that such antibodies affect serum Es and Pg levels.

Our study was aimed at revealing putative features of mutual effects of IgA-Bp, IgA-Es and IgA-Pg on serum Es and Pg level both in healthy and BC females as well as healthy and LC males.

Serum levels of Es and Pg and IgA-Bp, IgA-Es and IgA-Pg were measured by ELISA in 190 nonsmoking healthy and 518 BC females as well as 312 smoking healthy and 196 LC males.

It was found that healthy subjects vs cancer patients prominently differed by assessing individual Pg/Es ratios: healthy vs BC females had it set at 6.6 vs 2.9 (p < 0.0001), respectively, whereas in healthy vs LC males it was at 5.2 vs 10.1 (p < 0.0001), respectively.

Individual Pg/Es ratio paralleled in healthy females with high vs low IgA-Bp/IgA-Pg > 1.5 and IgA-Es/IgA-Pg > 1.5 ratios (3.5 vs 9.7, p < 0.0001). No T such associations were observed in BC patients. In addition, the lowest individual Pg/Es ratio in healthy males was found together with IgA-Es/ IgA-Pg > 1.5 ratios accompanied with IgA-Bp/IgA-Pg ≤ 1.5 (2.9) and peaked in case of concurrently low IgA-Bp/IgA-Pg ≤ 1.5 and IgA-Es/IgA-Pg ≤ 1.5 (5.2, p = 0.005) or high IgA-Bp/IgA-Pg > 1.5 and IgA-Es/IgA-Pg > 1.5 (6.5, p = 0.002). In contrast, the lowest Pg/Es ratio (7.4) was revealed in LC patients simultaneously bearing high IgA-Bp/IgA-Pg > 1.5 and low IgA-Es/IgA-Pg ≤ 1.5 ratios compared to simultaneously low ratios (11.3, p = 0.002).

In conclusion, individual Pg/Es ratios depended on individual IgA-Bp/IgA-Pg and IgA-Es/IgA-Pg ratios. A cooperative influence of serum antibodies specific to environmental chemical carcinogens and endogenous steroids on hormone balance was featured both in healthy subjects as well as BC females and LC males.

The data obtained may be useful while developing new strategies to cancer prevention: by using selective modulators of estrogen receptors and aromatase inhibitors as well as for development of anticancer vaccines.

Russian Journal of Immunology. 2020;23(1):69-78
pages 69-78 views

HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH PRIMARY IMMUNODEFICIENCY DERIVED FROM AN ALTERNATIVE DONOR BY USING NEW TRANSPLANT ENGINEERING TECHNOLOGIES

Balashov D.N., Maschan M.A., Shcherbina A.Y., Rumyantsev A.G.

Abstract

Analysis of the results of hematopoietic stem cell transplantation (HSCT) derived from alternative donors in patients with primary immunodeficiency syndromes. 110 HSCTs for patients with PIDs derived from alternative donors (unrelated, n = 85, haploidentical, t = 25) were performed at the Dmitry Rogachev National Medical Research Centre within 2012-2017 timeframe. In all cases, there were used conditioning regimes with reduced toxicity based on threosulfan TCRotP+/CD19+ depletion with immunomagnetic method were used as the basic cell transplant preparation. The cumulative probability of acute GVHD was 17% (95% CI 10-25) (n = 18); however, it should be noted that in 16 of 18 cases, an acute GVHD, stage II, was observed, showing a good response to the first line therapy; but acute GVHD, stage III, was documented only in 2 patients. Reactivation of cytomegalovirus infection remained one of the serious issues, with a cumulative probability of its reactivation reaching up to 50% and CMV visceral infection rate found in 15.4% cases. The conditioning regimen in patients with Wiskott-Aldrich syndrome by using granulocyte colony-stimulating factor and plerixafor demonstrated a full control over transplant dysfunction compared to control group.

Rate of immunological reconstitution upon inoculation of HSCT on the platform TCRotP+/CD19+ deletion did not differ in dynamics from that one after using undepleted HSCT together with native hematopoietic stem cell sources in a historical cohort. The overall survival probability for entire PID patient cohort was 84% (95% CI 77-92). No differences in patients transplanted from unrelated and haploidentical donors were revealed by assessing any of the studied parameters.

Introduction of new HSCT technologies allows us to dramatically minimize adverse outcomes of PIDs and opens new avenues for further research in cellular regulation of autoinflammatory oncological and infectious disorders resulting in lethal outcome in PID patients.

Russian Journal of Immunology. 2020;23(1):79-90
pages 79-90 views

SHORT COMMUNICATIONS

ASSESSED EFFICACY OF POLYOXIDONIUM IN MEDICATED TREATMENT OF MODELLED CHRONIC PERIODONTITIS (EXPERIMENTAL STUDY)

Sarkisyan N.G., Drozdova L.I., Umarova D.S., Solovyova D.A., Khlystova K.A.

Abstract

This article highlights current issues on medical treatment of chronic periodontitis. The lack of effective comprehensive approach to treatment of chronic periodontitis requires to seek for new treatment strategies, which will be based on pathogenetic features of disease development. Experimental study with Wistar rat strain was used as a model of chronic periodontitis created by inserting a 12 mm needle into the periodontal space of the lower incisor. More than 30 models of chronic periodontitis were obtained. A method of conservative therapy by using an immunomodulator (polyoxidonium) was proposed. The aim of the study was to evaluate efficacy of polyoxidonium in treatment of chronic periodontitis model. To do this, we compared efficacy of treatment with polyoxidonium and treatment with an antibacterial drug, Metrogil Denta gel. Development of model of chronic periodontitis was performed in two groups of our study. In the first group, periodontitis was treated with polyoxidonium injected into alveolar process mucosa of the lower jaw. In the second group – antibacterial gel “Metrogil Denta” was applied to the area of inflammation. Finally, clinical and histological assessment of therapeutic efficacy was performed. It was found that the main clinical parameters after immunomodulatory therapy were not inferior to those obtained after treatment with Metrogil Denta gel. During treatment, hyperemia, edema, and bleeding gums were decreased in both groups. Evaluation of clinical data after treatment with polyoxidonium suggested that improved parameters evidenced about good immune-mediated activity of the drug and need to continue further efficacy examination in treatment of inflammatory periodontal diseases. To assess the histological picture, 60 decalcified sections were examined (two per each animal, respectively). Data from control group without treatment were described previously, and were used for comparison. Histological examination confirmed ongoing healing process in all three groups. In group 1 treated with immunomodulator, pharmacological properties of polyoxidonium favorably affected regeneration of periodontal tissue, which, however, required longer period of time, more than 20 days. It proves a pronounced efficacy of polyoxidonium in treatment of inflammatory periodontal diseases, even as a standalone therapy without combining with antibacterial drugs.
Russian Journal of Immunology. 2020;23(1):91-96
pages 91-96 views

INCREASED SERUM LEVEL OF PEPTIDYL ARGININE DEIMINASE TYPE 4 IN VARIOUS MOLECULAR BIOLOGICAL SUBTYPES OF BREAST CANCER

Tereshin O.S., Semenova A.B., Vazhenin A.V., Dolgushin I.I., Nikushkina K.V., Nikonova T.I.

Abstract

Level of enzyme peptidyl arginine deiminase type 4 (PAD-4) was determined in serum samples collected from 98 females with primary breast cancer within January, 2017 – April, 2018 divided into 5 groups according to immunohistochemistry data: group 1 – luminal A cancer, 2 – luminal B Her-2 negative, 3 – luminal B Her-2 positive, 4 – non-luminal Her-2 positive, 5 – triple negative cancer. Samples were collected prior to the onset of any anti-cancer treatment, and in 41 cases – 15-24 days after performing radical surgery. Control samples were obtained from 20 healthy females. Serum PAD-4 level was measured with Human PAD-4 ELISA Kit (Wuhan Fine Biotech Co., Ltd, China) on automatic analyzer ADALTIS Personal LAB (Adaltis S.r.l., Italy). Statistical analysis was performed by using software IBM SPSS Statistics 19. Mean serum PAD-4 level before treatment was 9.0 ng/ml that did not change after surgery. However, mean PAD-4 level for healthy females was 1.5 ng/ml (0.0-2.0) ng/ml that significantly differed from cancer group (Mann–Whitney U test, U = 38.500, p<0.001). in contrast PAD-4 level in various cancer groups was: group 1 – 11.05 ng/ml, group 2 – 11.9 ng/ml, group 3 – 10.8 ng/ml, group 4 – 7.99 ng/ml, group 5 – 9.9 ng/ml. Thus, level of serum PAD-4 was higher in groups with more favorable luminal cancer, but further research is needed to make definitive conclusions.
Russian Journal of Immunology. 2020;23(1):97-102
pages 97-102 views

OBITUARY

АРИОН ВИТАЛИЙ ЯКОВЛЕВИЧ 10.12.1933 – 09.02.2020

Abstract

9 февраля 2020 года на 87-м году жизни скончался Виталий Яковлевич Арион, доктор биологических наук, профессор, заслуженный деятель науки РФ, академик РАЕН, лауреат премии Правительства РФ.
Russian Journal of Immunology. 2020;23(1):103
pages 103 views


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