Vol 8, No 1 (2018)

REVIEW ARTICLES

THE NEW LOOK AT NEUTROPHILIC GRANULOCYTES: RETHINKING OLD DOGMAS. PART 2

Nesterova I.V., Kolesnikova N.V., Chudilova G.A., Lomtatidze L.V., Kovaleva S.V., Evglevsky A.A., Nguyen T.L.

Abstract

Numerous modern basic research done undeniable fact that neutrophilic granulocytes (NG) are key effector and regulatory circuits both innate and adaptive immunity, and play a crucial role in the pathogenesis of a wide range of diseases. NG have potent receptor repertoire, providing a connection between them, cells of the immune system, as well as communication with endothelial cells, epithelial and other tissues. NG inducing stimuli activate and promote the translocation of cytoplasmic granules and vesicles surface molecules on the cytoplasmic membrane the secretion of a large spectrum of pro-and anti-inflammatory, immunoregulatory cytokines, colony, angiogenic factors and fibrogenic, TNF superfamily members, chemokines, regulatory protein, etc. Chromatin nuclei NG capable of restructuring under the influence of inducing stimuli, which is associated with the expression of multiple cytokine genes. NG receiving complex cytokine influence not only acquire new features, but also in various stages of activation and differentiation processes involved in intracellular intraphagosomalis degranulation and killing of implementing elimination microorganisms and extracellular neutrophil degranulation in the formation neutrophil extracellular traps (NET), while this dying through NETosis. Features NG phenotype and their functional properties, demonstrate the existence of subpopulations of NG with different capabilities: equipment of different receptor, the ability to restructure chromatin expressing cytokine genes and secrete cytokines to implement the contents of the granular system, produce reactive oxygen species, implement cytotoxicity form NET. In our opinion, there subpopulation NG: regulatory; suppressor; proinflammatory — initiating an inflammatory response; inflammation with a positive potential microbicidal (antibacterial, antiviral, antifungal); inflammatory cytotoxic potential of the negative — «aggressive»; anti-inflammation regulating regression; antitumoral — TAN1; pro-tumoral — TAN2; hybrid, combining the characteristics of NG and dendritic cells. The absence of adequate response, or hyperactivation blockade NG functions leads to the development of low-intensity infectious and inflammatory diseases, do not respond to conventional therapy of autoimmune diseases/chronic immune-dependent processes. Remo deling dysfunctions NG — the key to new immunotherapeutic strategies.

Russian Journal of Infection and Immunity. 2018;8(1):7-18
pages 7-18 views

NEW ASPECTS OF SEPSIS AND SEPTIC SHOCK PATHOGENESIS IN CHILDREN. THE COMPLEMENT SYSTEM AS TARGET FOR AN EFFECTIVE THERAPY

Prodeus A.P., Ustinova M.V., Korsunskiy A.A., Goncharov A.G.

Abstract

Nowadays sepsis is grave complication of infection end the cause of death reanimation. In this survey, we would like to emphasize the importance of the control over the activation over the compliment system. It has been proved of animal model a complement one of the key role in the development of hyperactive immunity response, later resulting in violation of immunity homeostasis. Mice which had C3–/–, C4–/– deficit, aft receiving a LPS dose intraperitoneallis showed a better survival to compare with the control group of animals. There exist clinical data which confirm active participation of the compliment in the chain of the septic process. The research showed the patient affected by sepsis, had protein C3 and C4 concentration correlating which mortality at the time of diagnosis. The is chemoattractants, protein C3a and C5a, turn tube the result of complements pathway activation. The chemoattractants, provoke the extraction a big number of cytokines. Vessels permeability increase and DIC-syndrome activation wis it, multiple organ dysfunction develops. Ishemiareperfusion launch triggers aseptic inflammation, which appears decentralization and DIC-syndrome. C1-INH controls the work of classical way complement and Hemostasis System. Researchers the deficit in C1-INH animals and patients affected bay sepsis, which is proved in laboratory and clinics. The remedy C1-INH (Berinert, CSL Behring) appeared over 25 years ago and was used and therapy hereditary angioedema. For the lasted years we accumulated a considerable quantity of fasts of C1-INH use which after pathologies: heart attack, Ischemia-reperfusion injury, trauma provoked by cardiopulmonary bypass. The use of C1-INH on animal models septic in clinical research their efficacy and safety.

Russian Journal of Infection and Immunity. 2018;8(1):19-24
pages 19-24 views

ORIGINAL ARTICLES

COMPARATIVE CHARACTERISTICS OF THE DEVELOPMENT OF INFLUENZA INFECTION IN MACROPHAGES DIFFERENTIATED FROM MONOCYTES OF THP-1 (INFLUENZA A VIRUSES OF SUBTYPES H1, H5 AND H9)

Sokolova T.M., Poloskov V.V., Shuvalov A.N., Rudneva I.A., Timofeeva T.A., Klimova R.R., Masalova O.V., Kushch A.A.

Abstract

Macrophages (Mf) play an important role in the pathogenesis of influenza infection, but the obtaining of Mf in large quantities is difficult. In connection with this, in the present study, THP-1 monocytes differentiated by phorbol ether (PMA) into macrophages (MF) were used to study influenza infection. Differentiated cells — THP-PMA Mf were infected with pandemic А(H1N1)pdm09 and avian influenza A viruses H5N2 and H9N2. Differences in the levels of penetration of viral RNA (gene M1) and nucleocapsid (NP) proteins of the investigated viruses were found. The levels of expression of viral RNA and proteins were significantly higher in cells infected with avian viruses compared to pandemic viruses. Of particular interest is the phenomenon of prolonged intracellular presence of viral RNAs and nuclear localization of NP protein. However, no infectious or haemagglutinating activity of the virus of all subtypes studied in the culture liquid was detected up to 96 h. This indicates the abortive nature of influenza infection in THP-PMA Mf. Thus, MF performs a special function of depositing viral components and delivering them to the sites of inflammation. The blocking mechanism in human and avian influenza A viruses with different pathogenicity may differ, due to the existence of multiple mechanisms of escape from the immune response. As a result of infection with the human virus А(H1N1)pdm09, the infection developed slowly and caused death of 25% of the cells by 72 h, whereas in the case of infection with avian viruses, 50% of the cells died after 24 hours and by 72 h all the THP-PMA MF died. Preprocessing with recombinant IFNα2b had a protective effect, suppressing the accumulation of the NP protein of the A/H5N2 virus in the THP-PMA Mf nuclei. The obtained data allow us to conclude that one of the reasons for the different course and outcome of influenza infection in human infection with influenza A viruses is the sensitivity of human macrophages to avian influenza viruses of subtypes H5 and H9 as compared to the pandemic virus. Our result on the THP-PMA Mf model is consistent with reports on the blocking of the stages of the release of infectious influenza A virions in primary cultures of monocytic and alveolar MF. Massive death of MF caused by avian influenza viruses explains their high pathogenicity.

Russian Journal of Infection and Immunity. 2018;8(1):25-32
pages 25-32 views

FEATURES OF BETA-LACTAMASE ACTIVITY IN FRANCISELLA TULARENSIS subsp. MEDIASIATICA

Bakhteeva I.V., Kravchenko T.B., Ryabko A.K., Titareva G.M., Lev I.O., Mokrievich A.N., Timofeev V.S.

Abstract

Small Gram-negative bacteria Francisella tularensis is the tularemia causative agent. This species subdivides on four subspecies — ssp. tularensis, holarctica, mediasiatica and novicida, which have some differences in their distribution areas, pathogenicity and epidemical potencial. Until recently only subspecies holarctica was found on the territory of the Russian Federation, but in 2013 a natural focus of tularemia in which circulates F. tularensis subsp. mediasiatica was found on the Altai. Till now this subspecies was found only in Central Asia. The data of laboratory studies indicate the ability of strains of this subspecies to cause infection in rabbits and mice which is comparable in severity to infection caused by subsp. holarctica strains. However, the virulence of F. tularensis subsp. mediasiatica for humans and its epidemical potential are still unclear, since no cases of human infection caused by the strains of this subspecies have been recorded, probably due to the geographical aspects — mountainous Altai and Central Asia are extremely sparsely populated regions. The main phenotypic feature of this subspecies is the lack of activity of β-lactamase, which is responsible for the natural resistance to β-lactam antibiotics (penicillins, cephalosporins and carbapenems). Despite the absence of detectable enzymatic activity, subsp. mediasiatica strains are resistant to these antibiotics. In this article we report that subsp. mediasiatica strains have β-lactamase activity despite to current opinion, but the of β-lactams hydrolysis rate is much more lower in comparison with reaction rate of subs. holarctica strains. In addition, in case of a decrease of the microbial cells number in the nutrient medium, antibiotic susceptibility appears. We identified a single specific for subsp. mediasiatica nucleotide substitution G/A at the 290 position of the blaB gene, which encodes the active serine β-lactamase. This substitution leads to the amino acid substitution Gly/Arg at the 97 position of the protein BlaB. We assume, that enzymatic activity decreasing is the most likely caused by this substitution), for example it may cause some conformational changes leading either to enzyme — substrate affinity decreasing or to in the lifetime of the enzyme-substrate complex increasing. On the basis of the found nucleotide substitution, we developed an allele-specific PCR test that makes it possible to determine whether the studied strain F. tularensis belongs to the subspecies mediasiatica.

Russian Journal of Infection and Immunity. 2018;8(1):33-42
pages 33-42 views

THE FUNCTIONAL ACTIVITY OF INNATE IMMUNITY CELLS IN BACTERIAL INFECTION ON BACKGROUND OF THERMAL STRESS

Plekhova N.G., Somova L.M., Drobot E.I., Lagureva A.V., Lyapun I.N., Kondrashova N.M., Ogneva S.D.

Abstract

Maintenance of thermo homeostasis under the coordinating influence of the hypothalamus is ensured by integrative interaction of various systems organisme, including the immune system. Temperature stress in infectious diseases activates the reaction of heat shock, the biochemical consequence of which is the initiation of the organism’s defense against the pathogen. Cells of innate immunity (neutrophils and macrophages) are the first line of protection against pathogenic agents and play a primary role in the development of bacterial infections. Of particular interest is the study of the duration of the effect of hyperthermia to achieve a balance between the bioenergetic costs of these cells, as well as the study of the course of the pathological process in an organism previously exposed to hige temperature. The functional status of neutrophils and macrophages, including phagocytosis, the activity of enzymes of the oxygen-dependent system: lactate dehydrogenase, cytochrome oxidase, myeloperoxidase, cellular stimulation (intracellular AMPase content) and the content of nitrogen oxide metabolites have been studied in the model of animals exposed to low and high temperatures. It has been established that under hyperthermia conditions, the change in the functional activity of cells by enzyme level is more pronounced than when exposed to animals with low temperature, especially 4 h exposure. In animals pre-exposed to heat stress, manifestations of pseudotuberculosis infection were more severe with an increase in mortality rates by 2.6 times, compared to animals infected by bacteria. These animals had a high stimulation of effector cells of inflammation in the initial periods (at 7 days) their metabolism was enhanced, which was expressed of the activity of enzymes of the oxygen-dependent system, as well as in high nitroxide-producing activity. In target organs (lung, liver, spleen) of experienced animals the severe disturbance of blood circulation in combination with significant destructive changes typical for generalized infection were showed. At dead animals on the background of marked hemorrhagic component pathological process and weak cell inflammatory response observed depletion of the immune system (delimphatization), indicating a decrease in defense reactions and the development of immunodeficiency. Thus, under conditions of heat stress (+30°С), the intensity of the reaction of innate immunity cells in terms of enzyme’s functional activity was higher than when exposed to animals of low temperature (+4°C). Under these temperature conditions, a high level of cell priming was determined, which reduced their killing potential. These data indicate the adequacy of the model used to reproduce induced secondary immunodeficiency in a congenital defense system. Moreover, in the pathogenesis of pseudotuberculosis infection against the background of prolonged action high temperature, the effects of phagocytes oxidative stress in the structural changes of immunocompetent organs were detected.

Russian Journal of Infection and Immunity. 2018;8(1):43-53
pages 43-53 views

SOCIETY OF ENVIRONMENTAL NICHE: ORAL CAVITY OF THE HEALTHY CHILDREN

Burmistrova A.L., Filippova Y.Y., Nokhrin D.Y., Timofeeva A.V.

Abstract

In recent years, saliva is increasingly being used as a diagnostic fluid for the evaluation of various biological parameters, namely, the levels of activity of the information signal molecules of the metaorganism — the immune-neuroendocrine nature, but less often the metabolites of the microbial community and the structure of the bacterial society. The paper assesses the microbial society of the oral cavity (saliva/smear from the surfaces of the microbiota) healthy children in order to create microbial images of «health» — control that can be used in the study of the microbial community in the development of local and/or systemic pathophysiological processes, including infections, in the child’s body. Using the method of Gas chromatography mass spectrometry of microbial markers, specific chemical markers of 38 taxa of microorganisms in the oral cavity of healthy children from 1.5 to 14 years have been determined. To determine the distribution of various representatives of microbial societies between ecological niches (saliva/smear) in the oral cavity and assess the effect on them of the age of children, a Canonical Correspondences Analysis was used. A high similarity of the microbiota structure of saliva and smear from microbiota living surfaces in healthy children was found, which may indicate cross paths of bacterial representatives of different species and genera of the microbial community, or their functional plasticity. Of greatest interest are the data on the number of bacteria of the genus Alcaligenes spp. in the smear from the surfaces of the microbiota, which is twice higher, than in saliva. Alcaligenes presents itself as a professional organizer of security measures in relation to the place of residence: it produces antibiotics and original antibacterial components that disorganize the growth of a wide variety of bacteria. In addition, it is able to initiate B-lymphocytes of lymphoid follicles to produce Alcaligenes-specific antibodies, to create from them their own «cloaking» coating, facilitating its entry into Peyer’s plaques through M-cells. It can be assumed that the level of Alcaligenes spp. in saliva to some extent reflects the migration of representatives of this genus, both from the palatine and from the nasopharyngeal tonsils. The age features of the microbiota of the ecological niche — the oral cavity are determined: the number of representatives of the genus Clostridium spp. increases with age in children. And the number of bifidobacteria decreases. The results obtained by us can be used as a control in systemic pathophysiological processes, including infectious etiology, as well as during therapy.

Russian Journal of Infection and Immunity. 2018;8(1):54-60
pages 54-60 views

INFECTION OF LABOUR MIGRANTS FROM CENTRAL ASIA AND RESIDENTS OF ST. PETERSBURG AND THEIR SUSCEPTIBILITY TO VARIOUS INFECTIOUS DISEASES

Kraeva L.A., Тоkarevich N.K., Lavrentyeva I.N., Roshchina N.G., Kaftyreva L.A., Kunilova E.S., Kurova N.N., Stoyanova N.A., Antipova A.Y., Svarval А.V., Zueva E.V., Porin A.A., Rogacheva E.V., Zheltakova I.R., Khamitova I.V., Timofeeva E.V., Bespalova G.I.

Abstract

Wide migration processes typical for megacities, including St. Petersburg, require a comprehensive study of the infection among migrants arriving on a work visa. Biological material for research was taken from 370 migrants who arrived in St. Petersburg on a work visa. The control group is represented by 320 adults of St. Petersburg. The methodology of the study of the biological material depended on the type of pathogen and included classical and modern methods of research. All obtained data are processed using adequate methods of mathematical statistics. C. diphtheriae strains in migrant workers were isolated 80 times more often than in permanent residents of St. Petersburg. In St. Petersburg gravis biovar occurs in 25% of cases, in the visiting contingent — in 83% of cases, which is an unfavorable prognostic sign. In migrants 17% of C. diphtheriae strains have a “silent” gene (tox+), which, under known conditions, can resume toxin production. The local people are protected from diphtheria by 95%, and labor migrant is only 66%. 17% of migrant workers with C. diphtheriae strains have a low level of protection against diphtheria, which poses a threat to them and those in contact with them. Infection with brucellosis pathogens of labor migrants from Uzbekistan is 9 times higher than the local population, persons from Tajikistan — 60 times higher. The infection rate of migrant workers from Uzbekistan and Tajikistan C. burnetii is 25 times higher than that of the local population. The chronic course of these infections complicates diagnosis and reduces the quality of life. According to the results of the screening test, S. Typhi bacterium carrier is distributed 7 times more in migrant workers from Uzbekistan and 2 times more in persons from Tajikistan than among the local population of St. Petersburg. The seroprevalence of toxic H. pylori in migrant workers is 84%, which is much higher than that of permanent residents of St. Petersburg (57%). The causes of this phenomenon have not been studied and require further study. Labor migrants from Central Asia have a low level of population immunity to parvovirus infection: 37% of seropositive persons from Uzbekistan and 62% from Tajikistan compared with 78% of the local population. This may contribute to the spread of parvovirus infection involving infection of seronegative residents of St. Petersburg risk groups, including blood donors, pregnant women, persons with immunodeficiencies, hematologic and oncologic patients. The results obtained ascertain the tense epidemiological situation among labour migrants in St. Petersburg for a number of infections. Reliable information will help to organize the correct further study of the problem and conduct appropriate measures to preserve the health of the local population and the visiting contingent.

Russian Journal of Infection and Immunity. 2018;8(1):61-70
pages 61-70 views

IMMUNOGENICITY OF THE THIRD GENERATION HEPATITIS B VACCINE (pre-S1/pre-S2/S)

Esaulenko E.V., Sukhoruk A.A., Zakharov K.A., Yakovlev A.A.

Abstract

Currently, second-generation hepatitis B vaccines are widely used. They are produced in biotechnological eukaryotic yeast-based systems and contain the S-protein domain of HBsAg particle in the complete absence of pre-S1 and pre-S2 domains. At the same time, these antigens were proved to significantly influence immunogenicity, which makes the development and use of third-generation vaccines containing all antigenic determinants a long-range objective. A randomized, double-blind clinical study was conducted to compare immunogenicity of second- and third-generation vaccines Engerix-B™ and Sci-B-Vac™, respectively. Healthy subjects of both sexes aged 18 to 45 years (n = 94) who are seronegative for HBsAg, HBsAb, HBcAb at screening and who previously had not received immunobiological agents for hepatitis B prophylaxis were included in the study. Group I (n = 47) received the second-generation vaccine Engerix-B™, Group II (n = 47) — the third-generation vaccine Sci-B-Vac™. Subjects received vaccines three times — on days 1, 28 and 180 of the study. HBsAb levels, rates of seroconversion (the proportion of subjects with HBsAb levels > 2.1 mIU/mL) and seroprotection (the proportion of subjects with HBsAb levels ≥ 10 mIU/mL) were assessed on days 28, 90, 180 and 210 of the study. Early seroconversion rate assessed on Day 28 was 76.60% in Group I and 93.88% in Group II (p < 0.05); seroprotection rate was 51.06 and 61.22%, respectively. These differences in the proportion of subjects who achieved seroconversion on Day 28 may indicate a faster immunological response to Sci-B-Vac™ vaccine. Statistically significant differences between the level of antibodies on days 90 and 180 (p < 0.05) were observed when analyzing the average values of HBsAb concentration in Groups I and II. The concentration of HBsAb on Day 90 was 378.68±60.95 mIU/mL in Group I, and 618.31±58.34 mIU/mL in Group II. On Day 180, the concentration of HBsAb reached 441.34±63.83 mIU/mL in Group I, and 757.72±55.14 mIU/mL in Group II. The significance of dependence of antibody level on sex, age and body weight was analyzed. It was revealed that the age of a vaccinated subject affects antibody level after administration of Engerix-B™ (p < 0.05). The results obtained suggest that there is a rapid and strong immune response to the third-generation vaccine Sci-B-Vac™. This may indicate advantage of the vaccine containing all three recombinant proteins of hepatitis B virus envelope, which, in turn, can play a key role in clinical practice for urgent prophylaxis of hepatitis B, as well as for treatment of immunocompromised conditions.

Russian Journal of Infection and Immunity. 2018;8(1):71-78
pages 71-78 views

SHORT COMMUNICATIONS

SUSCEPTIBILITY TO ANTIBIOTICS IN KLEBSIELLA PNEUMONIAE STRAINS ISOLATED IN A MULTIDISCIPLINARY MEDICAL CENTRE

Kozlova N.S., Barantsevich N.E., Barantsevich E.P.

Abstract

Susceptibility to 16 antimicrobial agents in 421 Klebsiella pneumoniae strains, isolated in a multidisciplinary medical centre from patients with nosocomial infections in 2015, was tested. The majority of studied strains were resistant to antibiotics: ampicillin/clavulanic acid (91.4%), ticarcillin/clavlanic acid (81.9%), piperacillin/tazobactam (69.4%), fluorochinolones (83.6%), III and IV generation of cephalosporines (79.8%), gentamycin (72.9%); one third (34.2%) demonstrated resistance to amikacin. K. pneumoniae strains demonstrated high level of carbapenem resistance (53.0% — to ertapenem, 42.8% — to meropenem and 37.1% — to imipenem), associated resistance to at least 3 different classes of antibiotics — caphalosporins, aminoglycozides, fluorochinolones, that amounted to more than half of the strains (57.7%), including 44.2% of the strains, additionally resistant to carbapenems. The lowest level of resistance was found to fosfomycin (8.5%) and tigecycline (7.4%), resistant cultures showed intermediate resistance with MIC 2 μg/ml to the latter. High diversity of antimicrobial resistance spectra was found, with high level of multidrug resistant strains (87.2%). Resistance to carapenems in K. pneumoniae isolated in the multidisciplinary medical center was determined by either blaOXA-48 (59.3% of isolates, resistant to carbapenems) or blaNDM-1 (40.7%).

Russian Journal of Infection and Immunity. 2018;8(1):79-84
pages 79-84 views

OPTIMIZATION OF THE METHOD OF OBTAINING PESTINE PP AND STUDYING ITS SPECIFIC ACTIVITY IN VITRO

Gostischeva S.E., Abzaeva N.V., Kovalev D.A., Ponomarenko D.G., Siritsa Y.V., Rakitina E.L., Afanasyev E.N., Kostuchenko M.V.

Abstract

The formation of immunity against infectious diseases is accompanied by an immunoallergic alteration of the organism, while the intensity of the allergic reaction is associated with the presence of specific immunity. Skin allergotesting is often used to determine the intensity of sensitization of the body. When determining the immunity of vaccines against the plague, previously an allergen was suggested as a pestin PP — a polypeptide polysaccharide complex of a plague microbe. The authors optimized the technique for obtaining the preparation of pestin with preservation of its chemical composition, high specificity and allergenic activity. It is known that a lack of allergic test in vivo is a high risk of formation of adverse reactions. A method for estimating adaptive antiplague immunity with the allergen pestin in antigen-specific cellular tests in vitro is proposed. The preparation of the allergen by a modified procedure was carried out by hydrolysis of the biomass of the vaccine strain of the plague microbe Yersinia pestis EV of the NIIEG line, followed by filtration and lyophilization of the precipitate. In the preparation obtained, the pH and the protein concentration were determined. To check the specificity, the samples were subjected to spectrophotometric and chromatographic analysis. To assess specific activity, blood samples of 17 people immunized with the plague live vaccine from the Yersinia pestis EV strain of the NIIEG line were used for epidemic indications. As a comparative control, a sterile isotonic sodium chloride solution was used. The contingent was examined before vaccination on days 7, 21 and 3 months after immunization by evaluating the expression intensity of basophils CD63. Biochemical analysis of the obtained by the modified procedure of the pestin and derivatives allowed to judge the qualitative composition, to show the absence of impurities of the protein nature, as well as to determine the carbohydrate profile. The use of the drug as an allergen to assess the formation of antiplague immunity in the vaccinated contingent confirmed its specificity. The obtained data showed the possibility and prospect of using the Pestin PP as a test allergen for the establishment of the reaction of activation of basophils in vitro.

Russian Journal of Infection and Immunity. 2018;8(1):85-90
pages 85-90 views

SCIENCE HISTORY

"THE TEACHER! BEFORE YOUR NAME..." (to the 120 th anniversary of Vladimir Ilyich Ioffe)

Totolian A.A.

Abstract

February 14th 2018 —  anniversary of the famous scientist, academician of the USSR Academy of Medical Sciences, great immunologist and microbiologist Vladimir Ilyich Ioffe the founder of the Russian school of clinical and epidemiological immunology. He created an authoritative Scientific School, anticipated many concepts of infectious immunology, justified and linked together theory, experiment and practical implementation of 3 fields of science: microbiology, immunology and epidemiology thus providing a fertile ground for breakthrough in infectious pathology. Ioffe has developed the principles of quantitative analysis of processes, created the methodology of titer tests to evaluate the strength of the body's defense system or organism allergization. His works have proved long before foreign scientists that scarlet fever and rheumatic fever were streptococcal infections, introduced immunogram as clinico-immunological characteristic of the patient’s disease, and reflected the patterns of disease development and manifestation. Ioffe’s publications provide comparative characteristics of experimental, clinical and epidemiological immunology as independent immunological scientific areas with its own content, aim and subject of research. Based on the wealth of experimental, clinico-immunological and epidemiological data Ioffe created such fundamental works as “Clinical and Epidemiological Immunology”, “Scarlet Fever”, “Whooping Cough”, “Immunology of Rheumatism”, which are still in the researchers’ focus of attention.

Russian Journal of Infection and Immunity. 2018;8(1):91-96
pages 91-96 views

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