Nobel prizes for investigations in immunology (1901‑2018)
1901. Nobel prize for implementation of immune sera for treatment of diphtheria and other infectious diseases
1905. Nobel prize for investigations in relation to tuberculosis
1913. Nobel prize for investigations of anaphylaxis
1919. Nobel prize for investigations in immunity (awarded in 1920 )
1930. Nobel prize for discovery of human blood groups
1951. Nobel prize for his discoveries concerning yellow fever and how to combat it
1957. Nobel prize for investigations of structure and function of antihistaminic drugs and other synthetic antagonists
1972. Nobel prize for investigations of the chemical structure of antibodies
1977. Nobel prize for the development of radio-immunoassays of peptide hormones
1984. Nobel prize for theories concerning the specificity in development and control of the immune system
1984. Nobel prize for the discovery of the principle for production of monoclonal antibodies with hybridomas
1987. Nobel prize for discovery of the genetic principle for generation of antibody diversity
1990. Nobel prize for discoveries concerning organ and cell transplantation
1996. Nobel prize for discoveries concerning the specificity of the cell mediated immune defence
1997. Nobel prize for the discovery of Prions - a new biological principle of infection
2008. Nobel prize for discovery of human immunodeficiency virus (HIV)
2011. Nobel prize for investigations of the activation of innate immunity
2011. Nobel prize for discovery of the dendritic cell and its role in adaptive immunity
2018. Nobel prize for discovery of cancer therapy by inhibition of negative immune regulation
2018. Nobel prize for the phage display of peptides and antibodies

Иммунология № 2, 2022

Immunologiya

The journal covers major theoretical and practical issues in general and applied immunology and allergology. It disseminates the results of original research in the fields of immunogenetics, molecular and cellular immunology, immunochemistry, immunomorphology, clinical immunology, and immunopathology.


Current issue
2 . 2022
Editorial

Rakhim Musaevich Khaitov (06.01.1944–11.03.2022)

Abstract
Immunogenetics

Congenital T- and NK-cell immunodeficiency with impaired expression of β-integrin on neutrophils in a patient with a mutation in the KMT2D gene: a description of a clinical case

Abstract

Background. Pathogenic mutations in the KMT2D or KDM6A genes are associated not only with the classic manifestations of Kabuki syndrome (KS), characterized by postnatal growth failure, dysmorphic facial features, skeletal anomalies, and mental retardation, but are also characterized by manifestations of common variable immunodeficiency, detected in at least 50 % patients. Persons with KS have a tendency to recurrent infections, primarily of the ENT organs, and hypogammaglobulinemia.

Aim – to demonstrate the difficulties of diagnosing the causes of congenital immunodeficiency in children and present a diagnostic search algorithm.

Material and methods. A child from the second birth at term from nonconsanguineous parents. The elder sister is healthy. Psychomotor development up to 12 months was normal. From the age of 14 months experienced purulent conjunctivitis, pharyngitis and rhinitis, resistant to ongoing therapy. At the age of 16 months unsteady gait, increasing muscle hypotension, periodic obsessive hand movements by the type of hyperkinesis were noted. Microcephaly with a head circumference 44 cm (< 5th centile). He was hospitalized with bilateral pneumonia, purulent conjunctivitis, left-sided otitis media.

Results. The absence of T-regulatory cells (CD4+CD25highCD127) and effector NK cells (CD16+CD56+CD3) in the peripheral blood with a decrease in CD4 levels resulting in granulomatous lung damage, proved by biopsy, enterocolitis and pansinusitis was revealed. The levels of CD4+CD3+-T-lymphocytes and CD4+/CD8+ index were also decreased. In addition, integrin-beta (CD18) expression was absent on granulocytes. Whole exome sequencing revealed a deletion in exon 24 of the KMT2D gene, which made it possible to make an accurate clinical diagnosis of kabuki syndrome. At the same time, the patient did not have characteristic hypogammaglobulinemia and dysmorphic features.

Conclusion. Severe infection is not always the primary clinical manifestation of some rare forms of congenital immunodeficiencies. The debut may be associated with non-infectious features, which does not exclude the presence of a congenital genetic defect, determining further a combination of clinical syndromes and requiring complex therapy and interaction of doctors of various specialties.

Cellular immunology

Indicators of human cellular immunity in conditions of artificial gravity creation using a short-arm centrifuge

Abstract

Introduction. Under conditions of space flight (SF), the human body is exposed to a number of adverse factors, one of which is microgravity, leading to the inhibition of the functions of various physiological systems, including the immune system. It is possible to eliminate the negative effects of microgravity by creating an artificial force of gravity (AFG) on board a spacecraft using a short-range centrifuge (SAC). The conducted ground-based experiments are designed to determine the optimal regimes for creating AFG at the SAC from the point of view of safety in relation to the human immune system.

The aim of the study – assessment of the direction and severity of changes in human cellular immunity before and after rotation on the SAC in various modes.

Material and methods. The study involved 10 practically healthy volunteers (men) aged 25–40 years, each subject underwent 3 rotations on the SAC, the acting factor in the tests was overloads of the «head–pelvis» direction (+Gz). The rotation modes differed from each other in the magnitude of the overload at the stop level, the duration of the «platform» during acceleration and deceleration, as well as the total rotation time. Venous blood sampling was carried out in vacuum tubes with potassium salt of ethylenediaminetetraacetic acid (K3 EDTA) before rotations (baseline), as well as after each of the rotations on the SAC. The following indicators of cellular immunity were evaluated in the blood samples of the subjects by flow cytometry: the content of helper T-lymphocytes (Th, CD3+CD4+), cytotoxic T-lymphocytes (CTL, CD3+CD8+), B-lymphocytes (CD3CD19+), natural killers (NK cells, CD3CD16+CD56+), non-classical monocytes (CD14+CD16++), monocytes and granulocytes with membrane expression of type III complement receptors (CR3, CD11b+CD18+) and toll-like receptors (TLR) – TLR2, TLR4, TLR6. The data obtained are presented as median (Me) and interquartile range (Q25–Q75). To assess the significance of differences in the studied parameters, the nonparametric Wilcoxon T-test was used for related samples at a significance level of p < 0,05.

Results. The study compared the indices of cellular immunity after each of the three rotations on the SAC with baseline values (before rotations). There was a decrease in the content of NK cells (rotation mode 1), TLR6-expressing monocytes and TLR2-expressing granulocytes (rotation mode 2). Rotation mode 3 did not lead to significant changes in the studied parameters of the immune system.

Conclusion. The obtained data on a decrease in the content of innate immunity cells indicate a possible inhibition of the immune system functional activity after rotation on the SAC under modes 1 and 2. However, after rotation in mode 3, the values of the studied parameters did not significantly differ from baseline, which, in our opinion, determines the safety for the immune system of using a short-arm centrifuge as a means of preventing the negative effects of microgravity on the human body.

Experimental model of antigen-collagen induced arthritis in mice

Abstract

Introduction. Rheumatoid arthritis (RA) is one of the most common autoimmune diseases with a complex pathogenesis. To develop and test new methods and approaches in RA therapy (biological preparations, cell technologies), an experimental model with similar pathogenetic reactions and immunological changes is needed. One such approach is the development of models of combined antigen-collagen-induced arthritis.

The aim of the study is to show the immunological and histological changes similar to RA in the antigen-collagen induced arthritis (AIA/CIA) model and the validity of its application in research activities and for the development of new therapeutic approaches.

Material and methods. Experimental AIA/CIA was induced according to 3 different protocols in 60 Balb/c mice. Arthritis was assessed visually by measuring paw swelling with a caliper at different times. The assessment of immunological changes included the analysis of the content of antibodies to type II collagen by ELISA, the content of T-regulatory cells by flow cytometry. In addition, a histological examination of the tissues of the joints was carried out, followed by an analysis of the data obtained.

Results. On the 10th day, a significant increase in the thickness of the paws was recorded in animals using the induction of experimental arthritis with different protocols. The intensity of swelling subsided by the 23rd day. A significant increase in the content of antibodies to type II collagen was observed in all experimental groups, but in animals on Protocol No. 1, the level of antibodies to type II collagen was significantly higher. A high level of T-regulatory cells was registered only in mice on Protocol No. 1 on the 10th day. Histological changes in the form of synovial hyperplasia, pannus, usurations were observed to varying degrees in all experimental groups, but the most pronounced changes were in animals on Protocol No. 1.

Conclusion. In experimental animals, in all the presented protocols, changes were observed that were closest to RA, when compared with classical models of experimental arthritis induction. Based on the fact that protocol 1 animals showed an increase in the content of T-regulatory cells, the levels of antibodies to type II collagen were consistently high, and histological changes were the most pronounced, it can be assumed that Protocol No. 1 of the combined AIA/CIA model on the Balb/c mice line is the most suitable for testing and developing of new methods for RA therapy.

Immunopathology

Effect of glyproline neuropeptides on the level of interleukins and neurotrophic factors under stress

Abstract

Introduction. At present, scientific works are giving special results, reflecting the study of the pathological impact of stress factors, including those of a social nature, on various systems of the body. Stress effect in biochemical terms is manifested by the release of glucocorticoids in the blood, referring this process to one of the main levers of influence on the immune system by changing the secretion of pro-inflammatory and anti-inflammatory cytokines by immunocytes. Currently, close attention is paid to the assessment of the role of interleukins, neurotrophic factors and other cytokines in the implementation of the stress response, as well as the search for means of correcting these disorders.

The aim – to study the effect of glyproline compounds on the level of interleukins (IL-1β and IL-6) and neurotrophic (NGF and BDNF) factors in the blood serum of white rats on a model of social stress.

Material and methods. Experimental studies were carried out on 90 nonlinear white male rats of 6 months of age. The maintenance of laboratory animals met the requirements of international and domestic regulatory documentation on working with animals. In the process of modeling social stress, all rats were divided by type of behavior to aggressors and victims. Experimental groups (n = 10) were formed in the study: control animals; animals exposed to stress for 20 days; groups of rats treated intraperitoneally at a dose of 100 mcg/kg in day, starting from the 1st day of stress factor exposure, with a course of 20 days neuropeptide compounds Thr–Lys–Pro–Arg–Pro–Gly–Pro (Selank), Pro–Gly–Pro, Pro–Gly–Pro–Leu. The levels of interleukins and neurotrophic factors in the blood serum of white rats were evaluated by enzyme immunoassay.

Results. According to the results of the study, it was found that under conditions of social stress, there was an increase in the concentration of pro-inflammatory interleukins and a decrease in the concentration of BDNF and NGF. The introduction of neuropeptide compounds against the background of stress contributed to the restoration of the level of the studied indicators, which is most likely due to the presence of neuropeptides of neuroprotective action due to the induction of the synthesis of neurotrophic factors.

Conclusion. Thus, the introduction of glyproline compounds Thr–Lys–Pro–Arg–Pro–Gly–Pro, Pro–Gly–Pro and Pro–Gly–Pro–Leu under stress conditions contributes to the restoration of levels of interleukins and neurotrophic factors, as a result of which the stress- and neuroprotective effect of the studied compounds is observed.

Clinical immunology

Cytokine patterns of fatal hyperinflammatory conditions, caused by secondary hemophagocytic lymphohistiocytosis, bacterial sepsis and COVID-19

Abstract

Introduction. In severe cases of coronavirus disease 2019 (COVID-19) pulmonary infiltration is accompanied by cytokine storm syndrome (CSS) development. Besides COVID-19, CSS can be triggered by the range of pathologies, which include hemophagocytic lymphohistiocytosis (sHLH) and septic shock (SS).

The aim of this study was to compare immunological profiles in fatal cases of COVID-19, sHLH and SS.

Material and methods. Serum levels of IL-1β, IL-2, IL-6, IL-8, IL-10, IL-17A, IL-18, IFN-γ, TNF-α, procalcitonin, neopterin, ferritin with percent of glycosylated fraction (% GF) were measured in 37 COVID-19 fatal cases, collected during 2020 year prospectively; and in 39 sHLH and 47 SS fatal cases, collected within 2018–2019 years retrospectively. Comparison groups also included 194 non-fatal COVID-19 cases and 20 healthy donors, collected during 2020 year. Cytokine concentrations, procalcitonin and neopterin were measured by enzyme-linked immunosorbent assay; the ferritin level was determined by the turbidimetry method. The percent of glycosylated ferritin fraction (% GF) was calculated by the modified method of M. Worwood et al.

Results. Deceased patients with COVID-19 had higher IL-6, IL-8, IL-10, IL-18, procalcitonin median levels compared to the survived. Meanwhile IL-8, IL-18, IFN-γ, TNFα and ferritin concentrations were significantly lower in deceased COVID-19 patients compared to sHLH and SS. The levels of IL-6 and procalcitonin in fatal COVID-19 were comparable to SS, but significantly higher than in sHLH. Leucocytes were higher in COVID-19 compared to both SS and sHLH.

Conclusion. Each fatal condition was accompanied by specific features of the cytokine profile: high IL-6 combined with low IFN-γ, TNFα in COVID-19; high IL-8, IL-6 with low IL-17A, IL-2 in SS; high IL-18, ferritin, IFN-γ with low IL-6, procalcitonin, % GF in sHLH.

Dynamics of immune status parameters in patients with COVID-19, receiving therapy with inclusion of an IL-6 receptor antagonist

Abstract

Introduction. Timely prescribing of proactive cytokine storm therapy in patients with COVID-19 using targeted therapy is an important component of success in the treatment of this disease. However, the blockade of receptors to proinflammatory cytokines, in particular to IL-6, leads to shifts in immunoregulatory processes, the nature of which can determine the effectiveness of the therapy and the course of the postCOVID period of rehabilitation of the patient.

The aim of the study – to study the dynamics of the parameters of innate and adaptive immunity in a patient with COVID-19 using an IL-6 receptor anatagonist.

Material and methods. 30 hospitalized patients were examined with the diagnosis: COVID-19 coronavirus infection (confirmed), moderate form; complication: bilateral polysegmental pneumonia. The comparison group consisted of practically healthy donors (30 people). The dynamics of laboratory parameters (general clinical, biochemical and immunological) were evaluated against the background of therapy with IL-6 blockers.

Results. The presence of lymphopenia in the patient, an increase in the level of CRP, LTK, fibrinogen, lactate, IL-6 require the use of proactive anti-cytokine therapy. The timely administration of these drugs (in particular, the IL-6 receptor inhibitor) has a positive effect on the course of the disease and the recovery of patients. In the immune system, after the introduction of monoclonal antibodies to IL-6 receptors, 2 weeks after administration, there is an increase in the maturation of T-lymphocytes, documented by an increase in the content of T-lymphocytes with helper function with a simultaneous decrease in the number of natural killers, B-lymphocytes and disimmunoglobulinemia of IgA, IgM and IgG classes.

Conclusion. The use of monoclonal antibodies to IL-6 receptors in patients with a moderate form of COVID-19 leads to dysregulatory processes in the immune system with their gradual normalization by 2 weeks after administration.

Peripheral blood B-lymphocyte subpopulations coexpressing CD5 and chemokine receptors in patients with chronic obstructive pulmonary disease

Abstract

Introduction. Autoantibodies to the lung cells, cell components, and extracellular matrix proteins were found in the lung tissue of patients with chronic obstructive pulmonary disease (COPD). CD5+ B-lymphocytes may be a significant source of these autoantibodies. However, the quantitative changes and the ability to migrate to the site of inflammation of this subpopulation of lymphocytes in patients with COPD remain unclear.

The aim of the study was to determine the quantitative changes in the subpopulations of B-lymphocytes expressing CD5 and chemokine receptors in the peripheral blood of patients with COPD.

Material and methods. The current study involved 51 smoking patients with COPD, 21 healthy smokers and 20 healthy non-smokers. Coexpression of CD5 and chemokine receptors CXCR3, CXCR4, CXCR5, and CCR7 in the peripheral blood was assessed using flow cytometry.

Results. There was a significant increase in the percentage of blood СD5+ B-cells, as well as B-lymphocytes coexpressing CD5 and CXCR3 in smoking patients with COPD compared with healthy smokers and healthy non-smokers. The proportion of peripheral blood B-cells expressing chemokine receptor CXCR3 but lacking CD5 was also higher in COPD patients than in healthy smokers and healthy non-smokers. The percentage of CD5+CXCR3high B-cells was increased in COPD patients with GOLD stages 3–4 compared with patients having GOLD stage 2. CAT score that denotes quality of life of COPD patients was positively correlated with the proportion of blood CD5+CXCR3high and CD5-CXCR3high B-lymphocytes. There were no differences in the proportion of CD5+ and CD5 B-lymphocytes expressing chemokine receptors CXCR4, CXCR5 and CCR7 between patients with COPD and healthy subjects. In all the three subject groups, a higher percentage of CD5+ B-cells expressing CXCR3 and CXCR4 and a lower percentage of CD5+ B-cells expressing CXCR5 was observed compared with the proportion of CD5 B-lymphocytes positive for corresponding receptors.

Conclusion. The results of the study demonstrate changes in the profile of B-lymphocyte chemokine receptors in peripheral blood of COPD patients depending on CD5 coexpression.

Methods

Development of criteria for immobilization of human erythrocytes of phenotypes R1R1 and R2R2 on the solid phase in determining the content of anti-D-antibodies IgG in immunoglobulin human antirhesus Rho(D) preparations by enzyme immunoassay

Abstract

Introduction. The content of anti-D-antibodies (Ab) IgG in human immunoglobulin antirhesus Rho(D) preparations is evaluated by direct competitive enzyme immunoassay (ELISA) using the International standard (IS) of anti-D immunoglobulin, commercial reagent and antigens (Ag) for the preparation of an immunosorbent. Freshly prepared and preserved D-positive erythrocytes human blood group I(0) of the R1R1 and R2R2 phenotypes obtained from at least 3 donors are Ag, which are immobilized in the solid phase in laboratory conditions. The features of their distribution in the solid phase when preparing an immunosorbent have not been studied, and the stage of reproducing the method is not standardized.

The aim of this study was to develop criteria for immobilization of human erythrocytes of the R1R1 and R2R2 phenotypes on the solid phase in determining the content of anti-D-Ab IgG in human immunoglobulin antirhesus Rho(D) preparations by direct competitive ELISA.

Material and methods. We used erythrocytes of human blood I(0) group of donors of the R1R1 and R2R2 phenotypes, IS of anti-D immunoglobulin, Standard of normal human immunoglobulin not containing anti-D-Ab IgG, biotinylated monoclonal anti-D-Ab. The immunosorbent was prepared by immobilization of pre-washed and hydrolyzed papain erythrocytes into the wells of a polystyrene tablet, quantitative assessment of their distribution in the solid phase was carried out by microscopy and computer morphometry. To establish the values of the immobilization criteria, a quantitative assessment of the anti-D-Ab IgG content in solutions of test samples with a known anti-D-Ab IgG content was carried out by direct competitive ELISA.

Results. Revealed that erythrocytes of the R1R1 and R2R2 phenotypes are not evenly distributed on the surface of the solid phase, with a tendency to aggregation depending on the phenotype. Formulas are proposed and calculated: the area of uniform distribution – relative area (Srel.), the total area of aggregated erythrocytes of the studied phenotypes (∑S), and their distribution coefficients (Kdistr.) on the solid phase. Developed criteria of immobilization of Ag on the solid phase: for erythrocytes of phenotype R1R1 Srel. must be at least 88 %, Kdistr. – no more than 0.22; for the phenotype R2R2 Srel. – at least 70 %, Kdistr. – not more than 0.23. It is shown that the results of determining the content of anti-D-Ab IgG in human immunoglobulin preparations antirhesus Rho(D) by direct competitive ELISA meet the criteria of acceptability, provided that the established criteria for immobilization of erythrocytes are met.

Conclusion. The developed criteria for the immobilization of erythrocytes of the R1R1 and R2R2 phenotypes are recommended for standardizing the stage of preparing an immunosorbent for determining the content of anti-D-Ab IgG in human immunoglobulin antirhesus Rho(D) preparations by direct competitive ELISA.

Reviews

Immunopathogenesis of COVID-19-related pediatric multisystem inflammatory syndrome

Abstract

This review presents information about the role of the immune system in the development of multisystem inflammatory syndrome in children (MIS-C) associated with a new coronavirus infection (COVID-19). The main clinical criteria for establishing a diagnosis are presented, a description of the clinical picture and characteristics of biomarkers in MIS-C. Most researchers consider activation of the immune system with the development of a hyperergic inflammatory reaction to be the main cause of the development of a multisystem inflammatory syndrome. At the same time, the heterogeneity of MIS-C is the basis of various hypotheses of its development. The role of predisposing factors in the development of various variants of the immune response in MIS-C has yet to be established, research is ongoing.

Anosmia in COVID-19 and allergic rhinitis. Effect of masking on the severity of symptoms

Abstract

SARS-CoV-2 is the cause of COVID-19, which has a serious effect on the lower respiratory system. COVID-19 causes bilateral pneumonia and acute respiratory syndrome.

Smell disorders are important diagnostic symptoms of COVID-19. This symptom is detected in about 90 % of cases. Anosmia may be the first or even the only symptom and may appear before other symptoms of SARS-CoV-2 infection. In the context of the COVID-19 epidemic, anosmia can be considered a clinical diagnostic criterion when laboratory tests are not available. The sense of smell is one of the most important senses needed to gain information about the environment. Anosmia can occur in both COVID-19 and allergic rhinitis (AR), which can make it difficult to detect the origin of these symptoms and make a diagnosis in the context of the COVID-19 pandemic.

Research results indicate AR is not an aggravating factor for COVID-19. Comorbidity of AR does not affect the reduction of the sense of smell in patients with COVID-19. Patients with AR are recommended to use antihistamines and intranasal corticosteroids for relief of symptoms. Control of AR symptoms can help prevent the spread of SARS-CoV-2 infection. It can be assumed that both local and oral corticosteroids at COVID-19 can be regarded as effective in the treatment of olfactory dysfunction. To restore the sense of smell in patients with AR and COVID-19, experts recommend regular olfactory training, which, at the moment, is the only modern scientifically based therapy for restoring post-viral loss of smell.

The use of face masks and respirators during a pandemic aims to minimize exposure to allergens and the SARS-CoV-2 virus. However, prolonged wearing of masks and respirators makes breathing even more difficult with rhinitis caused by AR or COVID-19, which reduces the quality of life and worsens the clinical picture.

Chronicle

The health of immune system: way that not passed yet

Abstract
EDITOR-IN-CHIEF
EDITOR-IN-CHIEF
Musa R. Khaitov

Corresponding member of Russian Academy of Sciences, MD, Professor, Director of the NRC Institute of Immunology FMBA of Russia

Оргздрав-2022. Эффективное управление в здравоохранении
РОСМЕДОБР 2021
Вскрытие
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