Vol 24, No 1 (2021)

We present to Russian-speaking audience a translation and commentary on the classification of inborn errors of immunity presented at the end of 2019 by the Committee on Congenital Immunity Errors at the International Union of Immunological Societies (IUIS). Inborn errors of immunity, or, as they were called earlier, primary immunodeficiencies, is a rapidly expanding class of diseases that includes the most diverse congenital pathologies which can manifest at any age by heterogenous symptomes. Clinical masks characterize these diseases, hence the time from the onset of clinical disorder to the final diagnosis may take many years. A doctor of any specialty encounters these patients, and the molecular mechanisms of pathology concern different organs and systems of the patients. The classification consists of ten tables covering more than 400 syndromes and their corresponding genes, or associated chromosomal abnormalities. This is a tool, which allows navigating a wide variety of different primary immunodeficiencies, autoimmune and autoinflammatory syndromes, complement defects, and bone marrow failure syndromes. We hope that, due to translation, current knowledge about these various diseases will become more close and available to the Russian-speaking audience.

Macrophage differentiation is known to be regulated by specific microenvironment invaded by these cells. However, despite numerous studies on pathogenesis of uterine leiomyoma, a common benign tumor of reproductive system, the features of macrophage polarization within myoma nodes are still scarcely studied. The aim of our work was to reveal some differentiation features of macrophages which invade the tissues of myomatous nodes in the patients with different types of uterine leiomyoma (UL) dependent on MRI patterns observed. We have performed a study of 42 patients in their reproductive age with intramural UL. All the patients were subjected to MRI of pelvic area. Twelve samples of endometrium have been taken from healthy women without any signs of UL, being used as controls. UL biopsies and endometrium in its projection served as study material. Phenotype of endometrial and UL-invading macrophages was evaluated by means of multi-color flow cytometry. Expression of Activin А and RARα mRNAs was estimated in endometrial and myoma node macrophages. Likewise, collagen type 1 mRNA expression was evaluated by means of reverse-transcription real time PCR. The collagen type 1 concentration in myomatous nodes was assessed by ELISA technique. We have revealed that peripheral blood monocytes, macrophages in endometrium, and UL nodes each consist of three different subpopulations, dependent on expression levels of expression levels of CD14 and CD16 membrane receptors. For endometrium projected onto myomatous node, the ratios of “intermediate” macrophages (CD14++CD16+), and alternatively activated macrophages (CD36+) was increased, thus exerting potentially negative effects upon reproductive functions in women with uterine leiomyoma. Immediately in myomatous tissue, we have found a shift of macrophage differentiation from ‘classic’ forms towards “intermediate” and “non-classical” macrophages associated with alternative activation. However, the percentage of scavenger receptor-expressing macrophages (CD36+, CD206+) was decreased in the myoma nodes. Enhanced expression of RARα mRNA was observed in macrophages invading the myomatous nodes, whereas Activin А synthesis was higher in the macrophages invading leiomyomas with MRI pattern of simple and degenerative nodes. Imbalance between “intermediate” and “non-classical” UL-invading macrophages was associated with fibrosis, or degenerative changes of myomatous tissues, thus, probably, representing an important pathogenetic link in development of different clinical variants of uterine leiomyoma.

The environmental issues in contemporary megapolis require studying of multiple candidate genes that may contribute to occurrence of reproductive disorders. Exogenous phenol compounds are contaminants that produce negative effects upon female reproductive system. Detoxification genes from CYP450 and GSTs family belong to the I and II detoxification phases of xenobiotics including phenols. Our goal was to examine some features of polymorphism in I and II phase detoxication genes in women with diagnosed miscarriage who were subjected to excessive phenol exposure. The test group consisted of 37 women who had miscarriage; the reference group included 41 conditionally healthy women. All the examined women lived under airborn exposure to phenol (an average of > 1.0 daily minimal acceptable concentration). The following parameters were examined in both groups: phenol contents in blood were detected with capillary gas chromatography; polymorphisms of CYP1A1 rs1048943 Ile462Val, CYP1A1_3 rs4646421 C6310T, GSTA4 rs3756980 T/C, GSTP1 rs1695 Ile105Val, GSTP1 rs1138272, and Ala114Val genes were revealed with polymerase chain reaction. There were significant discrepancies between the examined groups, both for phenol contents in blood, compared to upper standardized limits (p < 0.05). The examined gene polymorphisms fit the Hardy–Weinberg rule. Statistical analysis in multiplicative inheritance model allowed us to show that A allele in CYP1A1 rs1048943 Ile462Val gene, and A allele in GSTP1 rs1695 Ile105Val gene could be the factors associated with probable miscarriage risk in case of excessive contamination of biological media with exogenous estrogens (e.g., phenol). The examined gene polymorphisms may be suggested as marker genes for early prediction of miscarriage risk, when excessive contents of exogenous estrogen imitator (phenol) are present in biological media.

Detection of postmenopausal women at high risk for breast pre-cancer and cancer is a key condition to prevent these diseases. Aim of our research was to study possible usage of immunoassay for antibodies specific to benzo[a]pyrene, estradiol, and progesterone (IgA-Bp, IgA-Es, IgA-Pg) in determination of personal risks for fibrocystic disease and breast cancer at the early stage, with respect to hormone receptor status in tumor tissues. Blood serum IgA-Bp, IgA-Es, IgA-Pg were studied by ELISA in postmenopausal women: healthy controls (n = 401), patients with fibrocystic breast disease (n = 50), and breast cancer (stage I, n = 575, stages II-IV, n = 861). High individual IgA-Bp/IgA-Pg ratios of > 1.5 were found in 19.7% of healthy women, and in 50.0% of fibrocystic breast disease patients (p < 0.0001; OR = 4.1). IgA-Es/IgA-Pg ratios of > 1.0 were revealed in 48.4% healthy women and in 68.0% fibrocystic breast disease patients (p < 0.01; OR = 2.3). IgA-Bp/IgAPg values > 1.0 were found in 41.9% of healthy women, and, at higher rates, in the patients with breast cancer stage I: 68.3% ER- tumors (p < 0.0001; OR = 3.0) and 75.9% ER+ tumors (p < 0.0001; OR = 4.4). IgA-Es/ IgA-Pg ratios > 1.0 were revealed in 48.4% of healthy women, and in patients with breast cancer stage I: 65.3% ER- tumors (p < 0.003; OR = 2.0), and 76.8% ER+ tumors (p < 0.0001; OR = 3.5). Some associations of studied antibodies with cancer progression were revealed. Frequency of individual cases with IgA-Bp/IgA-Pg > 1.0 in patients with ER- tumors increased from 12.0% at stage I to 19.9% at stage II. Frequency of cases with IgA-Bp/IgA-Pg > 1.0 in the patients with ER+ tumors decreased from 62.0% at stage I to 57.3% at stage II (p = 0.002). Frequency of cases with IgA-Es/IgA-Pg > 1.0 in the patients with ER- tumors increased from 11.5% at stage I to 21.4% at stage II. Frequency of cases with IgA-Es/IgA-Pg > 1.0 in patients with ER+ tumors decreased from 63.3% at stage I to 56.1% at stage II (p < 0.001). The cases with individual excessive IgA-Bp and IgA-Es levels are associated with fibrocystic breast disease and ER+ breast cancer at the onset of the disease. Breast cancer progression was associated with the relative decrease of ER in tumor tissues, along with higher individual levels of IgA-Bp and IgА-Es and lower IgA-Pg levels. ELISA testing of IgА-Bp, IgА-Es, IgA-Pg could be recommended for detection of individual risk for fibrocystic breast disease and stage I of breast cancer, as well as for more efficient prevention and therapy by selective modulators of estrogen receptor (raloxifene, arzoxifene and lasofoxifine) and aromatase inhibitors (exemestane, anastrozole).

Etiologic role of human papilloma virus in cervical carcinoma is well known so this might be the base of application of interferonogenicimmunomodulators in their complex treatment. Evaluation of the role and place of immunotherapy and immunocorrection in combination treatment is one of the urgent problems in both clinical immunology and oncology. In this study we used one of them – allokin-alpha (alloferon) – together with plasmapheresis which contributes to detoxication and enhancement of the tumor cells` sensitivity to cytostatics in complex treatment of locally advanced cervical cancer patients receiving neoadjuvantpolychemotherapy (NCT). Clinical effect of such treatment was described in our previous studies. The purpose of the present research is to study the effect of the application of immunomodulatorallokin-alpha (A) and plasmapheresis (PP) in complex treatment of cervical cancer patients on their cell-mediated immunity and cytokines` composition in serum. Cervical cancer patients with locally-advanced tumors were divided into two groups. The control one received NCT, the basic one consisted of two subgroups – the 1st one in the course of NCT additionally received procedures of gravitational PP, the 2nd one received NCT, PP and 6 injections of allokin-alpha. Immunological parameters was tested in dynamics by flow cytometry and ELISA. Dynamics of cell-mediated immunity parameters revealed the decrease of CD19⁺ cells in patients of all the groups, of Treg in both subgroups of the basic group; of lymphocytes, CD3⁺ and CD8⁺ cells in patients after NCT + PP; activated CD3⁺HLA-DR⁺ cells in patients after NCT + PP + A though the amount of CD8+HLA-DR+ was elevated. When PP was applied CD3⁺ cells` levels was found to be lower than after additional administration of A. Analysis of the cytokines` levels showed the increase of IL-8 after NCT + PP, but administration of A caused its` decrease. IL-10 level was minimal in patients having received NCT + PP + A. Application of NCT + PP and NCT + PP + A prevented the elevation of inflammatory cytokines` levels (IL-1β and TNFα) which was observed in patients of the control group after the course of neoadjuvant treatment. Such a dynamics of cytokines levels suggests that application of allokin-alpha together with plasmapheresis and neoadjuvant chemotherapy might be useful in complex treatment of cervical cancer patients with locally advanced tumors.

The paper presents the results on spontaneous and induced production of IFNγ, IL-4, IL-13 cytokines in blood cells of patients with mandibular fractures and post-traumatic osteomyelitis. Osteomyelitis of the jaw represents one of the urgent challenges in modern medicine. There are many reasons for development of purulent necrotic processes of the jaw bones, including disorders of innate and adaptive immune response. Currently, the immunological aspects of post-traumatic complications of maxillofacial region remain poorly understood. There are no unambiguous and systematic studies of immune mechanisms in pathogenesis of post-traumatic osteomyelitis of the lower jaw. The aim of our study was to theoretically confirm application of recombinant interleukins (IL-1β, IL-2, IFNγ) in the patients with jaw fractures, in order to prevent osteomyelitis, as based on the studies of spontaneous and induced cytokine production (IFNγ, IL-4, IL-13). Spontaneous and stimulated production of IFNγ, IL-4, and IL-13 cytokines by blood cells was determined using specific reagent kits from R&D Diagnostic Inc. (USA). The results were recorded using an ELISA Multiscan analyzer (Finland). Statistical significance of intergroup differences was determined by the Mann–Whitney method. The level of statistical significance at which the null hypotheses were rejected was < 0.05. To stratify the cases of post-traumatic osteomyelitis and uncomplicated mandibular fracture, the models were developed with a singlelayer neural network, using the nnet R-studio package. To assess quality of the models, the areas under the ROC curves (AUC), Akaike criterion (AIC), and the relative classification accuracy (OTC) were used, which was determined as the ratio of correctly established model diagnosis numbers to the total number of patients. The study results demonstrate that the patients with mandibular fractures exhibit a moderate impairment of LPS-induced IL-4 and IFNγ production by leukocytes with IL-13 activation. In presence of osteomyelitis, this imbalance is promoted, thus suggesting an impaired ability of the cells to produce IL-4 and IFNγ. An opportunity for usage immunomodulation when treating the patients with mandibular fractures is represented by P = 1/(1+e-z) where z is defined via IL-1β, IL-2 and IFNγ levels on the first day of observation. In vitro supplementation with recombinant IL-1β and IFNγ modulates cell function, improving the cytokine profile. The prognostic models, imitating binary logistic regression, were used to demonstrate that recombinant IL-1β could be used to prevent patients with mandibular fractures from developing post-traumatic osteomyelitis (AIC = 13.2, AUC = 0.96, р = 0.026).