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Immune checkpoints (ICs) represent a broad set of stimulatory and inhibitory signaling pathways playing an important role in regulation of immune responses. Initially, ICs have been considered solely as cell membrane-bound receptor and ligand systems, triggering or blocking immune cell function. Over the past decade they have been proven to exist in soluble forms (sICs). sICs are biologically active regulators involved in paracrine and systemic modulation of immune responses, similar to cytokines. Normally, sICs exert both stimulatory and inhibitory effects on the immune system, and their balance may be disturbed in many malignant neoplasms, COVID-19, HIV infection. There is a lot of data on the connection between sICs and various diseases, but a number of key aspects of their biology have not been fully clarified. The most widely studied are PD-1 (programmed death receptor-1) and its ligands PD-L1 and PD-L2, CTLA-4 (cytotoxic T lymphocyte antigen-4), TIM-3 (T cell immunoglobulin and mucin-domain containing-3), VISTA (V-domain Ig-containing suppressor of T cell activation). The mechanisms of soluble form formation are complex and diverse and include alternative splicing, cleavage of membrane ectodomains, and proteolytic cleavage. The most important molecular mechanisms underlying the synthesis and release of sPD-1 and sPD-L1 are alternative splicing of mRNA and translation of isoforms lacking transmembrane domains, while the formation of sTIM-3 occurs by cleaving the extracellular regions of transmembrane proteins by protease ADAM10. The review article provides data on the main sICs, including sPD-1, sPD-L1, exosomal sPD-L1, sCTLA-4, and several others. The molecular mechanisms of their formation, biological functions in maintaining immune homeostasis, prognostic significance of changes in their content are described in patients with solid malignant tumors (nonsmall cell lung cancer, hepatocellular cancer, breast cancer, kidney cancer, skin cancer, gastric cancer, etc.), as well as for hematologic malignancies (lymphoma, chronic lymphocytic leukemia, acute myeloblastic leukemia, multiple myeloma).

Bruton's tyrosine kinase (BTK) inhibitors represent a class of drugs that have demonstrated their efficacy and safety in patients with chronic lymphocytic leukemia and non-Hodgkin's lymphomas who were considered refractory to any previously used type of therapy. BTK plays a key role in all stages of B lymphocyte development, but in recent years, there have been data indicating that BTK is also involved in the activation of myeloid cells.The aim of this study is to analyze and systematize all published materials on the immunomodulatory effects of BTK inhibitors (ibrutinib, acalabrutinib, etc.).A systematic review of the scientific literature was performed using a step-by-step search process in electronic databases (PubMed, Web of Science, ScienceDirect, and Scopus). The following keywords were used in the database search: “CLL”, “BTK”, “ibrutinib”, “COVID-19”, “allergy”, “inflammation.” The search for studies was conducted from the time of the first BTK inhibitor drug (ibrutinib) appearance in 2009 until December 2022.The results of the study on the influence of BTK inhibitors on the functional state of B and T lymphocytes, neutrophils, and monocytes/macrophages are presented. The immunomodulatory effects of ibrutinib on adaptive and innate immune system cells, including CD4+ and CD8+T lymphocytes and NK cells, are described. Since BTK inhibitors alter the functional activity of phagocytic cells and the ratio of T cell populations, there is a suggestion about the possibility of using these drugs for the treatment of other nosological forms, not only B cell malignancies, which is currently being studied in clinical trials. Data on the use of BTK inhibitors to combat hyperacute inflammation and to suppress allergic reactions, including anaphylaxis, are summarized. In addition, the expediency of short-term use of BTK inhibitors to reduce the risk of side effects during oral immunotherapy and for desensitization to drugs is discussed.The presented data indicate that BTK inhibitors are promising drugs with immunomodulatory effects. However, BTK inhibitors need to increase selectivity to reduce off-target effects on other kinases.

During the pandemic, a large number of works devoted to COVID infection have appeared, which have made it possible to understand the pathogenetic features of the disease and to accumulate significant clinical experience. However, the question remains about the degree of participation of humoral and cellular (primarily T-cell) immunity in the mechanisms of immune defense and resistance to COVID-19, the individual features of the immune response in different subjects. Post-COVID syndrome is currently a separate diagnosis included in the ICD-10 International Classification of Diseases, but the long-term effects of the SARS-CoV-2 on the immune system are not yet well established. At the same time, a long-term increased activity of the immune system can contribute to the development of autoimmune reactions. The review of the literature presents the results of studies, mainly devoted to immune system disorders after COVID infection. The changes in subpopulations of T-lymphocytes, B-lymphocytes, their functional properties, the complement system and other factors of humoral immunity, as well as the production of a number of cytokines are described. Data on immune disorders in post-COVID syndrome and during the convalescence period are presented in detail. Since COVID-19 is an infection that has a significant impact on the hematopoietic system and hemostasis, special attention is paid to the category of subjects with an increased risk of severe complications. Among the latter are elderly patients, persons suffering from diabetes mellitus, oncological and oncohematological patients, in particular, with hematopoietic and lymphoid tissue neoplasia, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma. The review pays special attention to the peculiarities of the course of COVID-19 and the response of the immune system to vaccination in patients with oncohematological diseases. Deciphering the significance of individual links of cellular and humoral immunity in patients who have undergone COVID-19 is an important issue in creating effective vaccines and improving therapeutic methods.

Transfusions of blood provide essential therapeutic measures in a number of pathological conditions. However, when carrying out blood component therapy, it is important to consider probability of post-transfusion complications. Most of them are immune-mediated side effects. The unfavorable consequences of blood transfusions can manifest at long-range time periods, and pathogenesis of these phenomena may be associated not only with the presence of alloantibodies. They may be caused by alloimmunization to HLA antigens, leukocyte factors, including cytokines, products of leukocyte degranulation, as well as storage-related erythrocyte damage («storage lesion»), immunomodulatory properties of extracellular vesicles or microparticles derived from blood components, and other factors. Despite significant number of publications on this issue, a lot of unresolved issues still remain, concerning transfusion-related effects of blood components on the immune system of recipients. The review article provides the results of current studies in this area. We present and discuss the results of current studies and the features of transfusion-mediated immunomodulation (TRIM) revealed over recent years, when transfusing different blood components. The role of plasma factors, microparticles, platelets and erythrocytes, HLA sensitization and microchimerism in the development of TRIM is highlighted, the data on occurrence and clinical features of TRIM in perioperative period are presented. A separate section of the review provides information about recent clinical studies, devoted to the issues of TRIM in different clinical cohorts, including newborns, patients with malignant neoplasms, immunocompromised patients after heart and vascular surgery. The data on TRIM incidence in the patients with exhausted immune system due to previous disease or treatment, severe comorbidity, extensive surgical thoracic/abdominal intervention and artificial circulation are also in scope. As based on the studies performed, the role of distinct measures, e.g., washing of erythrocyte concentrates, leukodepletion, and gamma irradiation are discussed in view of potential TRIM prevention. The results of published research do not allow us to draw definite conclusions about the effects of blood component transfusion on the immune system of recipients with respect to differences between the studied groups of patients, characteristics of the studied disorders and clinical situations, diversity of hemocomponents, as well as varying standards of transfusion therapy adopted in different countries. However, the systematic literature review may provide some guidance in transfusion-mediated immune modulation.

The main histocompatibility complex — HLA system (Human Leukocyte Antigens) is among the most important genetic factors determining response of humans to infectious agents. The key role that HLA molecules play in immune response is to present the pathogen-derived peptides. Enormous molecular variability of HLA alleles in human populations have attracted close attention and became the basis for numerous studies aimed at evaluating the role of HLA genotypes for individual features of immune response to COVID-19, the new infection caused by SARS-CoV-2 β-coronavirus. Many studies have focused on search of specific alleles associated with both susceptibility and resistance to this disease. Separate HLA patterns were reported already. These patterns may be either universal to several populations, or rather peculiar, since distribution of HLA genes is different for various populations, depending on the living conditions, including specific protection from environmental pathogens. Therefore, it is evident that individual effects of HLA genotype upon occurrence and course of SARS-CoV-2 infection should be performed in comparison with the HLA distribution among the residents of appropriate region. The objective of this study was to compare the distribution of HLA-A*, B*, DRB1* allele groups, and to analyze the frequencies of HLA-AB-DRB1 haplotypes in subjects with COVID-19 (n = 138), compared with the control group presented by residents of the North-Western Russia (n = 1456). The most significant differences between COVID-19 patients compared with a group from control population were revealed for the groups of HLA-A* alleles: the frequencies of HLA-A*02 and HLA-A*26 were significantly reduced (39.86% versus 51.72%, χ2 = 7,58, and 4.35% versus 9.07%, χ2 = 4.17, respectively). At the same time, the frequency of HLA-A*29 was increased more than 2-fold (5.80% versus 2.47%, χ2 = 4.03). This finding suggests that the allele groups A*02 and A*26 are associated with reduced likelihood of the disease, while A*29, is an apparent factor predisposing for susceptibility to the disease. It was found that occurrence of definite HLA haplotypes, including the A*02 allele group, is less common in persons who have undergone COVID-19, and are ranged at the 4th, 7th and 10th positions in frequency, while in the population control group such HLA haplotypes took the 3rd, 4th, 7th and 8th places. Further evaluation of the HLA gene polymorphism will allow to understand the predetermined immunogenetic basis for susceptibility, as well as clinical severity of COVID-19.