Recent studies suggest that immune response to pathogens may vary depending on changes in hormone levels. Toll-like receptors (TLRs) are the key components of the innate immune system and play a crucial role in HIV infection. Given the significant genetic diversity of HIV-1, this study examined the effect of female sex hormones on the several TLR2, TLR4, and TLR9 expression in human peripheral blood mononuclear cells (PBLs) isolated from different female donors and infected with different variants of HIV-1 subtypes A6 and B. Thus, high doses of hormones upregulated the TLR2 and TLR9 expression in PBLs infected only with v1.A6, which also correlated with an increased viral load: by 3.8 times (p = 0.0033) when cells were treated with estradiol and by 4.4 times (p = 0.006) when treated with progesterone. Hormones did not modulate TLRs expression in the cells infected with subtype B, with the exception of one donor. In PBLs from this donor infected with the v1.B variant, hormones upregulated TLRs expression, which also correlated with the increased viral load (1.3-fold increase (p = 0.0036)). Hence, it was shown that gonadal steroids can play an important role in HIV-1 replication and immune response to a pathogen. Moreover, it was shown that different isolates of the same subtype may have distinct biological properties. The detected diversity in the TLRs expression in infected PBLs from different donors indicates that host genetics may also play an important role in HIV susceptibility.

Most respiratory viral infections proceed in mild form including COVID-19. Gowever, some patients experience severe systemic inflammation, tissue damage, acute respiratory distress syndrome, and cytokine storm with potentially lethal outcomes. The cytokines have been thought to play an important role in immunopathology of viral infection. However, an excessive immune response, manifesting as massive release of pro-inflammatory cytokines, may cause immune damage in the body. Production and release of the cytokines in healthy individuals presumes a significant balance of inflammatory and homeostatic factors. Meanwhile, in the case of COVID-19 disease, uncontrolled increased production of cytokines often occurs with fatal consequences for patients. The aim of this work was to study the level of IL-1β, IL-18 and TNFα gene expression, as well as production of these cytokines at the level of mucous membranes of the upper respiratory tract, in particular in oral cavity, in patients with severe COVID-19 disease. The present study included patients who recovered from severe COVID-19. The control group consisted of conditionally healthy individuals. Expression levels of the IL-1β, IL-18, and TNFα genes were determined by RT-PCR. The levels of IL-1β, IL-18 and TNFα protein production were determined by multiplex enzyme immunoassay. The expression levels of IL-1β, IL-18 were reduced at the onset of the disease, as well as in the midpoint of the COVID-19 disease, but increased on the 30^th day. The protein production of these cytokines was also reduced in the first days from the onset of the disease. The levels of pro-inflammatory TNFα cytokine was high at the onset of the disease. The level of TNFα production at the onset of the disease was also higher relative to the control group. Subsequently, the TNFα gene expression levels decreased upon progression of the disease. Thus, the increased expression level of pro-inflammatory cytokines may be explained by the fact that the S protein of the SARS-CoV-2 virus induces increased expression of these cytokines in human monocytes. Meanwhile, appropriate protein levels remain low, especially on day 1 from the onset of the disease. Thus, one may conclude that the virus triggers pyropotosis, however, within 15-30 days from the onset of the disease, when viral replication is already minimal.

Toll-like receptors (TLRs) are the most studied among all Pattern Recognition Receptors, the main function of which is to initiate innate immune response by recognizing pathogen-associated molecular patterns of various microorganisms on the skin surface. TLR-mediated recognition plays an important role in linking innate and adaptive immunity that ultimately leads to the production of key cytokines, chemokines and antimicrobial peptides. Today, there is growing interest in research on single nucleotide polymorphisms (SNPs) in TLR genes and its influence on susceptibility to inflammatory disease, including atopic dermatitis. The aim of the research was to study the association of the rs5743708 gene polymorphism in the TLR2 gene, the rs4986791 gene polymorphism in the TLR4 gene and the rs352140 gene polymorphism in the TLR9 gene with the risk of developing severe cases of AD. A total of 100 patients with AD were included in the study (38 male and 62 female). The age range was from 18 to 65 years old. All participants were divided into 2 groups according to the SCORAD index (SCORing Atopic Dermatitis). The control group included 72 volunteers over 18 years old. The results of our study showed a statistically significant difference between the moderate AD group and healthy controls in the rs352140 gene polymorphism in the TLR9 gene (Figure 1). The frequency of the GG genotype of SNP rs352140 in TLR9 was 0.169 in the AD group versus 0.329 in the control group (p < 0.05; OR = 0.42; 95% CI = 0.18-0.97).In conclusion, the results of our study showed that the TLR9 rs352140 gene polymorphism may be linked to an increased risk of atopic dermatitis. Moreover, it was found that the GG genotype of SNP rs352140 in TLR9 can be used as a predictor of the risk of developing moderate AD.

Sepsis is a heterogeneous and life-threatening condition caused by a dysregulated immune response to infection. The most severe form of sepsis is septic shock, characterized by arterial hypotension, impaired tissue perfusion, and hypoxia. Despite new findings in antimicrobial and intensive care therapy, the incidence and mortality rates of sepsis remain high, which underscores the relevance of further studies on its pathogenesis. In recent years, the research has shifted from clinical signs to analysis of immunological and molecular mechanisms, which allowed to identify specific phenotypes and endotypes of the disease. Sepsis phenotypes are based on clinical manifestations and biomarkers, whereas its endotypes are defined by molecular mechanisms, including immune gene expression patterns. This article reviews key aspects of the innate and adaptive immune responses in sepsis, including activation of proinflammatory cytokines, development of coagulopathies, deterioration of endothelial integrity and microvascular regulation. Moreover, the potential mechanisms, e.g., hyperinflammation, simultaneous development of immunosuppression, and functional exhaustion of immunocompetent cells are highlighted. Thus, immunological biomarkers are considered a promising tool for patient‘s stratification, prognosis prediction and personalized therapy. Current immunodiagnostic methods are also discussed in this article, including quantitative analysis of cytokine levels and assessment of innate immune dysfunction markers. Hence, current understanding of sepsis as an immunologically heterogeneous syndrome enables researchers to expand existing concepts of its pathogenesis. In contrast to classical concept based on a shift from inflammation to immune suppression, the novel results suggest a simultaneous presence of both processes in the same patient, making it necessary to reconsider the existing diagnostic and therapeutic approaches.

Background: In addition to climatic and social factors, individual susceptibility to infectious diseases among residents of the North is influenced by nucleotide sequence variants in interferon system genes. The protein products of these genes are involved in the immune response. Aim: The study aimed to assess the prevalence of single nucleotide variants in interferon system genes (IFNAR1, IFNAR2, IFNGR1, IFNL4 (IL-28B)) in indigenous and non-indigenous residents of Arkhangelsk region. METHODS: A cross-sectional study was conducted on a random sample of adults aged 43–74 years residing in Arkhangelsk (N=232; 36.6% male). The study protocol included participant interviews and molecular genetic analysis to determine alleles and genotypes of the following single nucleotide variants: rs2257167 in IFNAR1, rs2229207 in IFNAR2, rs1327474 in IFNGR1, rs12979860 and rs8099917 in IFNL4 (IL-28B). The observed genotype distributions in indigenous and non-indigenous groups were evaluated for compliance with Hardy–Weinberg equilibrium and compared between the groups. Results: The study population included 86 indigenous and 146 non-indigenous residents of Arkhangelsk region. Among non-indigenous residents, the genotype distributions of the variants rs2229207 (IFNAR2) and rs12979860 (IFNL4 (IL-28B)) deviated from Hardy–Weinberg equilibrium due to an excess of heterozygotes. At the same time, for the rs1327474 (IFNGR1), the number of heterozygotes was lower than expected. The frequency of the C allele of rs2229207 (IFNAR2), associated with severe viral infections, was higher in the Arkhangelsk region population than in European and global populations. The homozygous CC genotype of rs2229207 (IFNAR2) was significantly less common in indigenous residents of the Arkhangelsk region (2.6%) than in non-indigenous residents (11.2%). A higher frequency of the heterozygous CT genotype of rs1327474 (IFNGR1) was observed in the non-indigenous residents. Conclusion: This study identified specific features of the genetic structure of the adult population of the Arkhangelsk region, shaped by migration from other regions to the North. These findings reflect a higher prevalence of genetic susceptibility markers for viral infections among the non-indigenous population of the European North.

Background. Primary adrenal insufficiency (PAI) is an endocrine disorder caused by the gradual destruction of all three layers of the adrenal cortex and characterized by insufficient secretion of cortisol and aldosterone. This condition significantly reduces patients’ quality of life, making its timely diagnosis crucial. Autoimmune disorders are the etiological factor in approximately 80% of PAI cases, making the search for predictive markers in innate immune genes one of the most promising areas for predicting the odds of developing PAI. Aims — to study the associations between single nucleotide polymorphisms in the TLR2 and TLR9 genes and the development of PAI. Methods. The study included 222 individuals: 72 patients with PAI and 150 controls. For the study, DNA was isolated from venous blood and subsequently analyzed using real-time PCR with fluorescently labeled probes. Statistical analysis of the results was performed using Fisher’s exact test (Fi), the χ2 test, the χ2 test with Yates’ correction, calculation of the odds ratio and 95% confidence interval. Results. The study revealed that the A allele (p 0.001) and the heterozygous genotype (p 0.001) of the rs5743708 polymorphism in the TLR2 gene were associated with the risk of developing PAI. Conversely, the homozygous genotype GG (p 0.001) reduced the odds of the pathology development by 11-fold. Analysis of the rs352140 single nucleotide polymorphism in the TLR9 gene also demonstrated an association between the A allele (p = 0.030) and the homozygous AA genotype (p = 0.0171) with the odds of developing PAI. Conclusions. Based on the data obtained in this and our previous study, a scheme was proposed that includes four polymorphic markers to predict the odds of developing 1-HH.