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Juvenile-onset recurrent respiratory papillomatosis (JORRP) is caused by persistent infection of epithelial cells by low-risk human papillomavirus (HPV) types 6 and 11. While multiple infiltrated immune cells have been reported to mediate disease progress, knowledge of HPV-reactive T-cell subsets in papillomas remains elusive. Through single-cell RNA sequencing and RNA microarray, we found that CD8+ tissue-resident memory T (CD8+ TRM) cells with strong interferon-gamma (IFN-γ) production expanded, and were negatively correlated to the disease severity in the frequency of surgery. These IFN-γ+ CD8+ memory T cells were readily activated and expanded in vitro by autologous dendritic cells loaded with HPV11 E7 peptide pool. Moreover, T cell receptor (TCR) clonal expansion was observed in JORRP papilloma tissues, indicating a biased TCR repertoire toward HPV-specific recognition. Finally, we identified and characterized HPV11 E7-specific candidate TCR clonotypes from IFN-γ+ CD8+ memory T cells, suggesting their potential application in TCR-engineered T cells (TCR-T) therapy for HPV11-related diseases. Our findings provided insights into the specific local immune response to HPV6/11 infection and highlighted the importance of IFN-γ+ CD8+ TRM cells in anti-HPV6/11 T-cell immunity.IMPORTANCEThe persistent recurrence of human papillomavirus (HPV) 6/11 infection in papillomas underscores the failure of local immune responses in patients with juvenile-onset recurrent respiratory papillomatosis (JORRP). Our previous study demonstrated that T cells constitute the predominant immune cell population in JORRP papilloma tissues. Understanding the T-cell-mediated immune responses within JORRP papilloma tissues is crucial for disease control. In the present study, we characterized CD8+ tissue-resident memory T (CD8+ TRM) cells as the primary T-cell subset responsible for local anti-HPV6/11 immunity. Moreover, we identified two HPV11 E7-specific candidate T cell receptor (TCR) clonotypes out of IFN-γ+ CD8+ memory T cells. Overall, our findings provided insights into the local immune responses to HPV6/11 infection and offered information for developing more effective immunotherapeutic strategies against JORRP.

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Breast cancer (BC) is one of the most common malignancies in women worldwide. Numerous studies in immuno-oncology and successful trials of immunotherapy have demonstrated the causal role of the immune system in cancer pathogenesis. The interaction between the tumor and the immune system is known to have a dual nature. Despite cytotoxic lymphocyte activity against transformed cells, a tumor can escape immune surveillance and leverage chronic inflammation to maintain its own development. Research on antitumor immunity primarily focuses on the role of the tumor microenvironment, whereas the systemic immune response beyond the tumor site is described less thoroughly. Here, a comprehensive review of the formation of the immune profile in breast cancer patients is offered. The interplay between systemic and local immune reactions as self-sustaining mechanism of tumor progression is described and the functional activity of the main cell populations related to innate and adaptive immunity is discussed. Additionally, the interaction between different functional levels of the immune system and their contribution to the development of the pro- or anti-tumor immune response in BC is highlighted. The presented data can potentially inform the development of new immunotherapy strategies in the treatment of patients with BC.

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Despite the great interest in the development of a vaccine against African swine fever (ASF) in wild boar, the immunological mechanisms that induce animal protection are still unknown. For this purpose, tertiary lymphoid organs (TLOs) of wild boar were characterised and compared with mucosa-associated lymphoid tissues (MALTs) by histopathology, histomorphometry and immunohistochemistry (CD3, CD79, PAX5, LYVE1, fibronectin). In addition, real-time polymerase chain reaction (qPCR) and immunohistochemistry (p72) were used to evaluate the presence of ASF virus (ASFV) in blood and tissues samples, respectively. TLOs were observed in animals infected with a low-virulent ASFV isolate (LVI), animals co-infected with low and high-virulent ASFV isolates (LVI-HVI) and animals infected only with the high virulence isolate (HVI). TLOs in LVI and LVI-HVI groups were located adjacent to the mucosa and presented a similar structure to MALT. Immunoexpresion of p72 observed in the inflammatory cells adjacent to TLOs/MALTs confirmed its development and reactivity generated by ASF attenuated isolates. Immunohistochemical evaluation, based on cellular composition (T and B lymphocytes), and histomorphometrical study revealed a more pronounced maturation of TLOs/MALTs in the LVI-HVI group. It is currently unclear whether these formations play a protective role by contributing to local immunity in chronic inflammatory diseases. However, the structural similarities between TLOs and MALTs and the location of TLOs close to the mucosa suggest that they may perform a similar function, facilitating a local protective response. Nevertheless, further investigations are warranted to assess the cellular and humoral dynamics of these lymphoid organs induced by attenuated isolates.

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BACKGROUND: Coinfection of human immunodeficiency virus type 1 (HIV-1) is the most significant risk factor for tuberculosis (TB). The immune responses of the lung are essential to restrict the growth of Mycobacterium tuberculosis and avoid the emergence of the disease. Nevertheless, there is still limited knowledge about the local immune response in people with HIV-1-TB coinfection. METHODS: We employed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid from 9 individuals with HIV-1-TB coinfection and 10 with pulmonary TB. RESULTS: A total of 19 058 cells were grouped into 4 major cell types: myeloid cells, T/natural killer (NK) cells, B cells, and epithelial cells. The myeloid cells and T/NK cells were further divided into 10 and 11 subsets, respectively. The proportions of dendritic cell subsets, CD4+ T cells, and NK cells were lower in the HIV-1-TB coinfection group compared to the TB group, while the frequency of CD8+ T cells was higher. Additionally, we identified numerous differentially expressed genes between the CD4+ and CD8+ T-cell subsets between the 2 groups. CONCLUSIONS: HIV-1 infection not only affects the abundance of immune cells in the lungs but also alters their functions in patients with pulmonary TB.

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IMPORTANCE: Vaccines targeting highly conserved proteins can protect broadly against diverse viral strains. When a vaccine is administered to the respiratory tract, protection against disease is especially powerful. However, it is important to establish that this approach is safe. When vaccinated animals later encounter viruses, does reactivation of powerful local immunity, including T cell responses, damage the lungs? This study investigates the safety of mucosal vaccination of the respiratory tract. Non-replicating adenoviral vaccine vectors expressing conserved influenza virus proteins were given intranasally. This vaccine-induced protection persists for at least 15 months. Vaccination did not exacerbate inflammatory responses or tissue damage upon influenza virus infection. Instead, vaccination with nucleoprotein reduced cytokine responses and histopathology, while neutrophil and T cell responses resolved earlier. The results are promising for safe vaccination at the site of infection and thus have implications for the control of influenza and other respiratory viruses.

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Local immune activation at mucosal surfaces, mediated by mucosal lymphoid tissues, is vital for effective immune responses against pathogens. While pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can spread to multiple organs, patients with coronavirus disease 2019 (COVID-19) primarily experience inflammation and damage in their lungs. To investigate this apparent organ-specific immune response, we develop an analytical framework that recognizes the significance of mucosal lymphoid tissues. This framework combines histology, immunofluorescence, spatial transcript profiling, and mathematical modeling to identify cellular and gene expression differences between the lymphoid tissues of the lung and the gut and predict the determinants of those differences. Our findings indicate that mucosal lymphoid tissues are pivotal in organ-specific immune response to SARS-CoV-2, mediating local inflammation and tissue damage and contributing to immune dysfunction. The framework developed here has potential utility in the study of long COVID and may streamline biomarker discovery and treatment design for diseases with differential pathologies at the organ level.

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The review presents current data on the use of positron emission tomography and single-photon emission computed tomography in multiple sclerosis (MS) to assess the activity of the pathological process, including neuroinflammation, demyelination, activation of microglia, neurodegeneration and local blood flow disorders. These methodologies are a new approach for studying the mechanisms of action and evaluating the clinical effect of disease modifying therapy of MS, especially those capable of penetrating into brain tissue. Among them, the most attention is attracted by cladribine tablets acting on the mechanism of immune reconstitution therapy, most likely with the modulation of immune reactions directly in the brain tissue.

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OBJECTIVE: The aim: To determine the dental status and state of local immunity in young adults who have suffered from the coronavirus disease. PATIENTS AND METHODS: Materials and methods: The main group consisted of 30 people aged 20-22 years, who suffered from the coronavirus infection Covid19 6.1±1.2 months ago. The comparison group included 20 people who did not have a coronavirus infection. The control group consisted of 35 people, randomized by age and sex, who did not have signs of caries and periodontal tissue disease and did not have coronavirus disease. All patients were examined for dental status and local immunity. RESULTS: Results: The analysis of indicators of dental status revealed the possibility of the existence of a relationship between the signs of acute SARS-Cov2 viral infection and the development of caries and periodontal tissue diseases. Significant changes in the local immunity of the oral cavity were found in the examined patients, which had a pathogenetic influence on the development and progression of caries and periodontal tissue diseases: a significant increase in the level of Ig G, as well as a probable decrease in the concentration of SIg A relative to the comparison group, a probably higher normative value of pathogenic small- and medium-molecular CICs with a significant decrease in the level of physiological large-sized CICs relative to the comparison group, a decrease in the content of anti-inflammatory IL-4, as well as increased concentration of pro-inflammatory cytokines. CONCLUSION: Conclusions: Young adults who have suffered a coronavirus infection during the last 6 months have significantly higher caries prevalence, bleeding index, PMA index and hygiene index, halitosis, which indicates deeper tissue damage and tooth pathology with the formation of dentition defects than in the comparison group. Indicators of local immunity of the oral fluid have a deep and specific character.

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Targeting the site of infection is a promising strategy for improving vaccine effectivity. To date, licensed COVID-19 vaccines have been administered intramuscularly despite the fact that SARS-CoV-2 is a respiratory virus. Here, we aim to induce local protective mucosal immune responses with an inhaled subunit vaccine candidate, ISR52, based on the SARS-CoV-2 Spike S1 protein. When tested in a lethal challenge hACE2 transgenic SARS-CoV-2 mouse model, intranasal and intratracheal administration of ISR52 provided superior protection against severe infection, compared to the subcutaneous injection of the vaccine. Interestingly for a protein-based vaccine, inhaled ISR52 elicited both CD4 and CD8 T-cell Spike-specific responses that were maintained for at least 6 months in wild-type mice. Induced IgG and IgA responses cross-reacting with several SARS- CoV-2 variants of concern were detected in the lung and in serum and protected animals displayed neutralizing antibodies. Based on our results, we are developing ISR52 as a dry powder formulation for inhalation, that does not require cold-chain distribution or the use of needle administration, for evaluation in a Phase I/II clinical trial.

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BACKGROUND: Allergic disease reflects specific inflammatory processes initiated by interaction between allergen and allergen-specific IgE. Specific immunotherapy (SIT) is an effective long-term treatment option, but the mechanisms by which SIT provides desensitization are not well understood. OBJECTIVE: Our aim was to characterize IgE sequences expressed by allergen-specific B cells over a 3-year longitudinal study of patients with aeroallergies who were undergoing SIT. METHODS: Allergen-specific IgE-expressing clones were identified by using combinatorial single-chain variable fragment libraries and tracked in PBMCs and nasal biopsy samples over a 3-year period with antibody gene repertoire sequencing. The characteristics of private IgE-expressing clones were compared with those of stereotyped or "public" IgE responses to the grass pollen allergen Phleum pratense (Phl p) 2. RESULT: Members of the same allergen-specific IgE lineages were observed in nasal biopsy samples and blood, and lineages detected at baseline persisted in blood and nasal biopsy samples after 3 years of SIT, including B cells that express IgE. Evidence of progressive class switch recombination to IgG subclasses was observed after 3 years of SIT. A common stereotyped Phl p 2-specific antibody heavy chain sequence was detected in multiple donors. The amino acid residues enriched in IgE-stereotyped sequences from seropositive donors were analyzed with machine learning and k-mer motif discovery. Stereotyped IgE sequences had lower overall rates of somatic hypermutation and antigen selection than did single-chain variable fragment-derived allergen-specific sequences or IgE sequences of unknown specificity. CONCLUSION: Longitudinal tracking of rare circulating and tissue-resident allergen-specific IgE+ clones demonstrates persistence of allergen-specific IgE+ clones, progressive class switch recombination to IgG subtypes, and distinct maturation of a stereotyped Phl p 2 clonotype.

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Miscarriage is one of the main causes of reproductive loss, which can lead to a number of physical and psychological complications and other long-term consequences. However, the role of vaginal and uterine microbiome in such complications is poorly understood. To review the published data on the function of the female reproductive tract microbiome in the pathogenesis of early miscarriages. The articles published over the past 20 years and deposited in PubMed, Google Academy, Scopus, Elibrary, ResearchGate, and EBSCO databases were analyzed. The review presents new data on the impact of the vaginal and uterine microbiome on the local immunity, including defense against sexually transmitted infections, and its association with other factors of miscarriages. The studies on the microbiome of non-pregnant women with recurrent miscarriages in the anamnesis, patients undergoing IVF, and pregnant women with miscarriages, as well as new directions in the microbiome research are discussed. The majority of studies have demonstrated that the dominant species of the vaginal and uterine microbiome in patients with early miscarriages are non-Lactobacillus bacteria. As many of these bacteria have not previously been detected by cultural studies and their role in obstetric complications is not well defined, further research on the female reproductive tract microbiome, including the microbiome of the cervix uteri, is needed to develop new approaches for the prognosis and prevention of miscarriages.

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The involvement of commensals and opportunistic pathogens and the role of protective mechanisms in the development of dental diseases in children with cystic fibrosis require more detailed study. AIM: The aim of the study was to determine the ecological characteristics of the oral microbiota and some antimicrobial factors of saliva in children with mucoviscidosis. MATERIALS AND METHODS: The study involved an assessment of oral microbiota as complex ecological system that protects the human body from colonization by pathogenic flora in children with cystic fibrosis. Bacteriological studies have been performed on clinical material from 30 children with mucoviscidosis diagnosed with dental and periodontal diseases. RESULTS: In the microbiological study of plaque microbiota, 70 strains of opportunistic pathogens were isolated in patients with mucoviscidosis. The most significant were alpha-hemolytic Streptococci (40%). The proportion of bacteria of Neisseria genus in patients with cystic fibrosis was lower and amounted to 24.3%. C. albicans fungi were isolated in comparable values (18.5%), S. aureus (8.5%), as well as gram-negative strains of E. aerogenes (4.3%) and E. coli (4.3%) significantly dominated. The results indicate that opportunistic pathogens S. aureus, E. aerogenes and E. coli partially replaced the representatives of the normal oral microbiota alpha-hemolytic streptococci and non-pathogenic species of Neisseria genus in patients with mucoviscidosis. CONCLUSIONS: Microbiota of plaque in children with mucoviscidosis is characterized by an expansion of the spectrum of opportunistic pathogens due to Staphylococcus aureus, enterobacteria and C. albicans fungi, which indicates a violation of the microbiocenosis due to reduced mucosal immunity. Mucosal immunity of the oral cavity in children with mucoviscidosis is characterized by a 1.5-fold decrease in lysozyme activity and the level of secretory IgA in the saliva of children.

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A woman had undergone excision for primary melanoma of the left heel and dissection of groin lymph nodes. The recurrent tumor on the lateral left lower leg developed six months ago and the depigmented plaques spread extensively on the left lower limb. The depigmented macules were localized to the left lower limb and were not seen in other areas. Although the left groin lymph node had been dissected, the local immune environment of anti-tumor immunity was preserved. The cause of melanoma-associated vitiligo is regarded to be anti-tumor autoimmune mediated, and this phenomenon is recently recognized during the therapy with immune checkpoint inhibitors in the treatment of stage III and IV melanoma.

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Immunomodulatory drugs are widely used as drugs for the treatment of inflammatory diseases of microbial etiology in clinical medicine. The authors evaluated the effectiveness of the therapeutic effect of the Cycloferon immunomodulator in the treatment of chronic purulent-inflammatory diseases of the reproductive tract using clinical, microbiological and immunological parameters. It was shown that under the influence of immunomodulatory therapy, the restoration of the qualitative and quantitative composition of the normoflora was observed with the elimination of etiologically significant microorganisms. The immunocorrective effect of therapy on the indices of local immunity was established: the concentration of lactoferrin increased in the cervical secretion, the level of cytokines IL-1ß and γ-IFN normalized, the amount of secretory IgA increased significantly, which contributed to the enhancement of local protective reactions, as well as the clinical efficacy of therapy, which was manifested in the reduction and/or disappearance of pain syndrome and the absence of relapse for 2 or more years. Conducted researches allow us to speak of immunotropic drugs as a promising direction in the treatment of inflammatory processes of the reproductive tract, a significant advantage of which is rational immunomodulation directly in the focus of inflammation, the availability of treatment, the absence of side effects with adequate therapeutic regimens, which makes it relevant to further study this direction of immunocorrection and its implementation into wide clinical practice.

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BACKGROUND: Swine influenza A virus (IAV) and porcine reproductive and respiratory syndrome virus (PRRSV) are considered key viral pathogens involved in the porcine respiratory disease complex. Concerning the effect of one virus on another with respect to local immune response is still very limited. Determination of presence and quantity of cytokines in the lung tissue and its relation to the lung pathology can lead to a better understanding of the host inflammatory response and its influence on the lung pathology during single or multi-virus infection. The aim of the present study was to explore and compare the patterns of lung cytokine protein response in pigs after single or dual infection with swine IAV and/or PRRSV. RESULTS: Inoculation with IAV alone causes an increase in lung concentration of IFN-α, IFN-É£, TNF-α, IL-6, IL-8 and IL-10, especially at 2 and 4 DPI. In PRRSV group, beyond early IFN-α, IFN-É£, IL-6, IL-8 and IL-10 induction, elevated levels of cytokines at 10 and 21 DPI have been found. In IAV+PRRSV inoculated pigs the lung concentrations of all cytokines were higher than in control pigs. CONCLUSIONS: Current results indicate that experimental infection of pigs with IAV or PRRSV alone and co-infection with both pathogens induce different kinetics of local cytokine response. Due to strong positive correlation between local TNF-α and IL-10 concentration and lung pathology, we hypothesize that these cytokines are involved in the induction of lung lesions during investigates infection. Nevertheless, no apparent increase in lung cytokine response was seen in pigs co-inoculated simultaneously with both pathogens compared to single inoculated groups. It may also explain no significant effect of co-infection on the lung pathology and pathogen load, compared to single infections. Strong correlation between local concentration of TNF-α, IFN-É£, IL-8 and SwH1N1 load in the lung, as well as TNF-α, IL-8 and PRRSV lung titres suggested that local replication of both viruses also influenced the local cytokine response during infection.

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BACKGROUND: Antibiotics are known to be effective in treating bacterial infectious disease. Changes in microflora and mucosal dysbiosis may take place after antibiotic treatment. We investigated in this research the effect of anti-Helicobacter pylori treatment (AHT) on local immunity of the female genital tract. METHODS: The study identified the levels of cytokines IL-8 and TNF-α in vaginal secretion in a group of female patients with Helicobacter-associated acid-related diseases who were or were not treated with antibiotics against Helicobacter Pylori. RESULTS: Research outcomes turned out that the secretory cytokine (chemokine) IL-8 is dramatically increased in the vaginal mucosa in patients treated with antibiotics, specifically in post-menopause women. CONCLUSION: Helicobacter pylori eradication treatment affects the immune status of the female genital tract.

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Hepatocellular carcinoma (HCC) is characterized by high heterogeneity in both intratumoral and interpatient manners. While interpatient heterogeneity is related to personalized therapy, intratumoral heterogeneity (ITH) largely influences the efficacy of therapies in individuals. ITH contributes to tumor growth, metastasis, recurrence, and drug resistance and consequently limits the prognosis of patients with HCC. There is an urgent need to understand the causes, characteristics, and consequences of tumor heterogeneity in HCC for the purposes of guiding clinical practice and improving survival. Here, we summarize the studies and technologies that describe ITH in HCC to gain insight into the origin and evolutionary process of heterogeneity. In parallel, evidence is collected to delineate the dynamic relationship between ITH and the tumor ecosystem. We suggest that conducting comprehensive studies of ITH using single-cell approaches in temporal and spatial dimensions, combined with population-based clinical trials, will help to clarify the clinical implications of ITH, develop novel intervention strategies, and improve patient prognosis.

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The macroscopic and histological methods were employed to examine the autopsy specimens of salivary lingual glands obtained from 299 patients of both sexes and various age ranging from newborn to longevity. The age-associated alterations of minor lingual and pharyngeal glands were revealed, and the topographical relations between the glands and lymphoid cells were described. The characteristic sparsity of the glands in infancy is caused by nutritional uniformity at this period, when diminished production of secretory IgA results in frequent inflammatory processes in oral and pharyngeal cavities. With age, the glandular orifices widen, and their number increases thereby augmenting local immunity in the oral cavity and in oral aspect of the pharynx. Starting from elderly and senile age, the involutive alterations were observed, which were accompanied by diminished production of secretory immunoglobulin A and related degradation of local and humoral immunity.

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Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.

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OBJECTIVE: The aim: To improve the results of treatment of infected wounds. PATIENTS AND METHODS: Materials and methods:The clinical material is based on clinical observation and treatment of 29 patients with in fected wounds, whose treatment included combination drugs of local action on the basis of techno-molecular silver (in particular «Cadefort-Spray¼), by application to the wound surface. RESULTS: Results: Wound microbial factor, dynamics of wound process, indicators of immune status were evaluated: localadaptive immunity, atopic reactions. CONCLUSION: Conclusions: High efficiency of treatment was observed regardless of the phase of the wound process, which allowed to accelerate wound repair and stimulate the processes of regeneration, strengthen local adaptive immunity, prevent atopic reactions.

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