Adaptive Immunity In Patients Research Articles

Increased Activation Markers of Adaptive Immunity in Patients with Severe COVID-19.

Introduction: COVID-19 is a pandemic disease and is widespread over the world. This disease shows a 5.1% mortality. The understanding of the disease has expanded rapidly in many areas, including virological, epidemiological, clinical, and management dimensions. To better understand the inflammatory and immune profiles that impact the pathogenesis and development of severe COVID-19 symptoms, further studies are essential. This research aims to explore the inflammatory and adaptive immune responses associated with COVID-19, considering factors such as genetic diversity and environmental exposure among Saudi patients. The goal is to determine if patients with severe COVID-19 exhibit different disease phenotypes. Materials and Methods: This case-control study includes 115 participants (healthy and with COVID-19 infection), 55 of which had confirmed cases of COVID-19 in intensive care units (ICUs) at different hospitals in Makkah City, Saudi Arabia. Whole blood samples were collected from June to September 2021 for cellular analyses, and inflammation marker data were collected from hospital records. The expression of activation markers on B (CD27 and CD38) and T cells (CD27 and HLA-DR) was obtained using the flow cytometry technique. Also, serum was collected for cytokine measurements, including IL-6, INF-γ, and TNF- α. Results: The results indicated that lymphopenia and excessive T cell activation were more prevalent in severe cases than in healthy individuals. Furthermore, the results revealed that severe COVID-19 patients had an increased frequency of CD19+ B cells, with changes in B cell subsets. The current study implies impairment and changes in the phenotype of adaptive cells (including T and B cells), with an increase in HLA-DR molecules and inflammation markers with pro-inflammatory cytokines in severe COVID-19 cases. Conclusions: The current study implies impairment and changes in the phenotype of adaptive cells (including T and B cells), with an increase in HLA-DR molecules and inflammation markers in severe COVID-19 cases, which could be targeted for therapeutic interventions. This might be a valuable approach for the diagnosis and treatment of severe COVID-19 cases.

ROLE OF ADAPTATION TO CHRONIC HYPOXIA IN THE DEVELOPMENT OF DYSIMUNIC DISORDERS IN DIABETIC FOOT ULCER

The purpose of the study is to establish the relationship between the immune-mediated DFU in patients with T2DM and the degree of HIF-2-dependent adaptation to chronic hypoxia. Materials and Methods: We conducted a comparative analysis of patients’ clinical characteristics, laboratory markers of infection and individual parameters of adaptive immunity in patients of the main group with neuropathic and neuroischemic forms of T2DM (subgroup 1, n=51, ulcer area less than 6 cm2; subgroup 2, n=28, ulcer area more than 6 cm2), as well as in patients of the comparison group (n=44) with similar forms of T2DM. It was found that the nature of the response to hypoxia, mediated by HIF-2α, played an important role in regulating the activity of the adaptive immune response and the inflammatory-reparative process in patients with T2DM and destructed foot tissue. Results: The presence of foot wounds in patients with T2DM indicates a disruption of the HIF-2α-dependent adaptive response, which is accompanied by activation of inflammatory mediators and a decrease in IgG-dependent mechanisms. In patients with T2DM, increased HIF-2α expression in combination with increased production of immunoglobulins, is obviously a protective mechanism that prevents defects of foot tissue. Conclusion: The clinical and laboratory use of hypoxia biomarkers is promising for predicting the risk of infectious and destructive complications in patients with T2DM.

Large-Scale Characterization and Functional Assessment of Adaptive Immunity in Patients with MGUS and SMM Reveals Significant Defects

Introduction Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS) or Smoldering Multiple Myeloma (SMM) exhibit signs of immune dysregulation despite their early stage of oncogenesis. The SARS-CoV-2 pandemic and subsequent broad vaccination of the population presented an opportunity to compare the real-life immune response of patients and healthy individuals following exposure to a common antigen. Here, we have used SARS-CoV-2 vaccination as a model to study the adaptive immune response and have thus comprehensively assessed the adaptive immune response of patients with MGUS/SMM to SARS-CoV-2 vaccination compared to healthy donors (HD). Methods We performed (i) paired 5' single-cell RNA and T cell receptor (TCR) sequencing on 224 peripheral blood mononuclear cell (PBMC) samples drawn serially before and after two doses of SARS-CoV-2 vaccination (HD, n=26; MGUS, n=20; SMM, n=48; Multiple Myeloma (MM), n=24), (ii) ELISA for anti-Spike IgG antibodies post-vaccination (post-vx), (HD, n=237; MGUS, n=550; SMM, n=947) and MMR antibodies at baseline (HD, n=20; SMM, n=20), (iii) bulk TCR sequencing pre- and post-vx (HD, n=2; SMM, n=2) (Adaptive Biotechnologies), and (iv) IFN gamma ELISpot assay following in vitro stimulation with Spike peptide (HD, n=20; SMM, n=20). All post-vx samples were drawn after 2 doses of vaccination. Results Patients and HD showed comparable anti-Spike antibody titers within 14-50 days post-vx, however, we observed faster waning in patients with MGUS/SMM, who had significantly lower titers 50-100 days post-vx (p=0.014 & p=0.007, respectively), suggesting a potential defect in long-lived plasma cell maintenance. Indeed, patients with SMM showed significantly lower titers of antibodies against Mumps and Rubella, antigens encountered in childhood, compared to age-matched HD (p=0.002 & p=0.03, respectively), showing that this defect may also lead to loss of plasma cell memory. Next, we performed single-cell RNA/TCR-seq to assess the patients' T cell response to vaccination. Patients with SMM showed a significant increase in TCR repertoire diversity post-vx (paired t-test, p=0.046), suggesting at least partial preservation of T cell responses with recruitment of rare clones. Indeed, using bulk TCR-seq, we observed Spike-specific T cells in patients with MGUS/SMM. Interestingly, however, a significant enrichment in Spike-specific clones by single-cell TCR-seq was only observed in HD post-vx (paired t-test, p=0.01), suggesting patient T cell responses may be suboptimal. Functional assessment of T cell activation following stimulation with the Spike peptide showed significantly lower activation in patients with SMM compared to HD (t-test, p=0.002), confirming the suspected defect. Notably, a larger proportion of Spike-specific clones in patients was of the Treg phenotype compared to HD (empirical p=0.002), which may partly explain the observed defect. Conclusions This study demonstrates that despite the absence of symptoms, patients with MGUS/SMM may demonstrate defective humoral and cellular immune responses, including loss of plasma cell memory. Specific interventions, such as changes in the vaccination schedule, may be warranted for this population, and the morbidity associated with these defects should be studied further.

Features of innate and adaptive immunity in patients with moderate course of COVID-19 with various degrees of lung tissue damage

Objective: to study changes in innate and adaptive immunity in patients with a moderate course of COVID-19 with varying degrees of lung tissue damage. 40 patients with a moderate form of COVID-19 and varying degrees of damage to the lung tissue (up to 25% and up to 50%) and 30 patients from the control group (healthy donors) were examined using methods: computed tomography of the lungs, evaluation of a complete blood count, biochemical parameters, immunological studies, statistical. Differences in all patients with the control group consisted in a decrease in the absolute content of lymphocytes, in a significant increase in the relative content of natural killers and cytokine imbalance. The most significant differences were registered in the content of IL-6, depending on the degree of damage to the lung tissue. A smaller area of lung damage reflects a milder course of the disease, which does not exclude the need for dispensary observation and rehabilitation after discharge.

Patterns of CMV infection after letermovir withdrawal in recipients of posttransplant cyclophosphamide–based transplant

AbstractReactivation of latent cytomegalovirus (CMV) is increased in recipients of allogeneic hematopoietic cell transplantation (allo-HCT) with seropositive CMV using posttransplant cyclophosphamide (PT-Cy)–based graft-versus-host disease (GVHD) prophylaxis. Letermovir, a novel DNA terminase complex inhibitor, reduces the incidence of clinically significant CMV infection (csCMVi) in this population; however, parameters that predict csCMVi after letermovir withdrawal are not well described. Here, we examined clinical and immunological parameters in 294 recipients of PT-Cy–based allo-HCT, including 157 patients with CMV, of whom 80 completed letermovir prophylaxis without csCMVi and subsequently stopped letermovir. In this population, the median duration of letermovir exposure was 203 days (interquartile range [IQR], 160-250 days). After letermovir withdrawal, the 90-day cumulative incidence of csCMVi was 23.0% (95% confidence interval, 14.3-32.8). There were no episodes of CMV end-organ disease. Hypogammaglobulinemia before letermovir discontinuation was predictive of csCMVi (hazard ratio, 0.33; 95% confidence interval, 0.12-0.93; P = .03), whereas T-cell and B-cell reconstitution before letermovir withdrawal were not predictive of csCMVi. Higher numbers of natural killer cells were found before letermovir withdrawal in patients who experienced csCMVi (median, 202 vs 160; P = .03). In recipients with seropositive CMV, CD3+CD4–CD8+ T-cell reconstitution was faster in patients with CMV regardless of letermovir exposure. Taken together, these data suggest that csCMVi after letermovir withdrawal was frequent in patients treated with PT-Cy, despite prolonged exposure. Strategies to boost CMV-specific adaptive immunity in patients with persistent hypogammaglobulinemia is a logical pathway to reduce csCMVi after letermovir withdrawal.

Features of the functioning of the innate and adaptive immunity system in patients with COVID-19 of the older age group

Goal. Characteristics of innate, cellular and adaptive immunity in patients of the older age group with COVID19.Materials and methods. Blood leukocytes were induced by Newcastle disease virus (α-interferon), phytohemagglutinin (γ-interferon), SARS CoV 2: RBD antigens and S-protein; interferon activity in human fibroblast culture and enzyme immunoassay were evaluated. In serum, IgG antibodies to SARS CoV2 and autoantibodies to interferon and to the endothelium of blood vessels were determined using a mono-layer of human umbilical vein cells. Statistical processing was performed in Excel 2016.Results. A decrease in the production of α-interferon and γ-interferon was revealed: 1 week -74.2±15.1; 3 week-144.0±35.7 (p=0.01); control – 266.6 ±82 (relative to 3 weeks p=0.004) and IFN γ: 1 week -6.8±2; 3 week – 14.4 ±3.5 (p=0.03); control – 28.87.15 (relative to 3 weeks (p=0.007). Decreased production of γ-interferon by leukocytes of patients with induction by SARS CoV2 RBD and S-trimer anti-gens was revealed. Antibodies to SARS CoV2 were detected starting from the 2nd week of the disease, a large spread of indicators was noted. Autoantibodies to α2-interferon and to vascular surface antigens were detected.Conclusion. The state of innate immunity in patients of the older age group with severe and moderate COVID-19 was characterized by a decrease in the activity of the interferon system. Decreased activity of cellular immunity to SARS CoV2 antigens was noted. Adaptive immunity was characterized by the development of an imbalance in the form of the appearance of autoantibodies to α-interferon and vascular endothelium.

Immunological efficacy of cavitated solutions in the complex therapy of chronic rhinitis

Quantitative and qualitative indicators of nasal lavages in patients with chronic rhinitis have been studied. The results of the study have shown that an increase in the number of viable neutrophilic granulocytes and in their lysosomal activity, a decrease in the activity and intensity of phagocytosis, inhibition of biocidal properties according to the spontaneous HCT test, and a decrease in the content of secretory IgA are recorded in patients with chronic rhinitis. The use of a 0.9 % sodium chloride cavitated solution led to the restoration of quantitative and qualitative indicators of innate immunity and some indicators of adaptive immunity in patients’ nasal secretions.

Immunological factor development of external genital endometriosis

External genital endometriosis (EGE) is one of the common gynecological diseases of women of reproductive age with a relapsing, progressive course that worsens the quality of life of patients due to pain, emotional imbalance, fear of relapse and possible surgical intervention. Currently, endometriosis is recognized as one of the most common diseases associated with infertility. Thus, among fertile women with preserved childbearing function, the disease is generally diagnosed in approximately 6-7%, while among patients suffering from infertility, its frequency can reach 20-48%.However, the causes that determine reproductive dysfunction in patients with EGE are not well understood. Much attention is currently paid to the role of immunity in the formation of endometriosis. Patients with EGE show changes in both local immunity factors and immunological components of circulating blood.Purpose of the study: the study of factors of innate and adaptive immunity in patients of reproductive age with external genital endometriosis (EGE).The study included 71 patients with various stages of external genital endometriosis, the control group included 24 patients without endometriosis. Determination of the population composition of peripheral blood lymphocytes, the level of monocytes expressing TLR, activation markers, was carried out by laser flow cytometry — Immunotex (France), Caltag (USA), FITC (fluorescein isothiocynate) — labeled CD3, CD4, CD8, CD16, CD19, HLA-DR, CD282, CD284 and PE (phycoerythrin) - labeled with CD25, CD69, CD95, CD107a, CD14.External genital endometriosis is characterized by: at stages I-II of the disease - a violation of the early stages of the innate immune response (an increase in the number of monocytes expressing TLR-4, a violation of the activation and differentiation processes of immunocompetent cells, which is reflected in a decrease in the expression of CD16, CD8, CD16+HLA-DR+, CD16+CD107a+, CD8+CD107a+, at III-IV stages of the disease, there is a decrease in the level of CD16 and activation markers CD69, HLA-DR, CD107a on their surface, which is combined with a decrease in the expression of CD8, CD16, HLADR and CD107a on their surface. CD95+ and CD8+CD95+ were found at various stages of EGE.The results obtained allow us to understand the features of the functioning of innate and adaptive immunity at various stages of external genital endometriosis, and the studied immunological parameters can be used as diagnostic criteria for the formation of various stages of EGE. These data can serve as a theoretical basis for further identification of markers of EGE progression, as well as the mechanisms underlying immune inflammation.

Understanding of SARS-CoV-2 pathogenicity in COVID-19 cynomolgus macaque model and consideration of its reinfection

Abstract Although rapid vaccination has been progressing in the world as a countermeasure against COVID-19, the pandemic of SARS-CoV-2 is still raging worldwide due to the continuous emergence of several variants. We have established the COVID-19 cynomolgus macaque (CM) model using healthy young CMs and advanced-age CMs and the differences observed between the pathologies of young and elderly macaques were similar that those seen in humans. In the present study, we analyzed viral dynamics and pathology of SARS-CoV-2 variants of concern (VOCs) from Wuhan to Omicrons using the COVID-19 CM model. Delta infection displayed a greater virulence and Omicron infection showed a lesser virulence. Elucidation of how adaptive immunity in patients is induced by SARS-CoV-2 natural infection is critical for establishing a vaccine strategy, serologic therapies, public health control and prediction of infection. Therefore, we conducted the prolonged rechallenge analysis using the COVID-19 CM model reinoculated with either the same or a different strain of SARS-CoV-2 that was used for the initial infection. Re-infection was confirmed between different virus strains and PCR re-positivity was also observed between same VOC strain in some cases. Anti-RBD antibodies against Wuhan, Alpha, and Delta, were well induced by each VOC infection, but not against Omicrons. Antigen-specific cellular responses are also currently being analyzed. Overall, studies using COVID-19 CM models should contribute to the elucidation of the complicated pathophysiology of COVID-19. In addition, COVID-19 CM model should be useful for understand the virus evolution and to consider vaccine strategy to overcome the COVID-19 pandemic. AMED JP21fk0108414 AMED JP223fa727002 JSPS 21K19395

Underlying medical conditions and anti-SARS-CoV-2 spike IgG antibody titers after two doses of BNT162b2 vaccination: A cross-sectional study.

Patients with underlying medical conditions are at high risk of developing serious symptoms of the coronavirus disease 2019 than healthy individuals; therefore, it is necessary to evaluate the immune response to vaccination among them to formulate precision and personalized vaccination strategies. However, inconsistent evidence exists regarding whether patients with underlying medical conditions have lower anti-SARS-CoV-2 spike IgG antibody titers. We performed a cross-sectional study enrolling 2762 healthcare workers who received second doses of BNT162b2 vaccination from three medical and research institutes between June and July, 2021. Medical conditions were surveyed by a questionnaire, and spike IgG antibody titers were measured with chemiluminescent enzyme immunoassay using serum collected on the median of 62 days after the second vaccination. Multilevel linear regression model was used to estimate geometric mean and ratio of mean (95% confidence interval, CI) for the presence and absence of medical conditions and treatments. Among all participants (median age, 40 years [interquartile range, 30-50]; male proportion, 29.4%), the prevalence of hypertension, diabetes, chronic lung disease, cardiovascular disease, and cancer was 7.5%, 2.3%, 3.8%, 1.8%, and 1.3%, respectively. Patients with treated hypertension had lower antibody titers than those without hypertension; the multivariable-adjusted ratio of mean (95% CI) was 0.86 (0.76-0.98). Patients with untreated and treated diabetes had lower antibody titers than those without diabetes; the multivariable-adjusted ratio of mean (95% CI) was 0.63 (0.42-0.95) and 0.77 (0.63-0.95), respectively. No substantial difference was observed between the presence or absence of chronic lung disease, cardiovascular disease, or cancer. Patients with untreated hypertension and patients with untreated and treated diabetes had lower spike IgG antibody titers than participants without those medical conditions, suggesting that continuous monitoring of antibody titers and further booster shots could be necessary to maintain adaptive immunity in patients with hypertension or diabetes.

CHARACTERISTICS OF THE IMMUNE STATUS IN PATIENTS WITH DECOMPENSATION OF LIVER CIRRHOSIS

Liver cirrhosis continues to be an acute problem of modern medicine due to the high rates of its prevalence and mortality. The high mortality rate is caused by the development of the number of life–threatening complications in decompensated forms of liver cirrhosis – hepatorenal syndrome, infections and varicose bleeding. Hepatorenal syndrome and infections are the result of immunological shifts occurring during decompensation of liver cirrhosis. Currently available literature data do not allow us to create a complete picture of the functional state of various links of adaptive immunity with decompensated liver cirrhosis. The aim of the research was to study the characteristic features of adaptive immunity in patients with decompensated liver cirrhosis. Material and methods. The prospective cohort study included 136 patients with decompensated liver cirrhosis, who received inpatient treatment in the hepatological department of the multidisciplinary hospital. The cohort of examined patients was divided into two groups, one of which included patients with liver cirrhosis of viral origin (n = 78), the other – patients with alcoholic liver cirrhosis (n = 58). In addition to the generally accepted standard methods, the patient examination program included immunological tests: identification of T- and B-lymphocytes, immunoregulatory and activated subpopulations of T-lymphocytes by the method of immunophenotyping peripheral blood mononuclear cells using monoclonal antibodies. The serum levels of immunoglobulins IgM, IgG, IgA, circulating immune complexes were determined by immunoturbidimetric method. Results. The study of indicators of the humoral link of adaptive immunity revealed an increase in the number of B cells, an increase in IgM, IgG, IgA and circulating immune complexes in patients with decompensated liver cirrhosis. The cellular link of adaptive immunity was characterized by an increase in the relative content of T helper cells, activated T cells against the background of a decrease in the number of immature T cells and T regulatory cells. Conclusions. The distinctive features of adaptive immunity in patients with decompensated liver cirrhosis are simultaneous activation of both humoral and cellular components, which, apparently, supports the systemic inflammatory process and the associated progressive liver fibrosis.

THE STUDY OF THE IMMUNE STATUS IN POST-COVID SYNDROME BY FLOW CYTOMETRY

A novel coronavirus infection was described in 2019 in Wuhan, China. From the first months of the spread of the infection around the world, evidence began to appear that patients after recovery had various symptoms. Duration, intensity, and variability of symptoms vary among patients and are often not associated with the severity of the most acute illness. Recently the concept of post-COVID syndrome (post-COVID or long-COVID in the English-language literature) has acquired increasingly clear diagnostic criteria. Persistent symptoms and / or the appearance of delayed complications after 4 weeks or more from the onset of symptoms of an acute illness are commonly called post-COVID syndrome. The wide range of symptoms that can occur in patients with post-COVID syndrome is now a major health concern worldwide. A proper clinical evaluation will help determine the etiology and build a treatment plan. Longer studies aimed at identifying the effects of COVID-19, possible risk factors for their development, a detailed study of the pathogenetic mechanisms of SARS-CoV-2, and the development of treatment and rehabilitation methods to improve the mental and physical health of surviving patients are relevant elements of study for the foreseeable future. T-lymphocytes are a poorly studied population of T lymphocytes. These cells are more often localized in the mucous membranes of the body which have the properties of innate and acquired immunity. The main biological functions are cytolysis, immunoregulation which indicates an important immunocompetent role of this type of cell population in severe infectious diseases. This article provides information on the fraction of T-lymphocytes during the formation of adaptive immunity in patients with post-COVID syndrome.

Analysis of SARS-CoV-2 pathogenicity in COVID-19 cynomolgus macaque model reflecting human COVID-19 pathological conditions

Abstract The pandemic of SARS-CoV-2 is still raging worldwide. Although rapid vaccination has been progressing in the world as a countermeasure against COVID-19, there are many issues regarding this disease including the emergence of variants and of their virulence that need to be elucidated, and a useful animal model is still necessary. We have established COVID-19 cynomolgus macaque (CM) model using healthy young CMs and CMs of advanced age (23 – 30 years of age, equivalent to 69 – 90 years of age in humans) with underlying diseases including diabetes and hyperlipidemia. There were differences between the pathological conditions in young macaques and elderly macaques of advanced age similar to observed in humans. In this study, we analyzed the virulence and pathology of SARS-CoV-2 variants of concern (VOCs) using COVID-19 CM model. Elucidation of how adaptive immunity in patients is induced by SARS-CoV-2 natural infection is critical for establishing a vaccine strategy, serologic therapies, public health control and prediction of infection. Therefore, we conducted the prolonged rechallenge analysis using COVID-19 CM model reinoculated with either the same or a different strain of SARS-CoV-2 that was used for the initial infection. Protective immunity against rechallenge of SARS-CoV-2 is under consideration, but in one elderly monkey reinfection showed transient pneumonia with increased levels of various serum cytokines and chemokines without detecting viruses in swab samples. Overall, the SARS-CoV-2-infected CM models reflected the pathology in humans, and studies using COVID-19 CM models should contribute to the elucidation of the complicated pathophysiology of COVID-19. Supported by grants from AMED (JP20fk0108414) and JSPS (21K19395)

Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma.

Tumor Treating Fields (TTFields), an approved therapy for glioblastoma (GBM) and malignant mesothelioma, employ noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to disrupt the mitotic spindle, leading to chromosome missegregation and apoptosis. Emerging evidence suggests that TTFields may also induce inflammation. However, the mechanism underlying this property and whether it can be harnessed therapeutically are unclear. Here, we report that TTFields induced focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that intensely recruited and activated 2 major DNA sensors — cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) — and their cognate cGAS/stimulator of interferon genes (STING) and AIM2/caspase 1 inflammasomes to produce proinflammatory cytokines, type 1 interferons (T1IFNs), and T1IFN-responsive genes. In syngeneic murine GBM models, TTFields-treated GBM cells induced antitumor memory immunity and a cure rate of 42% to 66% in a STING- and AIM2-dependent manner. Using single-cell and bulk RNA sequencing of peripheral blood mononuclear cells, we detected robust post-TTFields activation of adaptive immunity in patients with GBM via a T1IFN-based trajectory and identified a gene panel signature of TTFields effects on T cell activation and clonal expansion. Collectively, these studies defined a therapeutic strategy using TTFields as cancer immunotherapy in GBM and potentially other solid tumors.

Vitamin D Status and Immune Response in Hospitalized Patients with Moderate and Severe COVID-19.

A low 25-hydroxyvitamin D (25(OH)D) level is considered as an independent risk factor for COVID-19 severity. However, the association between vitamin D status and outcomes in COVID-19 is controversial. In the present study we investigate the association between the serum 25(OH)D level, immune response, and clinical disease course in patients with COVID-19. A total of 311 patients hospitalized with COVID-19 were enrolled. For patients with a vitamin D deficiency/insufficiency, the prevalence of severe COVID-19 was higher than in those with a normal 25(OH)D level (p < 0.001). The threshold of 25(OH)D level associated with mortality was 11.4 ng/mL (p = 0.003, ROC analysis). The frequency of CD3+CD4+ T helper (Th) cells was decreased in patients with 25(OH)D level ≤ 11.4 ng/mL, compared to healthy controls (HCs). There were no differences in the frequency of naive, central memory (CM), effector memory (EM), and terminally differentiated effector memory Th cells in patients with COVID-19 compared to HCs. The frequency of T-follicular helpers was decreased both in patients with 25(OH)D level > 11.4 ng/mL (p < 0.001) and 25(OH)D level ≤ 11.4 ng/mL (p = 0.003) compared to HCs. Patients with 25(OH)D level > 11.4 ng/mL had an increased frequency of Th2 CM (p = 0.010) and decreased Th17 CM (p < 0.001). While the frequency of Th2 EM was significantly increased, the frequency of Th17 EM was significantly decreased in both groups compared to HCs. Thus, 25(OH)D level is an independent risk factor for the disease severity and mortality in patients with COVID-19. We demonstrate that the serum 25(OH)D level ≤ 11.4 ng/mL is associated with the stimulation of Th2 and the downregulation of Th17 cell polarization of the adaptive immunity in patients with COVID-19.

Features of innate and adaptive immunity in patients with Parkinson's disease

Introduction. T cells play a significant role in neuroinflammation in Parkinson's disease (PD). Gamma delta T cells are an under-researched 'minor' subpopulation of T cells. An assessment of the immune system in patients with PD, with a focus on Т cells, provides new data on the pathogenesis of neurodegenerative diseases. The aim of the study was to examine the lymphocyte subpopulations, nonclassical Т cells, as well as cytokine production in patients with 3 stage PD complicated by motor fluctuations. Materials and methods. We examined 20 patients with 3 stage PD receiving dopaminergic combination therapy (main group) and 20 age-matched patients with chronic cerebrovascular disease (comparison group). Considering the suspected role of chronic constipation in maintaining dysbiosis and chronic inflammation in patients with PD, the presence of constipation was an inclusion criterion for this study. The subpopulation profile of the peripheral blood lymphocytes was assessed using flow cytofluorometry, as well as cytokine levels using enzyme linked immunosorbent assay. Results. It was found that the number of mature CD3+ T cells with or chains as the T-cell receptors (TCR) in the lymphocyte population was significantly lower in patients with PD median 74% (57.383.5)) than in the comparison group (median 80% (73.086.0); р = 0.014. There was also a statistically significant reduction in the number of CD3+CD56+ natural killer (NK) T cells in the group of patients with PD vs. the comparison group 4.7% (1.37.7) vs. 7.8% (0.824); р = 0.036. At the same time, the number of CD3CD56+ NK cells was significantly higher in the group of patients with PD (16.4% (934)) vs. the comparison group 8.7% (515); р = 0.001. Moreover, the main group had a statistically significantly higher number of activated CD3CD8+ NK cells 7% (4.513.5) vs. the comparison group 3.5% (0.864.9); р 0.001. Out of the total number of Т cells, the TCR CD4+CD8 subpopulation was statistically smaller in the group of patients with PD 13.6% (6.227.0) than in the comparison group 29.8% (4.052.1); р = 0.016. The study of cytokine levels in the group of patients with PD showed a significant increase in the induced production of interleukin-1 (IL-1), as well as a high (aberrant) spontaneous production of IL-10, which was 227.5 pg/ml in patients with PD when the normal range is 023 pg/ml. The correlation analysis showed that the TCR CD4+CD8 subpopulation and cytokines in the group of patients with PD had a statistically significant (p = 0.048) negative correlation with the induced production of IL-10 (r = 0.745) and a significant (p = 0.042) positive correlation with the induced production of the pro-inflammatory cytokine IL-1 (r = 0.648). There was a trend towards increased spontaneous production of IL-10 (r = 0.602; p = 0.0506) as the level of the TCR CD4+CD8 T helper cells decreased. Conclusion. Changes were found in the blood of patients with PD, which indicate a chronic inflammatory process: increased number of CD3CD56+ NK cells, including activated CD3CD8+ cells, and increased production of pro-inflammatory cytokine IL-1 and anti-inflammatory cytokine IL-10. A decrease was found in the level of a minor subpopulation of T cells, TCR CD4+CD8. The correlation found between this subpopulation and the production of pro- and anti-inflammatory cytokines indicates its role in regulation of chronic inflammation in PD.

Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses

BackgroundThere are no validated biomarkers that can aid clinicians in selecting who would best benefit from anticytotoxic T lymphocyte-associated antigen 4 monotherapy versus combination checkpoint blockade in patients with advanced...

Neutrophils contribute to elevated BAFF levels to modulate adaptive immunity in patients with primary immune thrombocytopenia by CD62P and PSGL1 interaction.

ObjectivesImmune thrombocytopenia (ITP) is an autoimmune disease characterised by impaired platelet production and increased platelet destruction. However, the involvement of neutrophils in ITP is yet to be explored.MethodsB‐cell activating factor (BAFF) expression and activation markers of neutrophils, as well as activation of platelets in ITP patients and healthy controls were measured. The interaction of CD62P on platelets and BAFF in neutrophils was analysed by correlation analysis and verified by co‐culture. The effects of neutrophils on apoptosis of acquired immune cells were evaluated in co‐culture systems with or without belimumab.ResultsThe BAFF expression and activation of neutrophils were increased in active ITP patients. BAFF levels in neutrophils were positively correlated with CD62P+ platelets and neutrophils produced increased BAFF by interfering with CD62P on platelets. Neutrophils inhibited the apoptosis of CD4+, CD8+ and CD19+ cells dependent on BAFF levels, and belimumab could interrupt the effects of neutrophils.ConclusionsNeutrophils were overactivated in ITP patients and participated in the progression of disease by producing excessive BAFF, which could be regulated by CD62P on platelets. Targeting BAFF by belimumab may be a novel potential therapy for ITP.

Аналіз ефективності лікувального комплексу у хворих гастроентерологічного профілю з кандидозом слизової оболонки верхнього відділу травного тракту

Проблема лікування кандидозу слизової оболонки верхнього відділу травного тракту залишається актуальною у зв’язку з необхідністю як проведення етіотропної терапії, так і врахування варіабельності імунної відповіді при взаємодії макроорганізму й Candida albicans. Зниження імунореактивності в цьому випадку потребує проведення коригуючого лікування. Мета дослідження — вивчити вплив лікувального комплексу з включенням поліпептидного імуномодулятора імунофан на показники вродженого та адаптивного імунітету у хворих означеної групи. Згідно з отриманими результатами, пацієнтів з інвазією грибів у слизову оболонку відрізняє наявність імунодефіциту за співвідношенням лейкоцити/CD3+, що в 1,3 раза вище, ніж у хворих з орофарингеальним та поверхневим кандидозом (р &lt; 0,01). Після проведеного лікування у групі хворих з інвазією кандид у слизову оболонку первинно підвищене значення НСТ-тесту і цитохімічного показника активності нейтрофілів знизилося на 40,40 % (р &lt; 0,05) і 29,03 % (р &lt; 0,05) відповідно. Ці зміни в сукупності з підвищенням рівня циркулюючих імунних комплексів у 1,4 раза порівняно зі значеннями до лікування (р &lt; 0,05) та у 1,5 раза — порівняно з конт­ролем (р &lt; 0,01) свідчать про більш глибокі дефекти в системи вродженого імунітету, що, очевидно, зумовлюють як більш тяжкий перебіг захворювання, так і труднощі в лікуванні. У цілому застосування лікувального комплексу призводить до відновлення Т-клітинної ланки імунітету хворих обох груп з нормалізацією співвідношення Т-хелпери/Т-супресори, до підвищення рівня лактоферину в ротовій порожнині та підвищення концентрації IgA та IgG у пацієнтів з інвазією. Отже, комплексний підхід до лікування хворих з кандидозом слизової оболонки верхнього відділу шлунково-кишкового тракту та визначення стратегії й тактики подальшого спостереження є необхідними для ефективного надання медичної допомоги даній групі пацієнтів.

Cellular changes in eculizumab early responders with generalized myasthenia gravis

Eculizumab (ECU), a C5 complement inhibitor, is approved to treat acetylcholine receptor autoantibody positive generalized myasthenia gravis (AChR MG). The clinical effect of ECU relies on inhibition of the terminal complement complex; however, the effect of ECU on lymphocytes is largely unknown. We evaluated innate and adaptive immunity among AChR MG patients (N = 3) before ECU and ≥3 months later while on stable therapy, and found reduced activation markers in memory CD4+ T cell subsets, increased regulatory T cell populations, and reduced frequencies of CXCR5+HLA-DR+CCR7+ Tfh subsets and CD11b+ migratory memory B cells. We observed increases within CD8+ T cell subsets that were terminally differentiated and senescent. Our data suggest complement inhibition with ECU modulates the adaptive immunity in patients with MG, consistent with preclinical data showing changes in complement-mediated signaling by T- and antigen-presenting cells. These findings extend our understanding of ECU's mechanism of action when treating patients with MG.