Percentages Of CD4 Research Articles

Durable natural killer cell response after three doses of SARS-CoV-2 inactivated vaccine in HIV-infected individuals.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine can induce a potent cellular and humoral immune response to protect against SARS-CoV-2 infection. However, it was unknown whether SARS-CoV-2 vaccination can induce effective natural killer (NK) cell response in people living with human immunodeficiency virus (PLWH) and healthy individuals. Forty-seven PLWH and thirty healthy controls (HCs) inoculated with SARS-CoV-2 inactivated vaccine were enrolled from Beijing Youan Hospital in this study. The effect of SARS-CoV-2 vaccine on NK cell frequency, phenotype, and function in PLWH and HCs was evaluated by flow cytometry, and the response of NK cells to SARS-CoV-2 Omicron Spike (SARS-2-OS) protein stimulation was also evaluated. SARS-CoV-2 vaccine inoculation elicited activation and degranulation of NK cells in PLWH, which peaked at 2 weeks and then decreased to a minimum at 12 weeks after the third dose of vaccine. However, in vitro stimulation of the corresponding peripheral blood monocular cells from PLWH with SARS-2-OS protein did not upregulate the expression of the aforementioned markers. Additionally, the frequencies of NK cells expressing the activation markers CD25 and CD69 in PLWH were significantly lower than those in HCs at 0, 4 and 12weeks, but the percentage of CD16 + NK cells in PLWH was significantly higher than that in HCs at 2, 4 and 12weeks after the third dose of vaccine. Interestingly, the frequency of CD16 + NK cells was significantly negatively correlated with the proportion of CD107a + NK cells in PLWH at each time point after the third dose. Similarly, this phenomenon was also observed in HCs at 0, 2, and 4 weeks after the third dose. Finally, regardless of whether NK cells were stimulated with SARS-2-OS or not, we did not observe any differences in the expression of NK cell degranulation markers between PLWH and HCs. s:SARS-CoV-2 vaccine elicited activation and degranulation of NK cells, indicating that the inoculation of SARS-CoV-2 vaccine enhances NK cell immune response.

Reduced fertility in an adenomyosis mouse model is associated with an altered immune profile in the uterus during the implantation period.

Does a reduction in fertility and/or systemic immune cell change occur during the early implantation period in a mouse model of adenomyosis? A reduction in fertility was observed in mice with adenomyosis, coinciding with local and systemic immune changes observed during the implantation period. Adenomyosis is a pathology responsible for impaired fertility in humans, with a still unclear pathophysiology. One hypothesis is that changes in immune cells observed in adenomyosis-affected uteri may alter fertility, notably the physiological immune environment necessary for successful implantation and a healthy pregnancy. Randomly selected CD-1 female neonatal pups were orally dosed by administration of tamoxifen to induce adenomyosis (TAM group), while others received solvent only (control group). From 6 weeks of life, CD-1 mice of both groups were mated to study impaired fertility and related local and/or systemic immune cell changes during the early implantation period. To evaluate fertility and pregnancy outcomes, ultrasound imaging was performed at E (embryonic day) 7.5 and E11.5 to count the number of gestational sacs and the number of resorptions in eight mice of the TAM group and 16 mice of the control group. The mice were sacrificed at E18.5, and morphometric, functional (quantitative reverse transcription PCR; RT-qPCR), and histological analyses were performed on the placentas. To identify local and/or systemic immune changes during the early implantation period, 8 mice of the TAM group and 12 mice of the control group were sacrificed at E4.5. Uterine horns and spleens were collected for flow cytometry and RT-qPCR analyses to study the immune cell populations. To investigate the profile of the cytokines secreted during the early implantation period at the systemic level, supernatants from stimulated spleen cells were analyzed by multiplex immunoassay analysis. By ultrasound imaging, we observed a lower number of implantation sites (P < 0.005) and a higher number of resorptions (P < 0.001) in the TAM group, leading to smaller litters (average number of fetuses per litter: 1.00 [0.00; 5.25] in the TAM group versus 12.00 [9.50; 13.75] in the control group (P < 0.001). Histological and morphometric analyses of the placentas at E18.5 showed a higher junctional/labyrinthine area ratio in the TAM group (P = 0.005). The expression levels of genes that play a role in vascularization and placental growth (Vegf (P < 0.001), Plgf (P < 0.005), Pecam (P < 0.0001), and Igf2 (P = 0.002)) were reduced in the TAM group. In the TAM group, the percentages of macrophages, natural killer (NK) cells, and dendritic cells (DC) were significantly decreased in the uterus around the implantation period. However, the number of M1 macrophages was increased. Both macrophages and DC had an increased activation profile (higher expression of MCHII, P = 0.012; CD80, P = 0.015; CCR7, P = 0.043 for macrophages, and higher expression of CD206, P = 0.018; CXCR4, P = 0.010; CCR7, P = 0.006, MCHII, P = 0.010; and CD80, P = 0.012 for DC). In spleen, an increase in the activation of macrophages (CCR7, P = 0.002; MCHII, P = 0.001; and CD80, P = 0.034) and DC was observed in the TAM group (CCR7, P = 0.001; MCHII, P = 0.001; Ly6C, P = 0.015). In the uteri and the spleen, we observed increased percentages of CD4+ T lymphocytes (P = 0.0237 and P = 0.0136, respectively) in the TAM group and, in the uteri, an increased number of regulatory T cells (P = 0.036) compared with the controls. Not applicable. This study is limited by the use of an animal model and the lack of intervention. These data support involvement of innate and adaptive immune cells in the implantation failure and the increased rate of resorption observed in the mouse model of adenomyosis. This substantiates the need for additional research in this domain, with the goal of addressing fertility challenges in women affected by this condition. None.

Inhalation of Citrus Reticulata essential oil alleviates airway inflammation and emphysema in COPD rats through regulation of macrophages

Ethnopharmacological relevanceChronic obstructive pulmonary disease (COPD) is a chronic inflammatory respiratory disease. Citrus Reticulata peel, the dried ripe peel of Citrus Reticulata species, has been found to have anti-inflammatory and cough attenuation effects. However, the therapeutic effects and its precise underlying mechanisms of atomizing inhalation using Citrus Reticulata essential oil (CREO) have not yet been fully elucidated. Aim of the studyThe aim of this study was to assess the therapeutic effects of Citrus Reticulata essential oil and its associated anti-inflammatory mechanisms in COPD rat model. MethodsA total of 80 SD rats were randomized into four groups: control group (Con), COPD model group (COPD), COPD + ipratropium bromide (IB), and COPD + citrus reticulata essential oil (CREO). To induce COPD in rats, cigarette smoke (CS) exposure was used, while CREO and IB groups were administered through atomizing inhalation. The clinical signs, pathological lesions of the lung, percentages of antigen-presenting lung macrophages (CD11b/c+/CD86+ cells) and CD8+ T cells, and the content and mRNA expression of cytokines of the lung were analyzed. ResultsThe findings revealed that atomizing inhalation of Citrus reticulata essential oil had therapeutic effects on COPD rats. The treatment resulted in improvement in the body weight and mental status of COPD rats, reduced pathological injury of the lung, and increased proportion of CD11b/c+/CD86+ cells in lung macrophages, while also decreasing the number of CD8+ T cells. In addition, the Citrus Reticulata essential oil reduced the contents of IL-18, IL-17A, IL-12p70, and GM-CSF, downregulated the relative mRNA expression of IFN-γ, IL-4, and MMP-12, and upregulated the mRNA expression of IL-10. ConclusionsCitrus reticulata essential oil can alleviate histological injury of the lung and regulate macrophages and CD8+ T cells in COPD rats. The study suggests that citrus reticulata essential oil could be a potential therapeutic agent for COPD.

Circulating memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio predict response and outcome to immunotherapy in advanced gastric cancer patients

BackgroundLimited benefit population of immunotherapy makes it urgent to select effective biomarkers for screening appropriate treatment population. Herein, we have investigated the predictive values of circulating CD8+ T cells and CD8+T/CD4+T cell ratio in advanced gastric cancer patients receiving immunotherapy.MethodsA retrospective cohort analysis of 187 advanced gastric cancer patients receiving sintilimab combined with oxaliplatin and capecitabine therapy in The Affiliated Xinghua People’s Hospital, Medical School of Yangzhou University between December 2019 and February 2023 was conducted. The corresponding clinical outcomes of the variables were analyzed by receiver operating characteristic (ROC) curve, chi-square test, Kaplan–Meier methods and Cox proportional hazards regression models.ResultsThe optimal cutoff values for percentages of CD8+ T cells, naive CD8+ T cells (CD8+ Tn) and memory CD8+ T cells (CD8+ Tm) expressing programmed cell death -1(PD-1) as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were 21.0, 21.5, 64.3 and 0.669, respectively. It was found that the mean percentages of CD8+ T and CD8+ Tm expressing PD-1 as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were significantly higher in responder (R) than non-responder (NonR) advanced gastric cancer patients associated with a longer progression free survival (PFS) and overall survival (OS). We also observed this correlation in programmed cell death-ligand 1(PD-L1) combined positive score (CPS) ≥ 5 subgroups. Univariate and multivariate Cox regression analyses demonstrated that lower CD8+ T and CD8+ Tm expressing PD-1 as well as PD-1+CD8+T/PD-1+CD4+T cell ratio were independent risk factors in advanced gastric cancer patients receiving immunotherapy plus chemotherapy.ConclusionThe circulating memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio revealed high predictive values for response and prolonged survival outcomes in advanced gastric cancer patients receiving immunotherapy. Memory PD-1+CD8+ T cells and PD-1+CD8+T/PD-1+CD4+T cell ratio might be effective for screening benefit population of immunotherapy in advanced gastric cancer patients based on this preliminary evidence.

Lifespan Socioeconomic Context Is Associated With Cytomegalovirus and Late-Differentiated CD8 + T and Natural Killer Cells: Initial Results in Older Adults.

Lower socioeconomic status (SES) can accelerate immune aging; however, it is unknown whether and how lifespan socioeconomic context (SEC)-the relative wealth and quality of the communities an individual lives in across their lifespan-impacts immune aging. We examined the effects of childhood and adulthood SEC on late-differentiated immune cells and investigated the mediating and moderating role of cytomegalovirus (CMV), a key driver of immune aging. Adults 60 years and older ( N = 109) reported their addresses from birth to age 60 years, which were coded for county-level employment, education, and income to construct a latent SEC variable, averaged across ages 0 to 18 years (childhood SEC) and 19 to 60 years (adulthood SEC). Blood was drawn semiannually for 5 years for CMV serostatus and flow cytometry estimates of late-differentiated CD8 + T and natural killer cells. Models were adjusted for chronological age, time, sex, and individual SES (current income and education). Lower childhood SEC was associated with higher percentages of late-differentiated CD8 + T and natural killer cells via CMV seropositivity (indirect effects, p values = .015-.028). In addition, an interaction between CMV serostatus and SEC on CD8 + T-cell aging ( p = .049) demonstrated that adulthood SEC was negatively associated with immune aging among CMV- but not CMV+ adults. Beyond current SES, SEC related to immune aging in distinct patterns by lifespan phase. Lower childhood SEC importantly may influence who acquires CMV, which in turn predicts higher levels of immune aging, whereas higher adulthood SEC was protective against immune aging among CMV- older adults. These initial results need to be explored in larger samples.

CTIM-36. IMMUNOHISTOCHEMISTRY EVALUATION ON PRE-TREATMENT TUMOR TISSUE PREDICTS TREATMENT RESPONSE TO MN-166 (IBUDILAST) AND TEMOZOLOMIDE COMBINATION THERAPY IN GLIOBLASTOMA PATIENTS

Abstract STUDY DESIGN MN-166-GBM-1201 is a Phase I/II open-label clinical trial to evaluate MN166 (ibudilast) and temozolomide (TMZ) combination treatment in newly diagnosed and recurrent glioblastoma (GBM) patients. 62 GBM patients (34 newly diagnosed and 28 recurrent) were enrolled in the study. All patients received MN-166 and TMZ combination treatment until disease progression or withdrawal from the study for other reasons. METHODS Pre-treatment tumor tissue at initial surgery from 24 study participants was evaluated to determine potential predictors of response to MN-166, which has been shown to inhibit the interaction between macrophage migration inhibitory factor (MIF) and CD74 with ERK phosphorylation downstream of CD74. We looked at CD11b and CD3 expression to characterize the immune profile within the tumors and Ki67 to determine percentage of proliferating tumor cells, all of which were calculated by a masked researcher. Then, patients were stratified based on progression within the first five months after receiving MN-166 and TMZ. RESULTS Patients who did not progress within 5 months had a significantly lower percentage of CD3+ T cell infiltration than nonresponding patients (p = 0.045), and CD74 expression was lower in patients with no progression (p = 0.16). The other markers demonstrated no differences. MN-166 and TMZ combination therapy was generally safe and well tolerated. CONCLUSION CD3 expression was a good predictor for tumor progression for five months in recurrent GBM patients treated with MN-166 and TMZ. T cell infiltration within GBM tumors has been an active area of research with the success of immune checkpoint blockade (ICB) therapies in other cancers. Moreover, MN-166 has been shown to impact immune suppressive myeloid cells, which are linked to the immune suppressive tumor microenvironment and a resistance mechanism to ICB. Collectively, we postulate that the efficacy of MN-166 for treatment of GBM could be further enhanced by co-treatment with ICBs.

Memory T Cells Discrepancies in COVID-19 Patients.

The immune response implicated in Coronavirus disease 2019 (COVID-19) pathogenesis remains to be fully understood. The present study aimed to clarify the alterations in CD4+ and CD8+ memory T cells' compartments in SARS-CoV-2-infected patients, with an emphasis on various comorbidities affecting COVID-19 patients. Peripheral blood samples were collected from 35 COVID-19 patients, 16 recovered individuals, and 25 healthy controls, and analyzed using flow cytometry. Significant alterations were detected in the percentage of CD8+ T cells and effector memory-expressing CD45RA CD8+ T cells (TEMRA) in COVID-19 patients compared to healthy controls. Interestingly, altered percentages of CD4+ T cells, CD8+ T cells, T effector (TEff), T naïve cells (TNs), T central memory (TCM), T effector memory (TEM), T stem cell memory (TSCM), and TEMRA T cells were significantly associated with the disease severity. Male patients had more CD8+ TSCMs and CD4+ TNs cells, while female patients had a significantly higher percentage of effector CD8+CD45RA+ T cells. Moreover, altered percentages of CD8+ TNs and memory CD8+CD45RO+ T cells were detected in diabetic and non-diabetic COVID-19 patients, respectively. In summary, this study identified alterations in memory T cells among COVID-19 patients, revealing a sex bias in the percentage of memory T cells. Moreover, COVID-19 severity and comorbidities have been linked to specific subsets of T memory cells which could be used as therapeutic, diagnostic, and protective targets for severe COVID-19.

Cytomegalovirus-Specific T Cells in Pediatric Liver Transplant Recipients.

Cytomegalovirus (CMV) infection is a major opportunistic infection after liver transplantation (LT) that necessitates monitoring. Because of the lack of studies in children, we aimed to investigate CMV-specific T cell immune reconstitution among pediatric LT recipients. The recipients were monitored for CMV infection and CMV-specific T cells from the start of immunosuppressive therapy until 48 weeks after LT. Clinically significant CMV viremia (csCMV) requiring preemptive therapy was defined as a CMV load of >2000 IU/mL. Peripheral blood CMV-specific T cells were analyzed by flow cytometry based on IFNγ secretion upon stimulation with CMV antigens including immediate early protein 1 (IE1) Ag, phosphoprotein 65 (pp65) Ag, and whole CMV lysate (wCMV). Of the 41 patients who underwent LT, 20 (48.8%) had csCMV. Most (17/20 patients) were asymptomatic and characterized as experiencing CMV reactivation. The onset of csCMV occurred approximately 7 weeks after LT (interquartile range: 4-12.9); csCMV rarely recurred after preemptive therapy. Lower pp65-specific CD8+ T cell response was associated with the occurrence of csCMV (p = 0.01) and correlated with increased viral load at the time of csCMV diagnosis (ρ = -0.553, p = 0.02). Moreover, those with csCMV had lower percentages of IE1-specific CD4+ and wCMV-reactive CD4+ T cells at 12 weeks after LT (p = 0.03 and p = 0.01, respectively). Despite intense immunosuppressive therapy, CMV-specific T cell immune reconstitution occurred in pediatric patients post-LT, which could confer protection against CMV reactivation.

CD84 (SLAMF5) As a Potential Target for Immunomodulation in Cutaneous T-Cell Lymphoma (CTCL)

Background: Cutaneous T-cell lymphoma (CTCL) develops from clonally expanded, skin-homing CD4 + T cells within a background of chronic inflammation. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of CTCLs. Patients with advanced-stage MF/SS experience progressively worsening disease and decreased overall survival (Scarisbrick et al., 2015). Immune cells and immune checkpoints (ICs) are essential factors for tumor growth and the host immune response in CTCL. Tumor-associated macrophages (TAMs [M2-like]) play a key role in CTCL growth, and neoplastic T cells escape immune surveillance via the PD-L1/PD1 axis (Wu et al., 2014). However, the approach of ICs inhibition with monoclonal antibodies (mAbs) in CTCL has been challenged due to modest efficacy and remaining immunosuppression. Hence, novel therapeutic strategies are needed to improve anti-tumor immunity in CTCL. We previously characterized CD84 (SLAMF5) as one of the key players in the tumor microenvironment (TME) by regulating multiple ICs, including PD-L1 and PD1, and modulating myeloid cell fractions and T cells in our preclinical MM models. Our CD84 targeting strategy using anti-CD84 mAb significantly reduced PD1 on effector CD8 + T cells and PD-L1 on the tumor and myeloid cells, decreased tumor burden, and increased the survival of the mice with myeloma (Lewinsky and Gunes et al., 2021). The role of CD84 in ICs regulation and anti-tumor immunity in CTCL remains to be explored. Methods and Results: In this study, we evaluated the role of CD84 in CTCL and, for the first time, reported CD84 as a potential target to reduce immunosuppression through the PD-L1/PD1 axis in CTCL. We found upregulated CD84 CD274 (PD-L1) , and PDCD1 (PD1) gene expressions in CTCL patients (n=5) compared to healthy individuals (n=4). We also noted higher CD84 geneexpression in SS patients (n=8) than in MF patients (n=6). We next evaluated CD84 expression on the formalin-fixed paraffin-embedded (FFPE) tumor sections derived from SS patients' skin lesions. We noted that CD84 is highly expressed in the TME and co-expressed in Ki67 + Sézary cells. We further evaluated the CD84 expression in immune cell clusters in SS patients and healthy individuals using publicly available single-cell RNA sequencing (scRNA-seq) datasets. We noted a profound CD84 expression in CD4 + T cells and CD163 + M2-like macrophages in SS patients. We also noted a strong correlation between CD84 and CD274 (p=0.0086) and CD84 and PDCD1 (p=0.0002) in SS patients. We next assessed the expressions of CD84, PD-L1 on CD163 + M2-like macrophages, and PD1 on T cell subsets in a coculturing setting with human SS cell line, Hut78, to determine the impact of Sézary cells on these cell compartments in the TME. We observed a significant increase in the percentages of CD163 + M2-like macrophages and CD4 + T cells and elevated CD84, PD-L1, and PD1 expressions on these cells following the coculturing of peripheral blood mononuclear cells (PBMCs) derived from healthy donors (HDs) with Hut78 cells (n=3, *P &amp;lt; 0.05, **P &amp;lt; 0.01). While the percentages of CD8 + T cells were slightly reduced, CD84 and PD1 expressions were elevated in these cells following the coculturing with Hut78 cells (n=3, *P &amp;lt; 0.05, ***P &amp;lt; 0.001). Dysregulation of STAT proteins, particularly STAT3, has been shown in MF/SS (Olszewska et al., 2020). To explore whether Sézary cells regulate STAT3 in CD163 + M2-like macrophages, we assessed pSTAT3 levels in CD163 + M2-like macrophages following the coculturing of HDs PBMCs with Hut78 cells. We found that Hut78 cellssignificantly increased intracellular pSTAT3 levels inCD163 + M2-like macrophages (n=3, *P &amp;lt; 0.05). Furthermore, we noted the inhibition of STAT signalingusing a pan-STAT inhibitor decreased PD-L1 and PD1 expression onCD163 + M2-like macrophages and T-cell subsets, respectively. Notably, we found the stimulation of CD84 signaling with an agonist anti-CD84 mAb enhanced pSTAT3 levels in CD163 + M2-like macrophages, suggesting the STAT pathway might regulate PD-L1 expression in immunosuppressive CD163 + M2-like macrophages through CD84 signaling in SS. Conclusion: Our preliminary data from this exploratory study indicate that CD84 may be a potential target to reduce immunosuppression in CTCL. Further studies are needed to explore the functions of CD84 as an immune receptor in CTCL TME and its therapeutic potential in CTCL.

The signature and predictive value of immune parameters in patients with secondary hemophagocytic lymphohistiocytosis

BackgroundSecondary hemophagocytic lymphohistiocytosis (sHLH) is a rare but fatal clinical syndrome, characterized by severe immune dysfunction and overwhelming inflammatory response. However, the host immune signature and also its role in predicting the clinical outcome are not fully described. ObjectiveThe present study aims to investigate the host immune status of sHLH patients in the early stage of the disease, including lymphocyte subsets, phenotypes and cytokines, and also to explore its clinical value in prognosis. MethodsSixty-four patients with sHLH admitted to a tertiary hospital in central China between 2018 and 2022 were enrolled, of which 21 were deceased. The subsets and phenotypes of lymphocytes, and the levels of cytokines in serum were analyzed. ResultsIn patients with sHLH, the percentages of total T cells, CD8+ T cells, HLA-DR+ T cells, HLA-DR+CD8+ T cells, CD45RO+CD4+ T cells, and the levels of IL-1β, IL-2R, IL-6, IL-8, IL-10 and TNF-α were significantly increased, while the percentages of CD4+ T cells, NK cells, CD45RA+CD4+ T cells, CD45RA+ regulatory T (Treg) cells, the counts of total T cells, total B cells, CD4+ T cells, CD8+ T cells, NK cells, and the ratio of CD4+ T/CD8+ T cells were significantly decreased, compared with healthy controls (HC). In addition, dysregulation of host immune response and high inflammatory status were more obvious in deceased patients than that of survivors. Kaplan-Meier survival analysis and multivariate logistic regression analysis demonstrated that lower levels of CD4+ T cells count and CD28+CD4+ T cells percentage, but higher levels of NK cells percentage and IL-1β were poor prognostic indicators of sHLH. ConclusionThe evaluation of immunological markers has critical value for selecting prognostic markers and potential treatment target among adults with sHLH.

Characteristics and prognostic implications of peripheral blood lymphocyte subsets in patients with anti-MDA5 antibody positive dermatomyositis-interstitial lung disease

ObjectivesTo examine the characteristics of blood lymphocyte subsets in dermatomyositis-interstitial lung disease (DM-ILD) inflicted patients with positive anti-melanoma differentiation-associated gene 5 (anti-MDA5), as well as its prognosis value in this set of patients.MethodsData were retrospectively collected from 253 DM-ILD patients from three hospitals in China between January 2016 to January 2021. Patients were grouped into anti-MDA5 antibody positive group (MDA5+ DM-ILD) and anti-MDA5 antibody negative group (MDA5− DM-ILD) based on myositis-specific autoantibody test results. Demographic characteristics, lymphocyte subsets patterns and other clinical features were compared between the two groups. The association of lymphocyte subsets with 180-day mortality was investigated using survival analysis in MDA5+ DM-ILD.ResultsOut of 253 eligible patients with DM-ILD, 59 patients were anti-MDA5+ and 194 were anti-MDA5−. Peripheral blood lymphocyte count, CD3+ count, percentage of CD3+, CD3+CD4+ count, and CD3+CD8+ count was lower in MDA5+ DM-ILD than in MDA5− DM-ILD− (all P < 0.001) as well as CD3−CD19+ count (P = 0.04). In MDA5+ DM-ILD, CD3+CD8+ count ≤ 49.22 cell/μL (HR = 3.81, 95%CI [1.20,12.14]) and CD3-CD19+ count ≤ 137.64 cell/μL (HR = 3.43, 95%CI [1.15,10.24]) were independent predictors of mortality. CD3+CD8+ count ≤ 31.38 cell/μL was associated with a higher mortality risk in all DM-ILD patients (HR = 8.6, 95%CI [2.12,31.44]) after adjusting for anti-MDA5 and other clinical characteristics.ConclusionSignificant lymphocytes decrease was observed in MDA5+ DM-ILD patients. CD3+CD8+ cell count was associated with worse prognosis in both MDA5+ DM-ILD and all DM-ILD patients.

Association of the CD28 markers with the disease activity in systemic lupus erythematosus patients

Background: Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with diverse manifestations and unpredictable activity. CD28 markers, particularly sCD28, is a promising biomarker for evaluating SLE disease activity. This study aimed to investigate the significance of CD28 markers in evaluating disease activity in SLE and the role of sCD28 in various clinical manifestations. Methods: A total of 40 female subjects, aged between 18 and 45 years, who fulfilled the 2019 EULAR/ACR classification criteria for SLE were recruited in this study. Twenty healthy matched individuals were also recruited as control. Comprehensive data on demographic information, clinical manifestations, laboratory test findings, and treatment history were collected from all participants. The Indonesian version of SLEDAI-2K score was utilized to assess disease activity, categorizing patients into active SLE and lupus low disease activity (LLDAS). Collected data were analyzed on SPSS for Windows version 25.0. Results: Patients with SLE in LLDAS category had significantly lower SLEDAI scores (1.8 ± 1.4 vs 11.7 ± 4.9, p&lt;0.001) with mild clinical manifestation. Active SLE patients had the lowest percentages of CD4+CD28+ cells (5.7 ± 4.1%) and the highest sCD28 concentration (26.2 ± 11.3 ng/ml) compared to other groups. Moreover, sCD28 concentration demonstrated a moderate positive correlation with SLE disease activity. In most cases, higher sCD28 concentrations were associated with clinical manifestations, particularly in neuropsychiatric lupus (OR 7.1 [1.8 – 67.9], p=0.047), nephritis (OR 14.5 [1.6 – 131.9], p=0.017), and mucocutaneous manifestations (OR 3.4 [1.9 – 12.8], p=0.035). Conclusions: Our study establishes the link between CD28 markers and disease activity, including certain clinical manifestations in SLE. We suggest that CD28 has a potential role in predicting disease activity. However, further research through longitudinal studies is required to strengthen these findings.

Histamine H4 Receptor Antagonist Ameliorates the Progression of Experimental Autoimmune Encephalomyelitis via Regulation of T-Cell Imbalance.

Multiple sclerosis (MS) is a degenerative condition characterized by immune-mediated attacks on the central nervous system (CNS), resulting in demyelination and recurring T-cell responses. The histamine H4 receptor (H4R) is mainly expressed in cellular populations and plays a vital role in inflammation and immunological responses. The role of H4R in neurons of the CNS has recently been revealed. However, the precise role of H4R in neuronal function remains inadequately understood. The objective of this work was to investigate the impact of JNJ 10191584 (JNJ), a highly effective and specific H4R antagonist, on the development of experimental autoimmune encephalomyelitis (EAE) and to gain insight into the underlying mechanism involved. In this study, we examined the potential impact of JNJ therapy on the course of EAE in SJL/J mice. EAE mice were administered an oral dose of JNJ at a concentration of 6 mg/kg once a day, starting from day 10 and continuing until day 42. Afterward, the mice's clinical scores were assessed. In this study, we conducted additional research to examine the impact of JNJ on several types of immune cells, specifically Th1 (IFN-γ and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A and RORγt), and regulatory T (Tregs; Foxp3 and TGF-β1) cells in the spleen. In this study, we further investigated the impact of JNJ on the mRNA expression levels of IFN-γ, T-bet, IL-9, IRF4, IL-17A, RORγt, Foxp3, and TGF-β1 in the brain. Daily treatment of JNJ effectively reduced the development of EAE in mice. The percentages of CD4+IFN-γ+, CD4+T-bet+, CD4+IL-9+, CD4+IRF4+, CD4+IL-17A+, and CD4+RORγt+ cells were shown to decrease, whereas the percentages of CD4+TGF-β1+ and CD4+Foxp3+ cells were observed to increase in EAE mice treated with JNJ. Therefore, the HR4 antagonist positively affected the course of EAE by modulating the signaling of transcription factors. The identified results include possible ramifications in the context of MS treatment.

OX40 (CD134) Expression on T Regulatory Cells Is Related to Serious Hypertensive Disorders in Pregnancy.

Hypertension is one of the leading causes of morbidity and mortality among women related to pregnancy, childbirth and the postpartum period. The pathogenesis of gestational hypertension is complex and still not fully understood. The aim of this study was to assess the population of circulating CD4+CD25+FoxP3+ cells and its differentiation in terms of OX40 expression in two forms of hypertension: isolated hypertension developing after the 20th week of pregnancy and pre-eclampsia. The study included a group of 60 patients with hypertension and 48 healthy controls. The analysis of the percentage of Tregs was performed by flow cytometry. There was no difference in the percentage of peripheral lymphocytes between the groups. In the group of women with preeclampsia compared to the group with gestational hypertension, significantly higher percentages of CD4+CD25+FoxP3+ cells (p = 0.03) and percentages of CD4+CD25+FoxP3+ cells expressing the OX40 antigen (p = 0.001) were observed. OX40 expression on Tregs seems to be related to more serious type of hypertensive disorders in pregnant women.

Definition of follicular helper T cell and cytokines expression in synovial fluid of rheumatoid arthritis.

This study aimed to assess the role of synovial fluid (SF) CD4+T, CD19+B, follicular helper cells (Tfh), and cytokines in the pathogenesis of rheumatoid arthritis (RA). This study enrolled 16 patients with RA and 8 patients with osteoarthritis (OA). The frequencies of the SF CD4+ T, CD19+ B, Tfh cells, and Tfh subsets were assessed using flow cytometry. The medical condition in patients with RA was evaluated using The Disease Activity Score 28 (DAS28), the Clinical Disease Activity Index (CDAI), and the Simplified Disease Activity Index (SDAI). Levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-cyclic citrullinated peptide (anti-CCP), and rheumatoid factor (RF) were measured. The cytokines IL-4, IL-13, IL-21, and BLyS were measured by ELISA test. The percentages of SF CD4+T, CD19+B, and PD-1+CXCR5+ Tfh in RA patients were higher than those in OA patients. And the Tfh2 was the main subset among Tfh subsets. In addition, levels of IL-21 and BLyS were higher in patients with RA compared to patients with OA. Furthermore, the treatment of TNF-α inhibitors may be associated with decreased levels of SF Tfh. Elevated SF Tfh, B cell, and cytokines expression profiles were observed in RA patients. Tfh2 was the major subset of the Tfh, and IL-21 and BLyS were significantly enhanced. Additionally, TNF-α inhibitors reduced Tfh in SF. Therefore, Tfh, B, and Tfh2 cells could play a significant role in the progression of RA. Key Points •Tfh cells in the synovial fluid are significantly higher in RA patients and are dominated by the Tfh2 subpopulation. •Synovial fluid Tfh cells decrease in RA patients after anti-TNF-α treatment.

Cluster of differentiation 4/cluster of differentiation 8 ratio of T-lymphocyte subsets in Egyptian patients with severe pre-eclampsia

This study was designed to evaluate the immunological role of CD4+Tcells, CD8+ T cells in the pathogenesis of severe pre-eclampsia. Consequently, we estimated their blood levels and the CD4+/CD8+Tcells ratio among patients with pre-eclampsia. The study included 50 primigravid patients in third trimester, recruited from El-Shatby Maternity University Hospital. After obtaining informed written consents, they were divided into two groups: Group A included 25 patients with severe pre-eclampsia, and Group B included 25 normal pregnant women. All patients underwent thorough history taking, complete clinical examination and ultrasound evaluation for fetal condition. Then the percentages of blood CD4+ T cells and CD8+ T cells were estimated via flow cytometry and CD4+/CD8+ T cells ratio was calculated. Patients with severe pre-eclampsia in Group A revealed an increase in CD4+ T cells and a decrease of CD8+ T cells together with an increase in CD4+/CD8+ T cells ratio in comparison with the normal pregnancy (Group B). These differences were statistically significant (p=0.041, p=0.0001 and, p=0.0001, respectively). In addition, there was a positive correlation of blood CD4+ T cells, CD8+ T cells, CD4/CD8 T cells ratio and severe pre-eclampsia. In conclusion, estimation of the percentage of CD4+ T cells, CD8+ T cells and their ratio may be used as a marker to predict pre-eclampsia and confirm its severity.

Innate immune dysregulation in multisystem inflammatory syndrome in children (MIS-C)

MIS-C is a systemic inflammation disorder with poorly characterised immunopathological mechanisms. We compared changes in the systemic immune response in children with MIS-C (n = 12, 5–13 years) to healthy controls (n = 14, 5–15 years). Analysis was done in whole blood treated with LPS. Expression of CD11b and Toll-like receptor-4 (TLR4) in neutrophils and monocytes were analysed by flow cytometry. Serum cytokines (IL-1β, IL-2, IL-6, IL-8, IL-10, IL-Ira, TNF-α, TNF-β, IFN-Υ, VEGF, EPO and GM-CSF) and mRNA levels of inflammasome molecules (NLRP3, ASC and IL-1β) were evaluated. Subpopulations of lymphocytes (CD3+, CD19+, CD56+, CD4+, CD8+, TCR Vδ1+, TCR Vδ2+) were assessed at basal levels. Absolute counts of neutrophils and NLR were high in children with MIS-C while absolute counts of lymphocytes were low. Children with MIS-C had increased levels of IL-6, IL-10, TNF-β and VEGF serum cytokines at the basal level, and significantly increased TNF-β post-LPS, compared to controls. IL-1RA and EPO decreased at baseline and post-LPS in MIS-C patients compared to controls. The percentage of CD3+ cells, NK cells and Vδ1 was lower while B cells were higher in children with MIS-C than in controls. Dysregulated immune response in children with MIS-C was evident and may be amenable to immunomodulation.

Clinical implications of aberrant PD-1 expression for acute leukemia prognosis

BackgroundAcute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the most common types of leukemia in adults with an overall poor prognosis. PD-1 alone or combined with other immune checkpoint blockade is a promising research direction for the treatment of acute leukemia (AL) patients. However, clinical Implications of aberrant PD-1 expression in peripheral CD4+ and CD8+ T lymphocytes of AML and ALL patients in assessing the prognosis of diseases, remains inconclusive.MethodsIn the present study, we used flow cytometry to evaluate PD-1 expression on the surface of CD4+ and CD8+ T lymphocytes in the peripheral circulation of AML and ALL patients and its clinical significance. A total of 53 AML patients, 44 ALL patients and 28 healthy controls were enrolled in this study and peripheral blood specimens were detected by flow cytometry.ResultsOur results indicated that percentages of CD4+ PD1+ and CD8+ PD1+ T lymphocytes in newly diagnosed and non-remission groups were significantly higher than healthy control both in AML and ALL patients. The high level of CD4+ PD1+ and CD8+ PD1+ T lymphocytes were respectively poor prognostic indicators of AML patients and ALL patients but had no significant correlation with most common clinical risks.ConclusionsOur findings show that aberrant PD-1 expression correlates with the prognosis of AL patient and may thus serve as poor prognostic indicators. Immunotherapy using PD-1 inhibitors may be a promising strategy for AML and ALL patients with peripheral circulating CD4+ PD1+ and CD8+ PD1+ T lymphocytes positively expressed, respectively.

Cardiac progenitor cells-derived exosomes alleviate myocardial injury by regulating Treg cell differentiation through the mTOR pathway in mice with myocardial infarction

To investigate the effect of cardiac progenitor cells-derived exosomes (CPCs-Exo) on Treg differentiation in mice with myocardial infarction (MI). Mouse models of MI established by ligation of the left anterior descending coronary artery (LAD) were treated with CPCs-Exos, and naive CD4+T cells were isolated from the spleen of the mice and divided into control group, CD4+T cell activation group (CD3+CD28), CPCs-Exos stimulation group (CD3+CD28+CPCs-Exos), mTOR activator group (CD3+CD28+CPCs-Exos+mTOR activator) and mTOR inhibitor group (CD3+CD28+CPCs-Exos+mTOR inhibitor). Western blotting was used to detect the expression levels of mTOR and p-mTOR in the treated cells. Flow cytometry was used to analyze the percentages of Treg and CD4+IL-10+T cells. The infarct size of the mice were measured with 2, 3, 5-triphenyltetrazole chloride (TTC) staining, and serum levels of LDH and CK-MB were detected using an automatic biochemical analyzer. Compared with the control group, the mouse models of MI showed significantly increased release of LDH (P<0.001) and CK-MB (P=0.0002) and increased percentages of Treg and CD4+IL-10+T cells. Treatment with CPC-Exos effectively reduced the MI area and lowered serum levels of LDH (P=0.003) and CK-MB (P=0.003) and the percentages of Tregs (P=0.001) and CD4+IL-10+T cells (P=0.004) in the MI mouse models. In the isolated CD4+T cells, CPCsExos treatment significantly up-regulated the percentages of Treg (P=0.01) and CD4+IL-10+ T cells (P=0.004) and increased the expression of mTOR (P=0.009) and p-mTOR (P=0.009), and these effects could be further enhanced by the mTOR activator but obviously attenuated by the mTOR inhibitor. CPCs-Exos promotes the differentiation of Treg in mice with MI by modulating the mTOR signaling pathway.

PD-L1 and PD-1 expression in pediatric post-transplant Burkitt lymphoma and other monomorphic post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLD) develop as a consequence of immune suppression. Programmed death protein 1 (PD-1), a regulator of host immune activation, binds to programmed death-ligand 1 (PD-L1) to suppress the T-cell immune response. PD-1/PD-L1 pathway may play a role in PTLD. The objective was to describe intratumoral expression of PD-L1 and PD-1 in pediatric monomorphic PTLD, and assess if density of these cells is associated with progression-free survival (PFS) and overall survival (OS). Clinical variables and outcome data were collected on B-cell monomorphic PTLD treated in Toronto, Canada between 2000 and 2017. Diagnostic area from tumor tissue was identified to count CD3-positive or PD-1-positive cells and CD3-negative lymphoma B cells or PD-L1-positive cells. CD3+ , PD-1+ , and PD-L1+ cell densities were compared between cases of PTLD. OS and PFS were analyzed. We identified 25 cases of B-cell monomorphic PTLD; majority Burkitt lymphoma (32%) and diffuse large B-cell lymphoma (56%). All cases had CD3+ cells infiltrating the tumor, and median percentage of CD3+ cells was 14% (interquartile range: 6.2%-25%). Twelve cases (48%) had PD-1+ cell infiltrating (range: 1%-83%) and 13 cases (52%) had no PD-1+ cells infiltrating. Sixteen cases (64%) had PD-L1+ cells present; however, there was no PD-L1 expression on any Burkitt lymphoma tissue. When comparing PD-1 and PD-L1 expression, there was no difference in OS or PFS. Intratumoral presence of PD-1+ and PD-L1+ cells varied in pediatric patients with monomorphic PTLD; however, no relationship to OS and PFS was identified.