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Chlamydia trachomatis imposes serious health problems and causes infertility. Because of asymptomatic onset, it often escapes antibiotic treatment. Therefore, vaccines offer a better option for the prevention of unwanted inflammatory sequelae. The existence of serologically distinct serovars of C. trachomatis suggests that a vaccine will need to provide protection against multiple serovars. Chlamydia spp. use a highly conserved type III secretion system (T3SS) composed of structural and effector proteins which is an essential virulence factor. In this study, we expressed the T3SS needle protein of Chlamydia muridarum, TC_0037, an ortholog of C. trachomatis CdsF, in a replication-defective adenoviral vector (AdTC_0037) and evaluated its protective efficacy in an intravaginal Chlamydia muridarum model. For better immune responses, we employed a heterologous prime-boost immunization protocol in which mice were intranasally primed with AdTC_0037 and subcutaneously boosted with recombinant TC_0037 and Toll-like receptor 4 agonist monophosphoryl lipid A mixed in a squalene nanoscale emulsion. We found that immunization with TC_0037 antigen induced specific humoral and T cell responses, decreased Chlamydia loads in the genital tract, and abrogated pathology of upper genital organs. Together, our results suggest that TC_0037, a highly conserved chlamydial T3SS protein, is a good candidate for inclusion in a Chlamydia vaccine. [ABSTRACT FROM AUTHOR]

With the great stride forward of socialist progress, various medical treatment measures have also made a leap forward in development, providing a deeper guarantee for people's life safety. At the same time, the research field of nanotechnology has gradually developed in the medical field, which plays an important role in the development of medicine, and massage exercise rehabilitation training also provides convenience for patients' recuperation. The purpose of this study is to study the application of composite NanoBone transplantation in patients with limb replantation and the application of massage exercise rehabilitation training in patients with limb replantation. The methods used in this paper are: consulting the literature to understand the composite NanoBone transplantation technology and massage exercise rehabilitation training methods, interviewing the patients and attending doctors, and asking about the selection method of experiment and questionnaire used in the paper, so as to carry out the questionnaire survey. The treatment group and the control group were set up to analyze the results. The results showed that there were no significant differences in T lymphocyte subsets, serum complement, and circulating immune complex in the replantation of amputated limbs. Combined with the clinical manifestations and pathological results, early rejection occurred, and the body temperature of the patients increased after clinical treatment; The characteristics of massage are not practical, the course of treatment is short, the effect is fast, the clinical operation is simple, easy to grasp, and has high clinical application and promotion value. The final test results showed that: comparing the two groups of patients before treatment, the VAS scores were 23% and 21%, respectively, and the treatment group scores were 23% and 21%, respectively. After treatment, the VAS scores of the test group and the control group were 29 % and 27%, respectively. The treatment group scored 2% higher than the control group. From this, it can be concluded that massage is better than traditional massage, and massage exercise has great application prospects in clinical practice. [ABSTRACT FROM AUTHOR]

Immunohistochemical staining is a common technique to study tissue morphology and in situ protein expression. With the rise of immunotherapy, more and more markers in the tumor microenvironment have been discovered. In this paper, the multiplex immunofluorescence staining method was used to stain paraffin sections of 35 cases of gastric adenocarcinoma tissue and 35 cases of colorectal adenocarcinoma tissue and its adjacent tissue. The infiltration of CD8+ T cells and CD103+CD8+ T cells in the slices was detected by using the slice scanner to form the map and CaseViewer2.0 software analysis. The experimental results in this paper showed that compared with adjacent tissues, the infiltration degree of CD8+ T cells in gastric adenocarcinoma tissue was significantly lower (Z = 2.244 , P = 0.025 , P < 0.05), and the infiltration degree of cells was significantly lower (Z = 2.785 , P = 0.005 , P < 0.05). In gastric adenocarcinoma tissue, the infiltration of CD8+ T cells was correlated with the tumor diameter of gastric adenocarcinoma (P = 0.002). There was a statistically significant difference. The degree of CD103+CD8+ T cell infiltration was related to the survival of patients with gastric adenocarcinoma (P = 0.002) and the degree of tumor differentiation (P = 0.004). The infiltration of CD103+CD8+ T cells in gastric cancer tissue and colorectal cancer tissue is related to the survival of patients. CD103+CD8+ T cells are thought to play a role in the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma. Experiments have shown that the more the CD103+CD8+ T cells, the better the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma, so the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma can be improved by increasing CD103+CD8+ T cells. [ABSTRACT FROM AUTHOR]

Umbilical cord blood (UCB) transplants (UCBTs) are becoming increasingly common in the treatment of a variety of hematologic and nonhematologic conditions. The T cells from UCB are naïve T cells, which have not yet been exposed to antigens and therefore do not contain T cells with specific immune functions against viruses. Cytomegalovirus (CMV) infections occur in more than 80% of patients after UCBT compared to other types of transplantation. Anti-CMV medications are currently restricted, with ganciclovir, foscarnet, and valganciclovir being the most common in China; however, with limited efficacy and considerable side effects, all these drugs are susceptible to viral resistance. In recent years, cytomegalovirus-specific T cells (CMVST) have advanced the treatment of viral infections in immunodeficient patients. CMVST usually uses the same donor as hematopoietic stem cell transplantation. CMVST should be administered to UCBT patients because of the absence of donors after UCBT. In China, there is no report on the use of CMVST to treat CMV infection after UCBT, and foreign reports are also limited. This paper reported a 20-year-old male patient with acute myeloid leukemia who developed cytomegalovirus retinitis (CMVR) after umbilical cord blood transplantation. After ineffective viral treatment, he was treated with a third-party donor CMVST and was successfully transformed into CMV nucleic acid negative. [ABSTRACT FROM AUTHOR]

Exercise training is not only a necessary means to improve the level of exercise, but also an important means to improve the body's immunity. Different time, intensity, items, and forms of exercise training have different effects on the body's immune function. As a double-edged sword to improve the body's immune function, exercise training is a different reaction mechanism of different immune cells after exercise training. This paper combined with foreign scholars' studies on the immune function of the body of literature from different exercise intensity, different time, different sports, different movement forms, and different external environment such as angle of view for athletes body's immune cells and humoral immunity summarized the various indexes such as combing, in order to help academia, medicine, and sports. It provides enlightenment to the contemporary public on how to participate in sports training more healthily. [ABSTRACT FROM AUTHOR]

Cutaneous leishmaniasis (CL) is a major public health problem worldwide and spreads to human via the bite of sand flies during blood meal. Following its inoculation, the promastigotes are immediately taken up by phagocytic cells and these leishmania-infected host cells produce proinflammatory cytokines that activate other immune cells and these infected host cells produce more cytokines and reactive nitrogen and oxygen species for efficient control of leishmania infection. Many experimental studies showed that resistance to infection with leishmania paraites is associated with the production of proinflammatory cytokines and activation of CD4+ Th1 response. On the other hand, vulnerability to this parasitic infection is correlated to production of T helper 2 cytokines that facilitate persistence of parasites and disease progression. In addition, some studies have also indicated that CD8+ T cells play a vital role in immune defense through cytokine production and their cytotoxic activity and excessive production of proinflammatory mediators promote amplified recruitment of cells. This could be correlated with excessive inflammatory reaction and ultimately resulted in tissue destruction and development of immunopathogenesis. Thus, there are contradictions regarding the role of immune responses in protection and immunopathogenesis of CL disease. Therefore, the aim of this paper was to review the role of host immune response in protection and its contribution to disease severity for CL infection. In order to obtain more meaningful data regarding the nature of immune response to leishmania, further in-depth studies focused on immune modulation should be conducted to develop better therapeutic strategies. [ABSTRACT FROM AUTHOR]

Allergic conjunctivitis (AC) is a common allergic disease that is often associated with the onset of rhinitis or asthma. The incidence of AC has increased significantly in recent years possibly due to air pollution and climate warming. AC seriously affects patients' quality of life and work efficiency. Th (T-helper) 2 immune responses and type I hypersensitivity reactions are generally considered the basis of occurrence of AC. It has been found that new subpopulations of T-helper cells, Th17 cells that produce interleukin-17 (IL-17), play an important role in the Th2-mediated pathogenesis of conjunctivitis. Studies have shown that Th17 cells are involved in a variety of immune inflammation, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and asthma. However, the role of Th17 and IL-17 in AC is unclear. This paper will focus on how T-helper 17 cells and interleukin-17 are activated in the Th2 immune response of allergic conjunctivitis and how they promote the Th2 immune response of AC. [ABSTRACT FROM AUTHOR]

The multifunctional role of mast cells (MCs) in the immune system is complex and has not fully been explored. MCs reside in tissues and mucous membranes such as the lung, digestive tract, and skin which are strategically located at interfaces with the external environment. These cells, therefore, will encounter external stimuli and pathogens. MCs modulate both the innate and the adaptive immune response in inflammatory disorders including transplantation. MCs can have pro- and anti-inflammatory functions, thereby regulating the outcome of lung transplantation through secretion of mediators that allow interaction with other cell types, particularly innate lymphoid cells (ILC2). ILC2 cells are a unique population of hematopoietic cells that coordinate the innate immune response against a variety of threats including infection, tissue damage, and homeostatic disruption. In addition, MCs can modulate alloreactive T cell responses or assist in T regulatory (Treg) cell activity. This paper outlines the current understanding of the role of MCs in lung transplantation, with a specific focus on their interaction with ILC2 cells within the engrafted organ. [ABSTRACT FROM AUTHOR]

Background. Chimeric antigen receptor (CAR) T cell therapy, a "living drug" immunotherapy, harnesses the power of T-cells from a patient (autologous) or healthy donor (allogeneic) to target and kill cancer cells and has shown unprecedented outcomes in patients with relapsed and refractory malignancies. Treatment with CAR-T cells requires the application of unique skillsets in recognised specialist centres for successful outcomes and requires management by the multidisciplinary team incorporating the specialist pharmacist. Method. A multimodal research strategy was employed for this literature review whereby PubMed, Google Scholar, Embase, Stella Library Search, EMA website, and EBMT website were sources of information. The search was limited from 2020 onwards with key terms referring to CAR-T cell therapy. Results and Discussion. There are six CAR-T cell products currently approved by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) which target haematological malignancies with abundant clinical trials underway exploring new and improved CAR designs and antigen targets. As CAR-T cell therapy is an advanced therapy medicinal product (ATMP), there is need for an extensive regulatory framework underpinning its safety and efficacy. The clinical pharmacist plays an integral role in the provision of safe and effective CAR-T cell therapy including governance, operational and clinical aspects of treatment. Pharmacists may also be involved through provision of "Qualified Person" (QP) expertise in clinical trials and for release within hospitals under certain circumstances. There is a need for harmonised and accessible guidance on the clinical delivery of ATMPs such as CAR-T cells, with fully delineated responsibilities of pharmacists involving the oversight and supervision of CAR-T cell treatment. Conclusion. There is an unmet need to provide suitable and applicable literature for clinical pharmacists who are involved in the delivery of CAR-T cells. We have provided an overview of T-cell biology and an explanation of CAR-T cell design and the biomanufacturing process. We reviewed the complex and multifaceted treatment cycle requiring considerable logistics, and described the involvement of the clinical pharmacist in each part of this cycle from patient selection to postinfusion care. Finally, we look to the challenges and future opportunities that will require the involvement of the clinical pharmacist. [ABSTRACT FROM AUTHOR]

Superantigens are virulence factors secreted by microorganisms that can cause various immune diseases, such as overactivating the immune system, resulting in cytokine storms, rheumatoid arthritis, and multiple sclerosis. Some studies have demonstrated that superantigens do not require intracellular processing and instated bind as intact proteins to the antigen-binding groove of major histocompatibility complex II on antigen-presenting cells, resulting in the activation of T cells with different T-cell receptor Vβ and subsequent overstimulation. To combat superantigen-mediated diseases, researchers have employed different approaches, such as antibodies and simulated peptides. However, due to the complex nature of superantigens, these approaches have not been entirely successful in achieving optimal therapeutic outcomes. CD28 interacts with members of the B7 molecule family to activate T cells. Its mimicking peptide has been suggested as a potential candidate to block superantigens, but it can lead to reduced T-cell activity while increasing the host's infection risk. Thus, this review focuses on the use of drug delivery methods to accurately target and block superantigens, while reducing the adverse effects associated with CD28 mimic peptides. We believe that this method has the potential to provide an effective and safe therapeutic strategy for superantigen-mediated diseases. [ABSTRACT FROM AUTHOR]

The density of CD169+ macrophages has been reported to positively correlate with the number of CD8+ T cells, although this remains controversial. To better understand this topic, we conducted a meta-analysis. We searched the PubMed, Medline, and Web of Science databases for studies that were published before May 2022 and performed a meta-analysis of the incidence of low and high CD169 expression in groups based on CD8 expression using the random-effects model. A total of 10 studies were included in the meta-analysis. The incidence of high CD169 expression in lymph nodes was significantly lower than that of low CD169 expression in the low CD8 expression group (odds ratio (OR): 0.76, 95% confidence interval (CI): 0.6, 0.96); however, the incidence of high CD169 expression in lymph nodes was higher than that of low CD169 expression in the high CD8 expression group (OR: 1.50, 95% CI: 1.08, 2.07). We also found that the expression of CD169 in tumors was lower than that in nontumor tissues (standardized mean difference: −5.29, 95% CI: −7.47, −3.11). The overall survival and hazard ratio of patients with high and low CD169 expression was 0.45 (95% CI: 0.37, 0.55). This analysis showed that high CD169 expression was associated with a high CD8 expression, and low CD169 expression was associated with low CD8 expression. The risk of death was 55% lower for patients with high CD169 expression, and high CD169 expression may be associated with favorable survival outcomes in cancer patients. However, the number and heterogeneity of the studies should be taken into consideration when evaluating the analysis. High-quality randomized controlled trials on the association between CD169 and CD8 expression are needed to verify these effects. [ABSTRACT FROM AUTHOR]

Metastatic melanoma is still associated with a poor prognosis, and there is increasing interest in immunotherapy alone or in combination with other adjuvant therapies. Γδ T lymphocytes play a pivot role in the immune response against cancer, but while γδ-based immunotherapy is already a clinical reality for several solid tumors, data on melanoma are still limited and fragmented. This systematic review presents preclinical and clinical evidence for a role of γδ T lymphocytes in immunotherapeutic strategies for advanced melanoma and discusses research state of the art and future perspectives. Current strategies focus on in vivo stimulation, and ex vivo adoptive therapy and vaccination; results are promising, but further studies are needed to better investigate the interactions in tumoral microenvironment and to improve clinical efficacy of immunotherapeutic protocols. [ABSTRACT FROM AUTHOR]

Background. Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL. Methods. In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated in vitro and/or in vivo. Results. As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. In vitro, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. In vivo, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells. Conclusion. Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients. [ABSTRACT FROM AUTHOR]

Since conserved viral proteins of influenza virus, such as nucleoprotein (NP) and matrix 1 protein, are the main targets for virus-specific CD8+ cytotoxic T-lymphocytes (CTLs), we hypothesized that introduction of the NP gene of wild-type virus into the genome of vaccine reassortants could lead to better immunogenicity and afford better protection. This paper describes in vitro and in vivo preclinical studies of two new reassortants of pandemic H1N1 live attenuated influenza vaccine (LAIV) candidates. One had the hemagglutinin (HA) and neuraminidase (NA) genes from A/South Africa/3626/2013 H1N1 wild-type virus on the A/Leningrad/134/17/57 master donor virus backbone (6 : 2 formulation) while the second had the HA, NA, and NP genes of the wild-type virus on the same backbone (5 : 3 formulation). Although both LAIVs induced similar antibody immune responses, the 5 : 3 LAIV provoked greater production of virus-specific CTLs than the 6 : 2 variant. Furthermore, the 5 : 3 LAIV-induced CTLs had higher in vivo cytotoxic activity, compared to 6 : 2 LAIV. Finally, the 5 : 3 LAIV candidate afforded greater protection against infection and severe illness than the 6 : 2 LAIV. Inclusion in LAIV of the NP gene from wild-type influenza virus is a new approach to inducing cross-reactive cell-mediated immune responses and cross protection against pandemic influenza. [ABSTRACT FROM AUTHOR]

Target selection is a key feature in cancer immunotherapy, a promising field in cancer research. In this respect, gangliosides, a broad family of structurally related glycolipids, were suggested as potential targets for cancer immunotherapy based on their higher abundance in tumors when compared with the matched normal tissues. GD2 is the first ganglioside proven to be an effective target antigen for cancer immunotherapy with the regulatory approval of dinutuximab, a chimeric anti-GD2 therapeutic antibody. Although the therapeutic efficacy of anti-GD2 monoclonal antibodies is well documented, neuropathic pain may limit its application. O-Acetyl-GD2, the O-acetylated-derivative of GD2, has recently received attention as novel antigen to target GD2-positive cancers. The present paper examines the role of O-acetyl-GD2 in tumor biology as well as the available preclinical data of anti-O-acetyl-GD2 monoclonal antibodies. A discussion on the relevance of O-acetyl-GD2 in chimeric antigen receptor T cell therapy development is also included. [ABSTRACT FROM AUTHOR]

Although Kampo—a traditional Japanese herbal medicine—contributes in the control of tumor growth in vivo in experimental animals, most of the antitumor effects are prophylactic and not therapeutic. In this study, we determined whether oral administration of an herbal mixture containing Ganoderma lucidum (WTMCGEP; Wisteria floribunda, Trapae fructus, Myristica fragrans, Coicis semen, Ganoderma lucidum, Elfvingia applanata, and Punica granatum), anecdotally used in Japan for the palliative care of patients with cancer, exhibits a therapeutic effect on tumor growth in vivo in a hypodermic murine CT26 colorectal tumor model. An in vitro tumor assay revealed that WTMCGEP extract has some direct influence over suppression of tumor growth. In wild-type BALB/c mice, WTMCGEP did not show any antitumor effect in vivo. However, in BALB-CD1d−/− mice with partly mitigated immunosuppression by reason of them being devoid of both antitumoral type I and immunosuppressive type II natural killer T (NKT) cells, WTMCGEP therapeutically suppressed tumor growth. CD8+ T cell depletion significantly accelerated tumor growth in WTMCGEP mice; therefore, its antitumor activity was primarily in a CD8+ T cell-dependent manner. Regarding immunosuppressive cells in tumor-bearing CD1d−/− mice, WTMCGEP did not influence the abundance of tumor-infiltrating CD4+ and Forkhead box protein 3+ regulatory T cells. However, it reduced both intratumoral and splenic Ly6G+ Ly6Clo polymorphonuclear myeloid-derived suppressor cells, which were most likely involved in tumor growth inhibition related to higher frequency of intratumoral CD107a+ CD8+ T cells in these mice. Overall, these data illustrate that the deficiency of NKT cells urges WTMCGEP to exert a therapeutic antitumor effect mainly through CD8+ T cells. Our efforts are the first to scientifically demonstrate the WTMCGEP's contribution to tumor immunity. [ABSTRACT FROM AUTHOR]

Mounting evidence has confirmed that essential hypertension (EH) is closely related to low-grade inflammation, but there is still a lack of in-depth understanding of the state of immune cells in the circulating blood of patients with EH. We analyzed whether hypertensive peripheral blood immune cell balance was destroyed. The peripheral blood mononuclear cells (PBMCs) of all subjects were analyzed using time-of-flight cytometry (CyTOF) based on 42 kinds of metal-binding antibodies. CD45+ cells were categorized into 32 kinds of subsets. Compared with the health control (HC) group, the percentage of total dendritic cells, two kinds of myeloid dendritic cell subsets, one intermediate/nonclassical monocyte subset and one CD4+ central memory T cell subset in the EH group, was significantly higher; the percentage of low-density neutrophils, four kinds of classical monocyte subsets, one CD14lowCD16- monocyte subset, one naive CD4+ and one naive CD8+ T cell subsets, one CD4+ effector and one CD4+ central memory T cell subsets, one CD8+ effector memory T cell subset, and one terminally differentiated γδ T cell subset, decreased significantly in EH. What is more, the expression of many important antigens was enhanced in CD45+ immune cells, granulocytes, and B cells in patients with EH. In conclusion, the altered number and antigen expression of immune cells reflect the imbalanced immune state of the peripheral blood in patients with EH. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) acts as a crucial role in the occurrence and development of osteosarcoma (OS). Despite this, the mechanism controlling the components of immunity and stroma in the tumor microenvironment remains a mystery. To conduct this study, we download and collate transcriptome data from the TARGET database, whose full name is Therapeutically Applicable Research to Generate Effective Treatments, as well as available clinical information of OS. The CIBERSORT and ESTIMATE methodology are used to acquire the proportions of components of immunity and stroma and tumor-infiltrating immune cells (TICs). Protein-protein interaction (PPI) networks and Cox regression analysis are used to select differentially expressed genes (DEGs). A prognostic biomarker is determined by intersecting univariate COX and PPI results, which lead to the finding of Triggering receptor expressed on myeloid cells-2 (TREM2). Based on the next analysis, TREM2 expression is positively correlated with OS survival time. Immune function-related genes have enrichment in the group with high expression of TREM2, according to gene set enrichment analysis (GSEA). The percentage of TICs by CIBERSORT methodology revealed that the expression of TREM2 is positively associated with follicular helper T cells, CD8-positive T cells, and M2 macrophages and negatively correlated with plasma cells, M0 macrophages, and naive CD4-positive T cells. All results suggest a possible integral role of TREM2 in the immune-related events of TME. Therefore, TREM2 may be a potential indicator of remodeling of TME in osteosarcoma, which is useful and helpful in predicting the clinical prognostic outcome of OS patients and provide a unique perspective for immunotherapy for OS. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and, in its advanced stages, has a 5-year survival rate of only 3% to 5%. Despite novel mechanisms and treatments being uncovered over the past few years, effective strategies for HCC are currently limited. Previous studies have proven that aconite can suppress tumor growth and progression and prevent the recurrence and metastasis of multiple cancers, but the underlying molecular mechanisms are largely unknown. In this study, different doses of aconite were applied to mice bearing subcutaneous HCC tumors. It was found that aconite had a therapeutic effect on H22 tumor-bearing mice in a dose-dependent manner by reducing tumor volumes and prolonging survival times, which could be attributed to the immunoregulatory effect of aconite. Furthermore, results showed that high-dose administration of aconite could enhance adaptive immunity and natural killer (NK) cell-mediated immunity by regulating the secretion of interferon-γ, upregulating T cells and NK cells, and modulating the expression of the NK cytotoxicity biomarker CD107a and the inhibitory receptor TIGIT. This study revealed a novel mechanism through which aconite exerts antitumor effects, not merely through apoptosis induction pathways, providing more sound evidence that aconite has the potential to be developed into an effective anti-HCC agent. [ABSTRACT FROM AUTHOR]

Recently, PTP1B was identified as a novel immune checkpoint whose removal can unleash T cell responses. However, research on the influence of PTP1B as an immune regulator on liver cancer is limited. This study aimed to investigate the immunological correlation and function of PTP1B in liver cancer. The expression profiles and corresponding clinical information of liver cancer patients were obtained from the TCGA and ICGC databases. GSE146115 and GSE98638 retrieved from the GEO database were used for the single-cell RNA-seq analysis. The mRNA expression of PTP1B (PTPN1) was increased in patients with most malignancies (all p < 0.05), including liver cancer (p < 0.001). Furthermore, up-regulated PTPN1 was connected to advanced tumor stage (p < 0.05) and worse prognosis (p < 0.01) in liver cancer. Through Cox regression analysis, PTPN1 was considered as an independent prognosis factor of overall survival (p < 0.05) and acted as a high-risk factor (hazard ratio > 1). Gene function and pathway analysis suggested PTPN1 was involved in T cell-related immune responses. Moreover, a close relationship was also found between PTPN1 expression and immune checkpoints as well as immune cells, especially with T cell-related checkpoints (all p < 0.001) and T cells (all p < 0.001). Single-cell RNA-seq analysis further illustrated that the enrichment of PTPN1 in the T cell population may be linked to its exhaustion in the liver cancer microenvironment. Overall, PTPN1 (PTP1B) closely related to T cell may function as an immunotherapy target for liver cancer. [ABSTRACT FROM AUTHOR]

Background. Liangxue Tongyu prescription (LTP) is a commonly used formula for acute intracerebral hemorrhage (AICH) in clinical practice that has significant ameliorative effects on neurological deficits and gastrointestinal dysfunction, yet the mechanism remains elusive. The aim of this study was to investigate the pathway by which LTP alleviates brain damage in AICH rats. Methods. The AICH rat models were established by autologous caudal arterial blood injection. The neurological function scores were evaluated before and after treatment. The water content and the volume of Evans blue staining in the brain were measured to reflect the degree of brain damage. RT-PCR was used to detect the inflammatory factors of the brain. Western blotting was used to detect the expression of the tight junction proteins zonula occludens 1 (ZO-1), occludin (OCLN), and claudin (CLDN) in the brain and colon, followed by mucin 2 (MUC2), secretory immunoglobulin A (SIgA), and G protein-coupled receptor 43 (GPR43) in the colon. Flow cytometry was used to detect the ratios of helper T cells 17 (Th17) and regulatory T cells (Treg) in peripheral blood, and the vagus nerve (VN) discharge signals were collected. Results. LTP reduced the brain damage of the AICH rats. Compared with the model group, LTP significantly improved the permeability of the colonic mucosa, promoted the secretion of MUC2, SigA, and GPR43 in the colon, and regulated the immune balance of peripheral T cells. The AICH rats had significantly faster VN discharge rates and lower amplitudes than normal rats, and these abnormalities were corrected in the LTP and probiotics groups. Conclusion. LTP can effectively reduce the degree of brain damage in AICH rats, and the mechanism may be that it can play a neuroprotective role by regulating the function of the intestinal mucosal barrier. [ABSTRACT FROM AUTHOR]

Immune therapy of T-cell lymphoma requires assessment of tumor-expressed programmed cell death protein-1 (PD-1). Herein, we developed an immuno-PET technique that quantitatively images and monitors regulation of PD-1 expression on T-cell lymphomas. Methods. Anti-PD-1 IgG underwent sulfhydryl moiety-specific conjugation with maleimide-deferoxamine and 89Zr labeling. Binding assays and Western blotting were performed in EL4 murine T-cell lymphoma cells. In vivo pharmacokinetics, biodistribution, and PET were performed in mice. Results. 89Zr-PD-1 IgG binding to EL4 cells was completely blocked by cold antibodies, confirming excellent target specificity. Following intravenous injection into mice, 89Zr-PD-1 IgG showed biexponential blood clearance and relatively low normal organ uptake after five days. PET/CT and biodistribution demonstrated high EL4 tumor uptake that was suppressed by cold antibodies. In EL4 cells, phorbol 12-myristate 13-acetate (PMA) increased 89Zr-PD-1 IgG binding (305.5 ± 30.6 %) and dose-dependent augmentation of PD-1 expression (15.8 ± 3.8 − fold of controls by 200 ng/ml). FACS showed strong PD-1 expression on all EL4 cells and positive but weaker expression on 41.6 ± 2.1 % of the mouse spleen lymphocytes. PMA stimulation led to 2.7 ± 0.3 -fold increase in the proportion of the strongest PD-1 expressing EL4 cells but failed to influence that of PD-1+ mouse lymphocytes. In mice, PMA treatment increased 89Zr-PD-1 IgG uptake in EL4 lymphomas from 6.6 ± 1.6 to 13.9 ± 3.6 %ID/g (P = 0.01), and tumor uptake closely correlated with PD-1 level (r = 0.771 , P < 0.001). On immunohistochemistry of tumor sections, infiltrating CD8 α + T lymphocytes constituted a small fraction of tumor cells. The entire tumor section showed strong PD-1 staining that was even stronger for PMA-treated mice. Investigation of involved signaling revealed that PMA increased EL4 cell and tumor HIF-1 α accumulation and NF κ B and JNK activation. Conclusion. 89Zr-PD-1 IgG offered high-contrast PET imaging of tumor PD-1 in mice. This was found to mostly represent binding to EL4 tumor cells, although infiltrating T lymphocytes may also have contributed. PD-1 expression on T-cell lymphomas was upregulated by PMA stimulation, and this was reliably monitored by 89Zr-PD-1 IgG PET. This technique may thus be useful for understanding the mechanisms of PD-1 regulation in lymphomas of living subjects. [ABSTRACT FROM AUTHOR]

Premature ovarian failure (POF) is characterized by hormonal disorders, amenorrhea, and premature loss of fertility potential in women of reproductive age. Several studies have been conducted on the effectiveness of traditional Chinese medicine (TCM) in treating POF. TCM relied primarily on apoptosis, immunity, and aging to treat POF based on the studies of domestic and foreign literature. Zuogui pills inhibited mitochondrial-dependent apoptosis in the treatment of POF. Huyang Yangkun formula regulated the downstream of the Bcl-2 family to resist apoptosis through the aquaporin-1 protein. Modified Bazhen decoction regulated apoptosis in POF by regulating X-linked inhibitors of apoptosis protein. Bushen Tianjing recipe was effective in treating POF by promoting angiogenesis and preventing apoptosis. As for immunity, Bushen Jianpi prescription and Er-Xian decoction cured autoimmunity POF models and increased follicular development-related protein expression. Bushen Huoxue Tang improved ovarian function and reduced ovarian inflammation by regulating the Nrf2/Keap1 signaling pathway and T lymphocytes. Taohong Siwu decoction promoted the proliferation and differentiation of granulosa cells of POF mice by regulating the TGF-β1/Smads signaling pathway. In addition, ginsenoside Rg1 and Jiajian Guisheng formula treated POF by regulating cell aging-related mechanisms. Si Wu Tang treated POF by activating the angiogenesis-related proteins. The goal of this review is to serve as a reference for in-depth research into the treatment of POF with TCM and provide inspiration for new diagnostic methods and treatment options. [ABSTRACT FROM AUTHOR]

Interleukin-1receptor-associated kinase 1 (IRAK1) plays a critical role in systemic lupus erythematosus (SLE). It was reported that SLE was associated with an inflammatory response mediated by defective immune tolerance, including overproduction of autoantibodies, chronic inflammation, and organ damage. Previous reports stated paeoniflorin (PF) had an immunosuppressive effect. The purpose of this study was to determine the anti-inflammatory effect of PF in SLE and its underlying mechanisms. Followed by induced with lipopolysaccharide (LPS), the splenocytes and the isolated CD4+ T lymphocytes of MRL/lpr mice were divided into three groups: control group, LPS group, and LPS + PF group, respectively. MRL/MP mice were used as the control group (treated with distilled water). The MRL/lpr mice were randomly divided into three groups: the model group (treated with distilled water), the prednisone group, and the PF group. The MRL/lpr mice were treated with prednisone acetate (5 mg/kg) and PF (25, 50, and 75 mg/kg) for eight weeks. Subsequently, ELISA, qRT-PCR, western blotting, HE, and Masson staining were performed to detect various indicators. The results of Cell Counting Kit-8 (CCK-8) showed that 10 μg/mL of LPS had the optimum effect on cell viability, and 50 μmol/L of PF had no obvious cytotoxicity to LPS-treated cells. PF reduced the expression level of IRAK1-nuclearfactor-κB (NF-κB) and its downstream inflammatory cytokines in the splenocytes and CD4+ T lymphocytes of MRL/lpr mice stimulated by LPS, especially in the latter. The serum antibody contents in the PF group mice were reduced, and the kidney damage was also alleviated accordingly. Moreover, the IRAK1/inhibitor of the nuclear factor-κB kinase (IKK)/NF-κB inhibitor (IκB)/NF-κB pathways was found to be involved in the anti-inflammation effect of PF in the kidney and spleen. In conclusion, it is thought that PF may have the potential to be used as a therapeutic agent to reduce the inflammatory activity of SLE. Inhibition of the IRAK1-NF-κB pathway may help formulate novel therapeutic tactics for SLE. [ABSTRACT FROM AUTHOR]

Adoptive cellular therapy with chimeric antigen receptor (CAR) T cells has emerged as a potential novel treatment for various cancers. In this study, we have generated CAR T cells targeting mucin-1 (MUC1), which is an aberrantly glycosylated antigen overexpressed on breast cancer cells. Two different signaling domains, including CD28 and 41BB, were incorporated and directly compared the superiority of different costimulatory signals. Two different CAR MUC1 constructs were transduced into primary T cells and evaluated their characteristics and antitumor activities against MUC1+ cancer cells. CAR MUC1 T cells showed high transduction efficiency and antigen specificity toward MUC1+ cancer cell lines and primary breast cancer cells. When coculturing with target cells, the transduced cells exhibited potent antitumor activity in vitro and secrete proinflammatory cytokines. Upon antigen stimulation, incorporation of the 41BB signaling domain was able to improve T cell proliferation and reduce surface PD1 expression and the upregulation of suppressive cytokines, when compared with CAR MUC1 containing the CD28 domain. Our findings show that CAR T cell targeting MUC1 can be effective against MUC1+ breast cancer cell and support the further development of CAR MUC1 T cells containing 41BB signaling in preclinical and clinical studies of breast cancer treatment. [ABSTRACT FROM AUTHOR]

Normal density granulocytes (NDGs) can suppress T-cell responses in a similar way as myeloid-derived suppressor cells (MDSCs). In this study, we tested the hypothesis that NDGs from healthy donors preferentially inhibit T helper 1 (Th1) cells and investigated the myeloid-derived suppressive effect in different T-cell populations. We found that NDG-induced suppression of T-cell proliferation was contact dependent, mediated by integrin CD11b, and dependent on NDG-production of reactive oxygen species (ROS). The suppression was rapid and occurred within the first few hours of coculture. The suppression did not influence the CD8+/CD4+ ratio indicating an equal sensitivity in these populations. We further analyzed the CD4+ T helper subsets and found that NDGs induced a loss of Th1 surface marker, CD183, that was unrelated to ligand-binding to CD183. In addition, we analyzed the Th1, Th2, and Th17 cytokine production and found that all cytokine groups were suppressed when T-cells were incubated with NDGs. We therefore concluded that NDGs do not preferentially suppress Th1-cells. Instead, NDGs generally suppress Th cells and cytotoxic T-cells but specifically downregulate the Th1 marker CD183. [ABSTRACT FROM AUTHOR]

The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegenerative diseases. Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes (NFAT) signaling pathway, a Ca2+/calmodulin-dependent major proinflammatory pathway, in the pathogenesis of these diseases. Neurotoxins such as amyloid-β, tau protein, and α-synuclein trigger abnormal calcineurin/NFAT signaling activities. Additionally increased activities of endogenous regulators of calcineurin like plasma membrane Ca2+-ATPase (PMCA) and regulator of calcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations, in neurodegenerative diseases, psychotic disorders, epilepsy, and traumatic brain and spinal cord injuries. Treatment with calcineurin/NFAT inhibitors induces some degree of neuroprotection and decreased reactive gliosis in the central and peripheral nervous system. In this paper, we summarize and discuss the current understanding of the roles of calcineurin/NFAT signaling in physiology and pathologies of the adult and developing nervous system, with an emphasis on recent reports and cutting-edge findings. Calcineurin/NFAT signaling is known for its critical roles in the developing and adult nervous system. Its role in physiological and pathological processes is still controversial. However, available data suggest that its beneficial and detrimental effects are context-dependent. In view of recent reports calcineurin/NFAT signaling is likely to serve as a potential therapeutic target for neurodegenerative diseases and conditions. This review further highlights the need to characterize better all factors determining the outcome of calcineurin/NFAT signaling in diseases and the downstream targets mediating the beneficial and detrimental effects. [ABSTRACT FROM AUTHOR]

MHC molecule plays a key role in immunology, and the molecule binding reaction with peptide is an important prerequisite for T cell immunity induced. MHC II molecules do not have conserved residues, so they appear as open grooves. As a consequence, this will increase the difficulty in predicting MHC II molecules binding peptides. In this paper, we aim to propose a novel prediction method for MHC II molecules binding peptides. First, we calculate sequence similarity and structural similarity between different MHC II molecules. Then, we reorder pseudosequences according to descending similarity values and use a weight calculation formula to calculate new pocket profiles. Finally, we use three scoring functions to predict binding cores and evaluate the accuracy of prediction to judge performance of each scoring function. In the experiment, we set a parameter α in the weight formula. By changing α value, we can observe different performances of each scoring function. We compare our method with the best function to some popular prediction methods and ultimately find that our method outperforms them in identifying binding cores of HLA-DR molecules. [ABSTRACT FROM AUTHOR]

Background. Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, may be a potential treatment for many cancers, including cervical cancer (CC). However, the regulation of long noncoding RNAs (lncRNAs) in the process of ferroptosis and whether ferroptosis inducers could increase the cytotoxicity of conventional chemotherapy drugs remain to be further elucidated. Methods. We analyzed the variation of 55 differentially ferroptosis-related genes (FRGs) and the influence of mutations in CC patients. The patients with CC were classified into two ferroptosis clusters by the non-negative matrix factorization (NMF) algorithm. The principal components analysis (PCA) was used to measure the ferroptosis score (FerroScore) in patients with CC. Besides, FerroScore was used to predict the sensitivity of chemotherapy and responses to immunotherapy in patients with CC. Finally, experiments were performed to verify the regulatory effect of AC026790.1 on erastin-induced ferroptosis, as well as the effect of erastin in combination with cisplatin on the toxicity of CC cells (SiHa, HeLa). Result. There were significant differences in the overall survival and immune cell infiltration between the two ferroptosis clusters. Patients with low FerroScore were more sensitive to chemotherapy drugs such as cisplatin and docetaxel. The low-FerroScore group had higher CD8+ T cell infiltration and immune checkpoint expression, demonstrating that patients with lower FerroScores were more sensitive to immunotherapy, which was consistent with the result of the submap method. In vitro, overexpression of AC026790.1 could promote erastin-induced ferroptosis, and the combination of erastin and cisplatin could increase the toxicity of CC cells. Conclusion. FerroScore has a potential prognostic value for CC that may provide a reference for chemotherapy and immunotherapy. LncRNA AC026790.1 can influence ferroptosis, and the combination of ferroptosis inducers and chemotherapy drugs can provide a new perspective on cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Several studies have shown that lymphocyte subsets can mediate the occurrence of osteoporosis (OP); however, the predictive ability of lymphocyte subsets in senile OP has not been elucidated.Purpose: To investigate the ability of lymphocyte subsets to predict senile osteoporosis (OP).Methods and Materials: This study included 44 patients with senile OP and 44 without OP. Dual-energy X-ray absorptiometry (DEXA) was used to determine bone mineral density (BMD). Flow cytometry was used to analyze the absolute counts of the lymphocyte subsets and cytokine levels. Finally, the correlation between BMD and lymphocyte subset counts in the two groups was analyzed.Results: There were no significant differences in age, sex, or weight between the OP and non-OP groups. The absolute counts of total T lymphocytes and CD8+ T lymphocytes in the OP group were significantly lower than those in the non-OP group. The levels of IFN-γ or TNF-α in the OP group were significantly higher or lower, respectively, than those in the non-OP group. PCA showed that age, BMI, total T lymphocytes, CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes were the principal components of senile OP. The linear regression equation showed that BMD of the right femoral neck significantly decreased with a decline in CD8+ T lymphocyte counts.Conclusion: BMD decreased with a decrease in CD8+ T lymphocytes. The mechanism by which lower lymphocyte subsets lead to lower BMD may be related to abnormal bone metabolism caused by immune aging. Therefore, we considered that CD8+ T lymphocytes could be used to predict the incidence of senile OP. [ABSTRACT FROM AUTHOR]

Objective. The novel coronavirus nucleic acid results are the core indicators of illness monitoring. This study aimed to evaluate the relationship between immunological features and positive SARS-CoV-2 nucleic acid by analyzing the clinical and immunological features in nonsevere COVID-19 cases. Methods. Data from nonsevere COVID-19 patients admitted to Haihe Hospital from May 2020 to June 2021 were retrospectively reviewed and analyzed. Results. (1) A total of 122 cases were reviewed in the present study, including 38 mild and 84 moderate cases. The average age of mild cases was significantly different from moderate cases (P < 0.001). Eight patients complained of hyposmia and it was more frequent in mild cases (P < 0.001). The nucleic acid positive duration (NPD) of nonsevere novel coronavirus was 20.49 (confidence interval (CI) 17.50–3.49) days. (2) The levels of specific IgM and IgG for COVID-19 were higher in mild cases than in moderate cases (P = 0.023 and P = 0.047 , respectively). (3) The correlation analysis with antibodies and T-cell subtypes showed that the lymphocyte (LYM) count, T cells, CD4+T cells, and CD8+T cells had a linear correlation with NPD. (4) Among the 93 patients monitored, 62 COVID-19 cases presented a progressive rise of specific IgM and IgG. The daily increase rates of IgM and IgG were 38.42% (CI 28.22–48.61%) and 24.90% (CI 0.23–29.58%), respectively. Conclusion. The levels and daily increase rates of specific IgM and IgG against the virus can vary between cases. The NPD presented a linear correlation with the LYM, T cells, CD4+T cells, and CD8+T cells. Hence, more attention should be paid to these indicators in clinical practice. [ABSTRACT FROM AUTHOR]

Inflammation is a critical mediator of renal ischemia-reperfusion (I/R) injury (IRI), and T lymphocytes exert a key role in the renal IRI-induced inflammation. Connexin 43 (Cx43) is related to the maintenance of T lymphocyte homeostasis. Various preclinical researches have reported that estrogen is a renoprotective agent based on its anti-inflammatory potential. The present research is aimed at studying the role of T lymphocytes activated by Cx43 in 17β-estradiol-mediated protection against renal IRI. Female rats were classified into six groups: control rats, I/R rats, ovariectomized rats, ovariectomized I/R rats, and ovariectomized rats treated with 17β-estradiol or gap27. Levels of serum creatinine (Scr) and blood urea nitrogen (BUN) and Paller scoring were dramatically increased in I/R rats, especially in ovariectomized rats. By contrast, these indicators were markedly decreased by administering estradiol or gap27. Immunofluorescence staining revealed that CD4+ T cells infiltrated kidney tissues in the early stage of IRI. In both peripheral blood and renal tissue, the proportion of CD3+CD4+ T cells and ratio of CD4+ to CD8+ were high in I/R rats, especially in ovariectomized rats. The proportion of CD3+CD8+ T cells was low in peripheral blood but high in renal tissues. Administration of estrogen or Gap27 reversed these effects. IL-17 levels in both serum and tissue homogenate were significantly increased in ovariectomized rats subjected to I/R but significantly decreased in estrogen or gap 27 treated rats. The opposite trend was observed for IL-10 levels. Correlation analysis demonstrated that IL-17 was correlated positively with BUN, Scr, and Paller scores, while IL-10 was negatively correlated with these indicators. Western blot showed that Cx43 expression was markedly increased in the peripheral blood T lymphocytes of I/R rats, especially ovariectomized rats. After intervention with estrogen and gap27, Cx43 expression was significantly downregulated. These findings indicate that Cx43 may participate in the regulation of Th17/Treg balance by estrogen against renal IRI. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells are overactivated in systemic lupus erythematosus (SLE) patients and contribute to excessive immunity. Hematopoietic progenitor kinase 1 (HPK1), as an inhibitor of T cells, is underexpressed in SLE Tfh cells and consequently induces autoimmunity. However, the reason for downregulation of HPK1 in SLE Tfh cells remains elusive. By combining chromatin immunoprecipitation with quantitative polymerase chain reaction assays, it was found that histone H3 lysine 27 trimethylation (H3K27me3) at the HPK1 promoter in SLE Tfh cells elevated greatly. We also confirmed jumonji domain-containing 3 (JMJD3) binding at the HPK1 promoter in SLE Tfh cells reduced profoundly. Knocking down JMJD3 in normal Tfh cells with siRNA alleviated enrichments of JMJD3, H3K4me3, and mixed-lineage leukemia (MLL) 1 at the HPK1 promoter and increased H3K27me3 number in the region. HPK1 expression was lowered, while Tfh cell proliferation activity, IL-21 and IFNγ secretions in the supernatants of Tfh cells, and IgG1 and IgG3 concentrations in the supernatants of Tfh-B cell cocultures all upregulated markedly. In contrast, elevating JMJD3 amount in SLE Tfh cells by JMJD3-overexpressed plasmid showed opposite effects. The abundances of H3K4me3 and MLL1 at the HPK1 promoter in SLE Tfh cells were greatly attenuated. Our results suggest that deficient JMJD3 binding at the promoter dampens HPK1 expression in SLE Tfh cells, thus making Tfh cells overactive, and ultimately results in onset of SLE. [ABSTRACT FROM AUTHOR]

Background. Cell division cycle associated 3 (CDCA3) mediates the ubiquitination WEE1 kinase at G2/M phase. However, its contribution to cancer immunity remains uncertain. Methods. We first evaluated the effect of CDCA3 on the prognosis of patients with renal cell carcinoma (RCC). The results of bioinformatics analysis were verified by the tissue microarray, immunofluorescence (IF) staining, CCK-8 assay, colony formation, cell cycle, and Western blot. Results. Bioinformatics analysis predicated CDCA3 was an independent predictor of poor prognosis in RCC and was associated with poor TNM stage and grade. CDCA3 was related to the infiltration of CD8+ T cells and Tregs. Tissue microarray demonstrated that CDCA3 was strongly associated with poor prognosis and positively relevant to CD8+ T infiltration. In vitro experiments showed that exgenomic interference of CDCA3 could attenuate cellular proliferation, arrest cell cycle, and blockade accumulation of CDK4, Bub3, and Cdc20 in mitosis process. Conclusion. CDCA3 presents as a good biomarker candidate to predict the prognosis of RCC patients and potentiates the immune tumor microenvironment (TME) of RCC. [ABSTRACT FROM AUTHOR]

Vitiligo is a noncontagious autoimmune skin depigmenting disease. Regulatory T cells (Tregs) play a key role in maintaining peripheral tolerance; however, Tregs' number, suppressive function, and associated suppressive molecules (FOXP3, IL-10, and TGF-β) are found to be reduced in vitiligo patients. Although, the role of Tregs in vitiligo pathogenesis is well established, there are several contrary findings which suggest a controversial role of Tregs in vitiligo. Therefore, to clarify the role of Tregs in vitiligo pathogenesis, we aimed to study Tregs' frequency, suppressive capacity, and associated suppressive molecules (FOXP3, IL-10, and TGF-β) in vitiligo patients through meta-analysis approach. A total of 30 studies involving 1223 vitiligo patients and 1109 controls were included in the study. Pooled results from our meta-analysis suggested significantly reduced Treg cells' frequency in vitiligo patients (p = 0.002). Interestingly, Tregs' suppressive capacity was also significantly reduced in vitiligo patients (p = 0.0002); specifically, Treg-mediated suppression of CD8+T cells was impaired in vitiligo patients (p < 0.00001). Moreover, FOXP3, a key Tregs' transcription factor, was significantly reduced in blood and skin of vitiligo patients (p < 0.00001). Intriguingly, the FOXP3 expression was significantly reduced in the lesional skin as compared to perilesional and nonlesional skin (p = 0.007 and p = 0.04). Furthermore, the expression of key Treg-associated suppressive cytokines IL-10 and TGF-β were significantly reduced in vitiligo patients (p = 0.0005 and p = 0.01). The disease activity-based analysis suggested for reduced Tregs' frequency and FOXP3 expression in active vitiligo patients (p = 0.05 and p = 0.01). We also studied the effect of microRNA-based treatment, narrow band-UVB phototherapy, and Treg-associated treatments on Tregs' frequency, FOXP3, and IL-10 expression. Interestingly, we found increased Tregs' frequency, FOXP3, and IL-10 expression after the treatment (p = 0.007, p < 0.0001, and p = 0.002). Overall, our meta-analysis suggests that the Tregs play a crucial role in pathogenesis and progression of vitiligo, and hence, Treg-based therapeutic interventions could be effective in vitiligo patients. [ABSTRACT FROM AUTHOR]

Cationic amino acid transporters (SLC7A1/CAT1) are highly expressed in human ovarian cancer (OC) tissues. However, the specific biological functions and mechanisms involved remain unclear. We used bioinformatics analysis to explore SLC7A1 expression level, prognostic value, and tumor mutation burden (TMB) in ovarian cancer (OC) tissues. We performed in vitro experiments to identify the expression and biological function of SLC7A1 in epithelial ovarian cancer (EOC) tissues and cells. An amino acid autoanalyzer was used to detect the effect of SLC7A1 on amino acid metabolism in EOC cells. Finally, SLC7A1 in OC was evaluated for cell-to-cell signalling and immune infiltration using online databases. We found that increased SLC7A1 expression in EOC cells and tissues was associated with poorer survival outcomes (P < 0.05) but not with tumor stage or grade of OC (P > 0.05). SLC7A1 is involved in the transport of phenylalanine and arginine in EOC cells, and its knockdown reduced the proliferation and migration of EOC cells and the resistance of cells to cisplatin. Furthermore, the TIMER database indicated that SLC7A1 overexpression was significantly positively correlated with levels of CD4+ memory resting cells, CD8+ effector memory cells, M0 macrophages, and cancer-associated fibroblasts (CAFs) in OC (P < 0.05) and significantly negatively correlated with CD4+ memory-activated cells (P < 0.05). Cell immunofluorescence indicated that SLC7A1 overexpression may affect the distribution of immune-infiltrating lymphocytes in tumors by inhibiting the expression of CCL4. Therefore, we concluded that SLC7A1 is involved in the metabolic remodelling of amino acids in EOC to promote tumor development and cisplatin resistance and is related to the tumor-infiltrating immune microenvironment of OC. SLC7A1 is a biomarker for predicting EOC progression and cisplatin resistance and represents a promising target for EOC treatment. [ABSTRACT FROM AUTHOR]

Lung cancer is increasing every year and it has high morbidity and mortality. Antitumor immunotherapy is a new method for the treatment of lung cancer. Currently, tumor immunotherapy mainly includes classical immunotherapy and immune-targeted therapy To explore the influence of tumor T-lymphocyte (T-cell) infiltration in non-small-cell lung cancer (NSCLC) patients, 100 NSCLC patients diagnosed and treated in Changde Second People's hospital were recruited. Patients were followed up for 3 years. The subjects were divided into a survival group (group S) and a death group (group D). The patient's pathological tissue sections were made, and the degree of T-cell infiltration was counted by H&E (Hematoxylin and eosin) staining. The infiltration degree was graded, and the positive rate of T-cell subsets was calculated by immunohistochemical staining. The 3-year positive rate was 48%, with 48 cases in group S and 52 cases in group D. The positive rate of H&E staining of group S was 100%, including 0 cases of grade 0, 5 cases of grade 1 (10.42%), 16 cases of grade 2 (33.33%), and 27 cases of grade 3 (56.25%). The positive rate of group D was 86.54%, including 4 cases of grade 0 (8.89%), 10 cases of grade 1 (22.22%), 25 cases of grade 2 (55.56%), and 6 cases of grade 3 (13.33%). The total number of T-cell infiltrates in group S was much higher than that in group D (P < 0.05). Immunohistochemical results showed that the mean positive rate of CD8+ T-cell infiltration was 72.1% in group S and 47.6% in group D, with a considerable difference (P < 0.05). No remarkable difference was found in CD4+ and CD25+ (P < 0.05). CD8+ + CD4+, CD8+/CD4+, CD25+/CD8+, CD25+/CD4+, and CD25+/(CD8+ + CD4+) positive rates were calculated, and the difference between group S and group D was substantial in CD8+ + CD4+ (P < 0.05). The results showed that T cells infiltrated by tumors had an immunosuppressive effect on tumor cells. [ABSTRACT FROM AUTHOR]

Purpose. To identify the potential key genes and molecular pathways associated with keratoconus and allergic disease. Methods. The pubmed2ensembl database was used to identify the text mining genes (TMGs) collectively involved in keratoconus and allergic disease. The GeneCodis program was used to perform the Gene Ontology (GO) biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of TMGs. The protein-protein interaction (PPI) network of the TMGs was established by STRING; the significant gene modules and hub genes of PPI were further performed using the Cytoscape software. The DAVID database was used to perform the GO and KEGG analyses of the significant module. Results. In total, 98 TMGs collectively involved in keratoconus and allergic disease were identified. 19 enriched biological processes including 71 genes and 25 enriched KEGG pathways including 59 genes were obtained. A TMG PPI network was constructed, and 51 genes/nodes were identified with 110 edges; 3 most significant modules and 12 hub genes were chosen from the PPIs. GO enrichment analysis showed that the TMGs were primarily associated with collagen catabolic process, extracellular matrix organization and disassembly, cell adhesion and migration, collagen-containing extracellular matrix, extracellular matrix, and structure organization. KEGG pathway analysis showed that these DEGs were mainly involved in the IL-17 signaling pathway, inflammatory bowel disease, rheumatoid arthritis, allograft rejection, T cell receptor signaling pathway, cytokine-cytokine receptor interaction, and TNF signaling pathway. Conclusions. The results revealed that IL10, IL6, MMP9, MMP1, HGF, VEGFA, MMP3, MMP2, TGFB1, IL4, IL2, and IFNG were potential key genes involved in keratoconus. IL-17 signaling pathway was the potential pathways accounting for pathogenesis and development of keratoconus. [ABSTRACT FROM AUTHOR]

Anti-CD19 chimeric antigen receptor (CAR) T-cells are an effective treatment for refractory B-cell lymphoma, but CD19 deletion is prone to relapse. We conducted this study to find more effective dual CAR19/20 T-cells to target B-cell lymphoma and prevent antigen loss leading to recurrence. In this study, we transduced CD19 and CD20 CARs into human T cells in parallel and compared parallel dual CAR19/20, single CAR, and tandem CAR19/20 in vitro and in vivo. After transduction with the corresponding vectors, CD19 and CD20 CARs were dually expressed in human T cells. It was observed that parallel CAR19/20 T-cells contained a substantial proportion of naive subpopulations and were able to proliferate in vitro. Treatment with parallel CAR19/20, single CAR, or tandem CAR19/20 T-cells sustainably induced complete lysis of leukemia cells in a 5 : 1 ratio. Compared with single or tandem CAR T-cell-transplanted mice, parallel CAR19/20 T-cell-transplanted mice exhibited smaller tumor volume, more stable body weight, and longer survival. This suggests that parallel CAR19/20 has superior antilymphoma activity in vivo. In addition, parallel CAR19/20 T-cells were also able to kill patients' lymphoma cells in vitro. Therefore, it can be considered that parallel CAR19/20 is equally effective against single CAR and tandem CAR19/20 in vitro but more effective against lymphoma cells in vivo. This is a promising treatment to prevent the recurrence of antigen loss following CD19-targeted therapy in B lymphoma. [ABSTRACT FROM AUTHOR]

Bufei decoction (BFD) has been applied to treat chronic obstructive pulmonary disease (COPD) for centuries as a recognized traditional Chinese herbal formula. However, mechanisms of BFD on COPD are unclear. This study conducts an inquiry into the underlying mechanisms of the therapeutic effect of BFD on COPD. A COPD rat model with qi deficiency in lungs was established through induction using cigarette and sawdust smoking combined with intratracheal instillation of lipopolysaccharide following BFD treatment for 28 days. Changes in Th17/Treg cells of COPD rats with the syndrome of lung qi deficiency after BFD administration were verified using pulmonary function, ELISA, flow cytometry, histopathology, and Western blotting assays. The findings showed that BFD protected COPD rats from decreased lung function and lung injury. BFD administration reduced proinflammatory cytokines IL-6 and IL-17 secretion, promoted inhibitory cytokines IL-10 and TGF-β secretion, decreased Th17/Treg cell ratio, markedly downregulated the Th17 cell transcription factor ROR-γt expression, and upregulated transcription factor Foxp3 expression in Treg cells. We speculate that lung tonic soup improved pulmonary qi deficiency in rats with COPD by regulating the balance of Th17/Treg cells. [ABSTRACT FROM AUTHOR]

Purpose. The aim of this study is to evaluate the effect of Shenqi fuzheng injection on leukopenia and T-cell subsets in patients with non-small cell lung cancer (NSCLC) undergoing radiotherapy. Methods. A total of 124 patients with advanced NSCLC treated in the oncology department of our hospital from January 2017 to January 2019 were included and assigned at a ratio of 1 : 1 to receive conventional radiotherapy (control group, n = 62) or conventional radiotherapy plus Shenqi Fuzheng injection (study group, n = 62) via the random number table method. Results. The study group showed a significantly higher objective response rate (ORR) and a lower incidence of leukopenia versus the control group (P < 0.05). After the treatment, Shenqi Fuzheng injection resulted in significantly lower levels of carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) in the study group versus conventional treatment given to the control group. After the treatment, the control group showed significantly decreased ratios of CD3+ T cells, CD4+ T cells, and CD4+/CD8+, and an increased ratio of CD8+ T cells, and significant differences when compared with the study group. The T-cell subsets of the patients in the study group showed no significant changes than those between the treatment. The median OS was 20.0 months in the control group and 23.5 months in the study group. The differences between the two groups in terms of OS did not come up to the statistical standard. Conclusion. Shenqi Fuzheng injection for NSCLC patients undergoing radiotherapy elevates the number of white blood cells, regulates T-cell immune function, reduces tumor markers, and enhances clinical efficacy. Further clinical trials are, however, required prior to clinical promotion. [ABSTRACT FROM AUTHOR]

Regulatory T cells play an important role in the progression of atherosclerosis. GARP is a newly biological membrane molecule existed on activated Tregs, which is related to the release of TGF-β. The antiatherosclerosis effects of statins partly depend on their multiple immune modulatory potencies. In this paper, we present that atorvastatin could upregulate the expression of GARP and TGF-β in CD4+ T cells and increase the numbers of CD4+LAP+ and CD4+Foxp3+ regulatory T cells in ApoE−/− mice. Also, we indicate that atorvastatin promotes the aggregation of GARP+ and Foxp3+ cells and secretory of the TGF-β1 in atherosclerotic plaques. Furthermore, we prove that atorvastatin could delay the procession of atherosclerosis and improve the stability of atherosclerotic plaques. Interestingly, we report that inhibition of GARP distinctly inhibits the anti-inflammatory effects of atorvastatin. We conclude that atorvastatin improves the inflammatory response in atherosclerosis partly by upregulating the expression of GARP on regulatory T cells. [ABSTRACT FROM AUTHOR]

Fibrosis is a general complication in many diseases. It is the main complication during peritoneal dialysis (PD) treatment, a therapy for renal failure disease. Local inflammation and mesothelial to mesenchymal transition (MMT) are well known key phenomena in peritoneal damage during PD. New data suggest that, in the peritoneal cavity, inflammatory changes may be regulated at least in part by a delicate balance between T helper 17 and regulatory T cells. This paper briefly reviews the implication of the Th17/Treg-axis in fibrotic diseases. Moreover, it compares current evidences described in PD animal experimental models, indicating a loss of Th17/Treg balance (Th17 predominance) leading to peritoneal damage during PD. In addition, considering the new clinical and animal experimental data, new therapeutic strategies to reduce the Th17 response and increase the regulatory T response are proposed. Thus, future goals should be to develop new clinical biomarkers to reverse this immune misbalance and reduce peritoneal fibrosis in PD. [ABSTRACT FROM AUTHOR]

This paper analyzes the main trend of the development of acquired immunodeficiency syndrome (AIDS) vaccines in recent years. Designing an HIV-1 vaccine that provides robust protection from HIV-1 infection remains a challenge despite many years of effort. Therefore, we describe the receptor binding domain of gp120 as a target for developing AIDS vaccines. And we recommend some measures that could induce efficiently and produce cross-reactive neutralizing antibodies with high binding affinity. Those measures may offer a new way of the research and development of the potent and broad AIDS vaccines. [ABSTRACT FROM AUTHOR]

Anthraquinones are a class of aromatic compounds with a 9,10-dioxoanthracene core. So far, 79 naturally occurring anthraquinones have been identified which include emodin, physcion, cascarin, catenarin, and rhein. A large body of literature has demonstrated that the naturally occurring anthraquinones possess a broad spectrum of bioactivities, such as cathartic, anticancer, antiinflammatory, antimicrobial, diuretic, vasorelaxing, and phytoestrogen activities, suggesting their possible clinical application in many diseases. Despite the advances that have been made in understanding the chemistry and biology of the anthraquinones in recent years, research into their mechanisms of action and therapeutic potential in autoimmune disorders is still at an early stage. In this paper, we briefly introduce the etiology of autoimmune diabetes, an autoimmune disorder that affects as many as 10 million worldwide, and the role of chemotaxis in autoimmune diabetes. We then outline the chemical structure and biological properties of the naturally occurring anthraquinones and their derivatives with an emphasis on recent findings about their immune regulation. We discuss the structure and activity relationship, mode of action, and therapeutic potential of the anthraquinones in autoimmune diabetes, including a new strategy for the use of the anthraquinones in autoimmune diabetes. [ABSTRACT FROM AUTHOR]

Aims. The clinical diagnosis of Kawasaki disease (KD) is not easy because of many atypical manifestations. This study is aimed at finding potential diagnostic markers and therapeutic targets for KD and analysing their correlation with immune cell infiltrations. Methods. First, we downloaded the KD dataset from the Gene Expression Omnibus (GEO) database and used R software to identify differentially expressed genes (DEGs) and perform functional correlation analysis. Then, CIBERSORT algorithm was used to evaluate immune cell infiltrations in samples. Coexpression analysis between DEGs and infiltrating immune cells was performed to screen the main infiltrating immune cells. Subsequently, the least absolute shrinkage and selection operator (LASSO) logistic regression analysis was used to screen the core genes related to KD. Finally, correlation analysis between the core genes and the main infiltrating immune cells was performed. Results. 327 DEGs were screened out in this study. Among them, 72 shared genes were the category of genes most likely to be disease-causing for they did not change before and after treatment. After analysis, it was found that expression level of IL2RB in KD tissues was significantly upregulated, the number of resting CD4+ memory T cells was decreased, and the decrease was significantly negatively correlated with the upregulated expression of IL2RB. Therefore, it was speculated that the upregulated expression of IL2RB disrupted Th1/Th2 cell differentiation balance, which led to a decrease of resting CD4+ memory T cells and finally caused disorder of immune microenvironment in patients with KD. Conclusions. Upregulated expression of IL2RB leads to disorder of immune microenvironment in patients with KD and eventually causes the occurrence and development of KD. Therefore, IL2RB may serve as a diagnostic marker and potential therapeutic target for KD. [ABSTRACT FROM AUTHOR]

Background. Yuanzhi powder (YZP) has been extensively investigated as a natural prescription with therapeutic benefits for Alzheimer's disease (AD). However, its active compounds and underlying immune mechanism for treating AD are still unclear. This study aimed to investigate the immune mechanism of YZP against AD through high-performance liquid chromatography (HPLC)-based network pharmacology and gene chip technology. Methods. Active components of YZP were obtained from HPLC and public databases. Subsequently, GSE5281, GSE28146, GSE29378, and GSE97760 from the Gene Expression Omnibus (GEO) database were downloaded to extract AD difference genes (DEGs). The active components-targets network and protein interaction network were then constructed by Cytoscape. The biological processes and signaling pathways, which implicate the targets of YZP for AD, were analyzed using the ClueGo Cytoscape plug-in. Molecular docking experiments were performed to verify the affinity of targets and ligands. Ultimately, the link between the hub genes and immune cell infiltration was assessed via CIBERSORT. Results. 83 YZP active compounds and 641 DEGs associated with AD, including quercetin, berberine, 3,6′-disinapoylsucrose, coptisine, and palmatine, were evaluated. We showed that FOS, CCL2, and GJA1 were the core targets and that the gap junction is an essential signaling pathway in YZP for AD. Furthermore, the AD group had a higher infiltration level of naïve B cells and resting CD4 memory T cells, as determined by the CIBERSORT. Notably, the immune cells-targets network demonstrates that GJA1 and GRM1 are intimately related to naïve B cells and plasma cells. Conclusions. YZP may help treat AD by targeting proteins with key active compounds to regulate naïve B cells and plasma cells. Our results demonstrate a new immune mechanism for treating AD with YZP. [ABSTRACT FROM AUTHOR]

CD3+CD56+ natural killer T (NKT)-like cells have an immune function of T cells and NK cells, which play an important role in antitumor and antiviral immune responses. This study aims to establish a CD3+CD56+ NKT-like cell model by simulating the memory NK effect induced by cytokines IL-12, IL-15, and IL-18 (IL-12/15/18) and explore the formation mechanism. Our study found that the IL-12/15/18 preactivated CD3+CD56+ NKT-like cells exhibited enhanced IFN-γ production in response to restimulation with IL-12/15/18 for 6h on day 7. The intrinsic potential of these trained cells was significantly improved, showing an increase in IFN-γ, TNF-α, and cell proliferation potential. The IFN-γ release, granzyme B level, and proliferation ability significantly increased when stimulated by NK-cell-sensitive K562 tumor cells. Among these cytokines, the combination of IL-12/15/18 was particularly effective. After the preactivation of IL-12/15/18, some cell surface proteins related to function and differentiation, such as CD11b, CD62 L, NKp46, NKG2A, and CD127, showed an evident and consistent change trend. The CDK4/6 inhibitor can effectively weaken this effect, and the expression of cyclin D1, Rb protein phosphorylation, and E2F-1 decreased significantly. Our work revealed that cytokine IL-12/15/18 can induce CD3+CD56+ NKT-like cells to obtain enhanced training immunity, which was a memory-like phenomenon. [ABSTRACT FROM AUTHOR]

IgG4-related disease is a multiorgan immunological fibroinflammatory disorder characterized by lymphoplasmacytic infiltration and fibrosis in multiple organs accompanied by high serum IgG4 levels. The salivary glands are the most common organs involved in this disease. Recently, chronic sclerosing sialadenitis affecting salivary glands, formerly known as Kiittner's tumor, and Mikulicz's disease have been classified as a class of IgG4-related diseases. The etiopathobiology of IgG4-related disease is not fully understood. It has recently been hypothesized that the inflammatory and fibrotic process and the increased serum IgG4+ levels in IgG4-related disease are the result of an interaction between B cells and T helper cells, suggesting that T cells may play a key role in the pathogenesis of this disease. The aim of this review is to discuss the proposed roles of different T cell subsets in the pathogenesis of IgG4-related disease focusing on their roles in immunopathogenesis of IgG4-related sialadenitis. [ABSTRACT FROM AUTHOR]