Search

IntroductionGranulocytic myeloid-derived suppressor cells (G-MDSCs) show fast recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) constituting the major part of peripheral blood in the early phase. Although G-MDSCs mediate immune suppression through multiple mechanisms, they may also promote inflammation under specific conditions. MethodsG-MDSCs were isolated from 82 patients following allo-HSCT within 90 days after allo-HSCT, and their interactions with autologous CD3+ T-cells were examined. T-cell proliferation was assessed by flow cytometry following CFSE staining, while differentiation and interferon-γ secretion were characterized using chemokine receptor profiling and ELISpot assays, respectively. NK cell cytotoxicity was evaluated through co-culture with K562 cells. An aGVHD xenogeneic model in humanized mice was employed to study the in vivo effects of human leukocytes. Furthermore, transcriptional alterations in G-MDSCs were analyzed via RNA sequencing to investigate functional transitions.ResultsG-MDSCs promoted inflammation in the early-stage, by facilitating cytokine secretion and proliferation of T cells, as well as their differentiation into pro-inflammatory T helper subsets. At day 28, patients with a higher number of G-MDSCs exhibited an increased risk of developing grades II-IV aGvHD. Besides, adoptive transfer of G-MDSCs from patients at day 28 into humanized mice exacerbated aGvHD. However, at day 90, G-MDSCs led to immunosuppression, characterized by upregulated expression of indoleamine 2,3-dioxygenase gene and interleukin-10 secretion, coupled with the inhibition of T cell proliferation. Furthermore, transcriptional analysis of G-MDSCs at day 28 and day 90 revealed that 1445 genes were differentially expressed. These genes were associated with various pathways, revealing the molecular signatures of early post-transplant differentiation in G-MDSCs. In addition, genes linked to the endoplasmic reticulum stress were upregulated in patients without aGvHD. The acquisition of immunosuppressive function by G-MDSCs may depend on the activation of CXCL2 and DERL1 genes. ConclusionOur findings revealed the alteration in the immune characteristics of G-MDSCs within the first 90 days post-allo-HSCT. Moreover, the quantity of G-MDSCs at day 28 may serve as a predictive indicator for the development of aGvHD.

BackgroundEvidence shows people living with CHB even with a normal ALT (40U/L as threshold) suffer histological disease and there is still little research to evaluate the potential benefit of antiviral benefits in them.MethodsWe retrospectively examined 1352 patients who underwent liver biopsy from 2017 to 2021 and then obtained their 1-year follow-up data to analyze.ResultsALT levels were categorized into high and low, with thresholds set at >29 for males and >15 for females through Youden’s Index. The high normal ALT group showed significant histological disease at baseline (56.43% vs 43.82%, p< 0.001), and better HBV DNA clearance from treatment using PSM (p=0.005). Similar results were obtained using 2016 AASLD high normals (male >30, female >19). Further multivariate logistic analysis showed that high normal ALT (both criterias) was an independent predictor of treatment (OR 1.993, 95% CI 1.115-3.560, p=0.020; OR 2.000, 95% CI 1.055-3.793, p=0.034) Both of the models had higher AUC compared with current scoring system, and there was no obvious difference between the two models (AUC:0.8840 vs 0.8835)ConclusionMale >30 or female >19 and Male >29 or female>15 are suggested to be better thresholds for normal ALT. Having a high normal ALT in CHB provides a potential benefit in antiviral therapy.

BackgroundTumor vaccines have become crucial in cancer immunotherapy, but, only a limited number of phase III clinical trials have demonstrated clinical efficacy. The crux of this issue is the inability of tumor vaccines to effectively harmonize the tumor microenvironment with its intricate interplay. One factor that can hinder the effectiveness of vaccines is the natural immunosuppressive element present in the tumor microenvironment. This element can lead to low rates of T-cell response specific to antigens and the development of acquired resistance. Conversely, anticancer vaccines alter the tumor microenvironment in conflicting manners, inducing both immune activation and immunological evasion. Hence, comprehending the correlation between tumor vaccines and the tumor microenvironment would establish a foundation for forthcoming tumor treatment.ObjectiveOur review explores the realm of research pertaining to tumor vaccinations and the tumor microenvironment. Our objective is to investigate the correlation between tumor vaccines and the tumor microenvironment within this domain. We then focus our review on the dominant international paradigms in this research field and visually illustrates the historical progression and emergent patterns observed in the past.MethodsFrom January 1, 1999 to February 7, 2023, 1420 articles on the interplay between tumor vaccines and the tumor microenvironment were published, according to The Clarivate Web of Science (WOS) database used in our review. A bibliometric review was designed for this collection and consisted of an evaluation. The evaluation encompassed various discernible attributes, including the year of publication, the journals in which the articles were published, the authors involved, the affiliated institutions, the geographical locations of the institutions, the references cited, and the keywords employed.ResultsBetween the years 1999 and 2022, publications saw a significant increase, from 3 to 265 annually. With 72 papers published, Frontiers in Immunology had the most manuscripts published. The Cancer Research publication garnered the highest number of citations, amounting to 2874 citations. The United States exerts significant dominance in the subject, with the National Cancer Institute being recognized as a prominent institution in terms of both productivity and influence. Furthermore, Elizabeth M. Jaffee was recognized as the field’s most prolific and influential author with 24 publications and 1,756 citations. The co-occurrence cluster analysis was conducted on the top 197 keywords, resulting in the identification of five distinct clusters. The most recent high-frequency keywords, namely immune therapy, dendritic cell, tumor microenvironment, cancer, and vaccine, signify the emerging frontiers in the interaction between tumor vaccines and the tumor microenvironment.ConclusionOur review uncovers insights into contemporary trends, global patterns of collaboration, fundamental knowledge, research areas of high interest, and emerging frontiers in the field of TME-targeted vaccines.

Malignant tumors have a unique tumor microenvironment (TME), which includes mild acidity, hypoxia, overexpressed reactive oxygen species (ROS), and high glutathione (GSH) levels, among others. Recently, TME regulation approaches have attracted widespread attention in cancer immunotherapy. Nanoparticles as drug delivery systems have ability to modulate the hydrophilicity of drugs to affect drug uptake and efflux in tumor. Especially, the metal nanoparticles have been extensive applied for tumor immunotherapy due to their unique physical properties and elaborate design. However, the potential deficiencies of metal nanoparticles due to their low biodegradability, toxicity and treatment side effects restrict their clinical application. In this review, we briefly introduce the feature characteristics of the TME and the recent advances in tumor microenvironment responsive metal nanoparticles for tumor immunotherapy. In addition, nanoparticles could be combined with other treatments, such as chemotherapy, radiotherapy and photodynamic therapy also is presented. Finally, the challenges and outlook for improving the antitumor immunotherapy efficiency, side effect and potential risks of metal nanoparticles has been discussed.

The tumor microenvironment (TME) is a crucial driving factor for tumor progression and it can hinder the body’s immune response by altering the metabolic activity of immune cells. Both tumor and immune cells maintain their proliferative characteristics and physiological functions through transporter-mediated regulation of nutrient acquisition and metabolite efflux. Transporters also play an important role in modulating immune responses in the TME. In this review, we outline the metabolic characteristics of the TME and systematically elaborate on the effects of abundant metabolites on immune cell function and transporter expression. We also discuss the mechanism of tumor immune escape due to transporter dysfunction. Finally, we introduce some transporter-targeted antitumor therapeutic strategies, with the aim of providing new insights into the development of antitumor drugs and rational drug usage for clinical cancer therapy.

Interstitial lung disease (ILD) is one of the most serious lung complications of connective tissue disease (CTD). The application of proteomics in the past decade has revealed that various proteins are involved in the pathogenesis of each subtype of CTD-ILD through different pathways, providing novel ideas to study pathological mechanisms and clinical biomarkers. On this basis, a multidimensional diagnosis or prediction model is established. This paper reviews the results of proteomic detection of different subtypes of CTD-ILD and discusses the role of some differentially expressed proteins in the development of pulmonary fibrosis and their potential clinical applications.

BackgroundA third mRNA vaccine booster is recommended to improve immunity against SARS-CoV-2 in kidney transplant recipients (KTRs). However, the immunity against SARS-CoV-2 Ancestral strain and Delta and Omicron variants elicited by the third dose of inactivated booster vaccine in KTRs remains unknown.MethodsThe blood parameters related to blood cells count, hepatic function, kidney function, heart injury and immunity were explored clinically from laboratory examinations. SARS-CoV-2 specific antibody IgG titer was detected using an enzyme-linked immunosorbent assay. Cellular immunity was analyzed using interferon-γ enzyme-linked immunospot assay.ResultsThe results showed that there were no severe adverse effects and apparent changes of clinical laboratory biomarkers in KTRs and healthy volunteers (HVs) after homologous inactivated vaccine booster. A third dose of inactivated vaccine booster significantly increased anti-Ancestral-spike-trimer-IgG and anti-Ancestral-receptor binding domain (RBD)-IgG titers in KTRs and HVs compared with the second vaccination. However, the anti-Delta-RBD-IgG and anti-Omicron-RBD-IgG titers were significantly lower than anti-Ancestral-RBD-IgG titer in KTRs and HVs after the third dose. Notably, only 25.6% (10/39) and 10.3% (4/39) of KTRs had seropositivity for anti-Delta-RBD-IgG and anti-Omicron-RBD-IgG after booster, which were significantly lower than HVs (anti-Delta-RBD-IgG: 100%, anti-Omicron-RBD-IgG: 77.8%). Ancestral strain nucleocapsid protein and spike specific T cell frequency after booster was not significantly increased in KTRs compared with the second dose, significantly lower than that in HVs. Moreover, 33.3% (12/36), 14.3% (3/21) and 14.3% (3/21) of KTRs were positive for the Ancestral strain and Delta and Omicron spike-specific T cells, which were significantly lower than HVs (Ancestral: 80.8%, Delta: 53.8%, and Omicron: 57.7%).ConclusionsA third dose of inactivated booster vaccine may significantly increase humoral immunity against the Ancestral strain in KTRs, while humoral and cellular immunity against the Delta and Omicron variants were still poor in KTRs.

Th17 cells play an important role in the abnormal immune response in inflammatory bowel disease (IBD) and are involved in the development and progression of inflammation and fibrosis. An increasing amount of data has shown that gut microbes are important parts of intestinal immunity and regulators of Th17 cellular immunity. Th17 cell differentiation is regulated by intestinal bacteria and cytokines, and Th17 cells regulate the intestinal mucosal immune microenvironment by secreting cytokines, such as IL-17, IL-21, and IL-26. Solid evidence showed that, regarding the treatment of IBD by targeting Th17 cells, the therapeutic effect of different biological agents varies greatly. Fecal bacteria transplantation (FMT) in the treatment of IBD has been a popular research topic in recent years and is safe and effective with few side effects. To further understand the role of Th17 cells in the progression of IBD and associated therapeutic prospects, this review will discuss the progress of related research on Th17 cells in IBD by focusing on the interaction and immune regulation between Th17 cells and gut microbiota.

Acute pancreatitis is a common gastrointestinal disease characterized by inflammation of the exocrine pancreas and manifesting itself through acute onset of abdominal pain. It is frequently associated with organ failure, pancreatic necrosis, and death. Mounting evidence describes monocytes - phagocytic, antigen presenting, and regulatory cells of the innate immune system - as key contributors and regulators of the inflammatory response and subsequent organ failure in acute pancreatitis. This review highlights the recent advances of dynamic change of numbers, phenotypes, and functions of circulating monocytes as well as their underling regulatory mechanisms with a special focus on the role of lipid modulation during acute pancreatitis.

Human hepatitis B virus (HBV) is a small, enveloped DNA virus that causes acute and chronic hepatitis. Chronic hepatitis B (CHB) is associated with hepatocellular carcinoma pathogenesis. Interferons (IFNs) have been used for the treatment of CHB for a long time, with advantages including less treatment duration and sustained virological response. Presently, various evidence suggests that epigenetic modification of the viral covalently closed circular DNA (cccDNA) and the host genome is crucial for the regulation of viral activity. This modification includes histone acetylation, DNA methylation, N6-methyladenosine, and non-coding RNA modification. IFN treatment for CHB can stimulate multiple IFN-stimulated genes for inhibiting virus replication. IFNs can also affect the HBV life cycle through epigenetic modulation. In this review, we summarized the different mechanisms through which IFN-α inhibits HBV replication, including epigenetic regulation. Moreover, the mechanisms underlying IFN activity are discussed, which indicated its potential as a novel treatment for CHB. It is proposed that epigenetic changes such as histone acetylation, DNA methylation, m6A methylation could be the targets of IFN, which may offer a novel approach to HBV treatment.

BackgroundGlioma is a highly aggressive brain cancer with a poor prognosis. Necroptosis is a form of programmed cell death occurring during tumor development and in immune microenvironments. The prognostic value of necroptosis in glioma is unclear. This study aimed to develop a prognostic glioma model based on necroptosis.MethodsA necroptosis-related risk model was constructed by Cox regression analysis based on The Cancer Genome Atlas (TCGA) training set, validated in two Chinese Glioma Genome Atlas (CGGA) validation sets. We explored the differences in immune infiltration and immune checkpoint genes between low and high risk groups and constructed a nomogram. Moreover, we compiled a third validation cohort including 43 glioma patients. The expression of necroptosis-related genes was verified in matched tissues using immunochemical staining in the third cohort, and we analyzed their relationship to clinicopathological features.ResultsThree necroptosis-related differentially expressed genes (EZH2, LEF1, and CASP1) were selected to construct the prognostic model. Glioma patients with a high risk score in the TCGA and CGGA cohorts had significantly shorter overall survival. The necroptosis-related risk model and nomogram exhibited good predictive performance in the TCGA training set and the CGGA validation sets. Furthermore, patients in the high risk group had higher immune infiltration status and higher expression of immune checkpoint genes, which was positively correlated with poorer outcomes. In the third validation cohort, the expression levels of the three proteins encoded by EZH2, LEF1, and CASP1 in glioma tissues were significantly higher than those from paracancerous tissues. They were also closely associated with disease severity and prognosis.ConclusionsOur necroptosis-related risk model can be used to predict the prognosis of glioma patients and improve prognostic accuracy, which may provide potential therapeutic targets and a theoretical basis for treatment.

Fra-1(Fos-related antigen1), a member of transcription factor activator protein (AP-1), plays an important role in cell proliferation, apoptosis, differentiation, inflammation, oncogenesis and tumor metastasis. Accumulating evidence suggest that the malignancy and invasive ability of tumors can be significantly changed by directly targeting Fra-1. Besides, the effects of Fra-1 are gradually revealed in immune and inflammatory settings, such as arthritis, pneumonia, psoriasis and cardiovascular disease. These regulatory mechanisms that orchestrate immune and non-immune cells underlie Fra-1 as a potential therapeutic target for a variety of human diseases. In this review, we focus on the current knowledge of Fra-1 in immune system, highlighting its unique importance in regulating tissue homeostasis. In addition, we also discuss the possible critical intervention strategy in diseases, which also outline future research and development avenues.

Coronavirus disease 2019 (COVID-19) is a respiratory infectious disease that seriously threatens human life. The clinical manifestations of severe COVID-19 include acute respiratory distress syndrome and multiple organ failure. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19, spreads through contaminated droplets. SARS-CoV-2 particles have been detected in the saliva of COVID-19 patients, implying that the virus can infect and damage the oral cavity. The oral manifestations of COVID-19 include xerostomia and gustatory dysfunction. Numerous studies showed that the four structural proteins of SARS-CoV-2 are its potential pathogenic factors, especially the S protein, which binds to human ACE2 receptors facilitating the entry of the virus into the host cells. Usually, upon entry into the host cell, a pathogen triggers the host’s immune response. However, a mount of multi-omics and immunological analyses revealed that COVID-19 is caused by immune dysregulation. A decrease in the number and phenotypes of immune cells, IFN-1 production and excessive release of certain cytokines have also been reported. In conclusion, this review summarizes the oral manifestations of COVID-19 and multi-omics analysis of SARS-CoV-2 infection.

Lifestyle choices, external environment, aging, and other factors influence the synthesis of melatonin. Although the physiological functions of melatonin have been widely studied in relation to specific organs, the systemic effects of endogenous melatonin reduction has not been reported. This study evaluates the systemic changes and possible pathogenic risks in an endogenous melatonin reduction (EMR) mouse model deficient in the rate limiting enzyme in melatonin production, arylalkylamine N-acetyltransferase (Aanat) gene. Using this model, we identified a new relationship between melatonin, Alzheimer’s disease (AD), and gut microbiota. Systematic changes were evaluated using multi-omics analysis. Fecal microbiota transplantation (FMT) was performed to examine the role of gut microbiota in the pathogenic risks of EMR. EMR mice exhibited a pan-metabolic disorder, with significant transcriptome changes in 11 organs, serum metabolome alterations as well as microbiota dysbiosis. Microbiota dysbiosis was accompanied by increased gut permeability along with gut and systemic inflammation. Correlation analysis revealed that systemic inflammation may be related to the increase of Ruminiclostridium_5 relative abundance. 8-month-old EMR mice had AD-like phenotypes, including Iba-1 activation, A β protein deposition and decreased spatial memory ability. Moreover, EMR mice showed decreased anti stress ability, under high-fat diet, EMR mice had greater body weight and more obvious hepatic steatosis compared with WT group. FMT improved gut permeability, systemic inflammation, and AD-related phenotypes, while reducing obesity in EMR mice. Our findings suggest EMR causes systemic changes mediated by gut microbiota dysbiosis, which may be a pathogenic factor for AD and obesity, we further proved the gut microbiota is a potential target for the prevention and treatment of AD and obesity.

The liver is an immunologically tolerant organ and a common site of distant metastasis for various cancers. The expression levels of glucose-regulated protein 78 (GRP78) have been associated with tumor malignancy. Secretory GRP78 (sGRP78) released from tumor cells contributes to the establishment of an immunosuppressive tumor microenvironment by regulating cytokine production in macrophages and dendritic cells (DCs). However, the role of sGRP78 on tumor cell colonization and metastasis in the liver remains unclear. Herein, we found that GRP78 was expressed at higher levels in the liver compared to other tissues and organs. We performed intravital imaging using a sGRP78-overexpressing breast cancer cell line (E0771) and found that sGRP78 interacted with dendritic cells (DCs) and F4/80+ macrophages in the liver. Importantly, sGRP78 overexpression inhibited DC activation and induced M2-like polarization in F4/80+ macrophages. Moreover, sGRP78 overexpression enhanced TGF-β production in the liver. In conclusion, sGRP78 promotes tumor cell colonization in the liver by remodeling the tumor microenvironment and promoting immune tolerance. The ability of sGRP78-targeting strategies to prevent or treat liver metastasis should be further examined.

Myeloid-derived suppressor cells (MDSCs) are a major component of the immunosuppressive tumor microenvironment (TME) and have been recognized as a contributing factor to inflammation-related cancers. However, the molecular mechanisms of MDSCs accumulation and activation remain elusive. We previously showed that the proinflammatory molecule S100A9 in TME exerts a tumor-promoting effect in colorectal carcinoma (CRC). In this report, we investigated the effect and molecular mechanisms of S100A9 on the accumulation and immunosuppressive function of MDSCs in CRC. Elevated S100A9 and MDSCs were found in tumor tissue and peripheral blood from CRC patients. Circulating S100A9 and MDSCs were positively associated to each other, and both S100A9 and MDSCs were correlated to neoplastic progression. Using a CRC cell line LoVo-induced MDSCs model, we found that S100A9 stimulated chemotaxis and activation but not viability of MDSCs. Mechanistic studies demonstrated that activation of RAGE-mediated p38 MAPK and TLR4-mediated NF-κB signaling pathways were involved in S100A9-induced chemotaxis and MDSCs activation, respectively. Furthermore, ROC analysis showed that combination detection of S100A9 and MDSCs was superior to individual detection of these two factors for diagnosing CRC patients with advanced staging and lymphatic metastasis, which yielded an area under the ROC curve (AUC) of 0.92 with 86.7% sensitivity and 86.4% specificity, and an AUC of 0.82 with 75% sensitivity and 77.1% specificity, respectively. Collectively, our study suggests that the S100A9 plays a pivotal role in immunosuppressive TME by stimulating MDSCs chemotaxis and activation, and combination detection of S100A9 and MDSCs may serve as a potential marker for diagnosis of CRC progression.

Management of inflammatory bowel disease (IBD) is a real clinical challenge. Despite intense investigation, the mechanisms of IBD remain substantially unidentified. Some inflammatory conditions, such as matrix metalloproteinases (MMPs) and the nuclear factor-κB (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathways, are reported to contribute to the development and maintenance of IBD. Regulation of their common upstream signaling, that is, reactive oxygen species (ROS), may be important to control the progression of IBD. In the present study, we found that procyanidin, a powerful antioxidation flavonoid, has a significant effect on ROS clearance on THP-1 macrophages after lipopolysaccharide (LPS) or LPS-combined adenosine triphosphate stimulation, thus downregulating MMP9 expression, suppressing NF-κB signaling, and interrupting the formation of the NLRP3 inflammasome. Moreover, our in vivo data showed that procyanidin attenuated Dextran sulfate sodium-induced experimental colitis in a dose-dependent fashion by suppressing the expression of MMP9, NF-κB, and NLRP3 inflammasome signaling in colonic tissues in mice. Overall, our results suggested that targeting ROS could be a potential therapeutic choice for colonic inflammation.

Cell adhesion molecules (CAM) are crucial in several pathological inflammation processes in Alzheimer's disease (AD). However, their potential for clinical diagnostics remains unknown. The present investigation evaluated the clinical significance of ALCAM, VCAM-1, NCAM, and ICAM-1 levels in the plasma of participants with cognitive impairment (44 patients with mild cognitive impairment, 71 patients with Alzheimer's dementia, and 18 patients with other dementia) and 28 controls with normal cognitive ability. We also detected plasma levels of multiple inflammatory factors (IFN-gamma, IL-18, IL-1beta, IL-13, IL-8, IL-7, CCL11, MCP-1, TSLP, IL-10, BDNF, IL-17, IL-5, TREM-1) using Multiplex liquid chip and plasma levels of Abeta1-42 and Abeta1-40 using liquid-phase flow cytometry (FCM). Our findings demonstrated a correlation of ALCAM and VCAM-1 with age, the severity of cognitive decline, and MTA, but no significant difference between groups for NCAM and ICAM-1. ALCAM and VCAM-1 both demonstrated a positive correlation with the degree of atrophy in the medial temporal lobe structure. Further analysis revealed no significant correlation in plasma between VCAM-1, ALCAM and Abeta1-40, Abeta1-42. Nevertheless, there was a significant correlation between VCAM-1, ALCAM and many inflammatory factors. Furthermore, the predictive value of ALCAM and VCAM-1 for AD was assessed using a multi-parameter regression model. ALCAM and VCAM-1 in combination with ApoE4, education, age, and MMSE could predict AD with high precision (AUC=0.891; AIC=146.9) without imaging diagnosis. ALCAM and VCAM-1 combination improved the predictive accuracy significantly. In a nutshell, these findings revealed ALCAM and VCAM-1 as reliable indicators of Alzheimer's disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Dai, Tang, Lu, Liu, Hou, Lu, Kong, Peng, Lin, Zheng, Xu, Ying, Ji, Pan, Wu, Zeng and Wei.)

By December 2020, the COVID-19 pandemic had caused more than 74 million confirmed cases and 1.6 million related deaths around the world. However, only a few drugs have been approved in certain areas and for use in conditional patients, and the vaccine candidates were only recently approved or authorized for emergency use without being fully implemented worldwide, suggesting that we are yet to reach effective control of the current outbreak as its uninhibited transmission continues precariously. Over the past few months, several therapeutic candidates have been proven ineffective in large clinical trials, while some other agents exhibited promising preliminary results. Meanwhile, the investigation of SARS-CoV-2-specific antivirals is underway. Despite still being preclinical, these agents could be beneficial for the long-term control of COVID-19 and deserve more research focus. In this article, we update the current status of therapeutic candidates that have been examined for COVID-19 management, including the virus-targeting inhibitors and host-targeting agents, with their antiviral efficacy in vitro , in vivo , and in clinical studies. Finally, we highlight the current challenges and future prospect of developing potent therapeutic agents against COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Lu, Wong and Lin.)

The T-cell receptor (TCR)/CD3 complex is crucial for T-cell development and regulation. In humans, CD3D, CD3E , and CD3Z gene defects cause severe combined T- and B-cell immunodeficiency. However, CD3G mutations alone lead to a less severe condition, which is mainly characterized by autoimmunity. In the present study, we report the case of a 36-year-old male who presented with recurrent sinopulmonary infections without opportunistic infections; this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation. This patient had the common variable immunodeficiency (CVID) phenotype and received regular immunoglobulin infusions over 20-years; he gradually developed nodular regenerative hyperplasia over a 5-year period. Distinct from the previously reported CD3G mutations, which mainly present as autoimmunity, the novel CD3G deletion (c.del213A) in our patient caused an obvious decrease in switched memory B cells and diminished CD40L expression. However, sufficient Treg suppression function was maintained so that he remained free of autoimmune thyroiditis (AIT), inflammatory bowel disease (IBD), and autoimmune pancytopenia. A PubMed search for this rare disease entity revealed seven Turkish and two Spanish patients (five unrelated families). Among a total of 20 alleles, there were 14 splicing mutations (80(-1)G>C), two missense mutations (c.1G>A), two nonsense mutations (c.250A>T), and two deletions (c.del213A). Three patients presented with isolated AIT without significant infections. Three patients died, one from a severe infection at 31 months, one from post-transplant respiratory failure due to viral pneumonia at 17 months, and one from graft-vs.-host disease at 47 months. Those experiencing opportunistic infections, severe life-threatening infections in need of hematopoietic stem cell transplantation, and IBD-like diarrhea had a significantly higher mortality rate compared with those without these features ( p = 0.0124, p = 0.01, and p = 0.0124, respectively). The patients with AIT had a significantly better prognosis ( p = 0.0124) to those without AIT. Our patient with the novel CD3G mutation presented with predominant B-cell deficiency overlapping with the CVID phenotype but without recognizable autoimmunity, which was consistent with his normal Treg suppression function., (Copyright © 2019 Lee, Fan, Lu, Chen, Kuo, Lin, Tsai, Jaing, Chen, Yeh, Yao and Huang.)

The "master transcription factor" FOXP3 regulates the differentiation, homeostasis, and suppressor function of CD4 + regulatory T (Treg) cells, which are critical in maintaining immune tolerance. Epigenetic regulation of FOXP3 expression has been demonstrated to be important to Treg cell development, but the induction of human Treg cells through epigenetic modification has not been clearly described. We report that the combination of the DNA methyltransferase inhibitor 5-azacytidine (5-Aza) and suboptimal T cell receptor (TCR) stimulation promoted CD4 + CD25 h FOXP3 + T cell induction from human CD4 + CD25 - T cells. 5-Aza treatment enhanced the expression of Treg cell signature genes, such as CD25, FOXP3, CTLA-4, and GITR, in CD4 + CD25 h cells. Moreover, 5-Aza-treated CD4 + CD25 h T cells showed potent suppressive activity in a cell contact-dependent manner and reduced methylation in the Treg-specific demethylated region (TSDR) in the FOXP3 gene. The analysis of cytokine production revealed that CD4 + CD25 - T cells with 5-Aza treatment produced comparable levels of interferon (IFN)-γ and transforming growth factor (TGF)-β, but less IL-10 and more IL-2, when compared to cells without 5-Aza treatment. The increased IL-2 was indispensible to the enhanced FOXP3 expression in 5-Aza-treated CD4 + CD25 h cells. Finally, 5-Aza-treated CD4 + CD25 h T cells could be expanded with IL-2 supplementation alone and maintained FOXP3 expression and suppressor function through the expansion. Our findings demonstrate that DNA demethylation can enhance the induction of human Treg cells and promise to solve one of the challenges with using Treg cells in therapeutic approaches.