Ewing sarcoma (EwS) is the second most prevalent pediatric bone malignancy, characterized by its aggressive behavior and unfavorable prognosis. The tumor microenvironment (TME) of EwS is shaped by immunosuppressive components, including myeloid-derived suppressor cells, tumor-associated macrophages, and immune checkpoint molecules such as PD-1/PD-L1 and HLA-G. These elements impair anti-tumor immune responses by modulating the function of tumor-infiltrating immune cells, such as regulatory T cells (Tregs), CD8+ T cells, and natural killer cells. Chemokines, including CXCL9 and CXCL12, and cytokines, such as transforming growth factor-beta and interleukin-10, further contribute to immune suppression and promote metastatic dissemination. Recent advances in immunotherapy have highlighted the therapeutic potential of modulating immune cells and signaling pathways to enhance anti-tumor immunity. This review provides a comprehensive analysis of the complex immune landscape within the EwS TME, focusing on the mechanistic roles of key immune components and their potential as therapeutic targets. Understanding these interactions could pave the way for innovative treatment strategies to improve clinical outcomes in patients with EwS.

Sepsis is a life-threatening complication caused by the overwhelming immune response to bacterial infection leading to the fatal organ damage and even death. Helminth infections modulate host's immune system through secreting functional proteins to reduce host immune attack as a survival strategy, therefore have been used for the therapy of some inflammatory or autoimmune diseases. Sj-Cys is a cysteine protease inhibitor secreted by Schistosoma japonicum exerting strong immunomodulatory function which has been used to treat sepsis, however, the mechanism underlying the therapeutic efficacy has not been fully elucidated. In this study, we expressed Sj-Cys as recombinant protein (rSj-Cys) in prokaryotic system and rSj-Cys was used to incubate with mouse bone marrow derived dendritic cells (BMDCs) in vitro. Our study revealed that rSj-Cys was able to induce differentiation of BMDCs to tolerant property (TolDCs). Adoptive transfer of rSj-Cys induced-TolDCs into mice with cecal ligation and puncture (CLP)-induced sepsis conferred a significant therapeutic effect on CLP-induced sepsis in mice with reduced mortality and vital organ damage. The therapeutic effect of Sj-Cys-induced TolDCs was associated with upregulation of CD3+CD4+CD25+Foxp3+ regulatory T cells (Tregs) and reduced inflammatory cytokines IL-6 and TNF-α and boosted level of regulatory cytokines IL-10 and TGF-β. The results identified in this study further suggest rSj-Cys has the potential to be developed into a drug substance for the treatment of inflammatory or autoimmune diseases due to its immunomodulatory effect on tolerant dendritic cells and regulatory T cells.

The tumor microenvironment (TME) plays a crucial role in cancer development and spreading being considered as "the dark side of the tumor". Within this term tumor cells, immune components, supporting cells, extracellular matrix and a myriad of bioactive molecules that synergistically promote tumor development and therapeutic resistance, are included. Recent findings revealed the profound impacts of TME on cancer development, serving as physical support, critical mediator and biodynamic matrix in cancer evolution, immune modulation, and treatment outcomes. TME targeting strategies built on vasculature, immune checkpoints, and immuno-cell therapies, have paved the way for revolutionary clinical interventions. On this basis, the relevance of pre-clinical and clinical investigations has rapidly become fundamental for implementing novel therapeutical strategies breaking cell-cell and cell -mediators' interactions between TME components and tumor cells. This review summarizes the key players in the breast and pancreatic TME, elucidating the intricate interactions among cancer cells and their essential role for cancer progression and therapeutic resistance. Different tumors such breast and pancreatic cancer have both different and similar stroma features, that might affect therapeutic strategies. Therefore, this review aims to comprehensively evaluate recent findings for refining breast and pancreatic cancer therapies and improve patient prognoses by exploiting the TME's complexity in the next future.

Chronic pain susceptibility varies across individuals, and the immune system, among other factors, appears to be involved in this variability. This study aims to examine whether modulating the immune system around the inciting events provides protection against the development of chronic pain and related comorbidities. Dimethyl fumarate (DMF) - an immunomodulator - or vehicle (VEH) was administered 7 days before spared nerve injury (SNI) in Wistar Han male rats. After the surgery, half of the animals from each group shifted treatments for an additional 7 days, resulting in 4 groups: continuous treatment (DMF-DMF), pretreatment (DMF-VEH), early treatment (VEH-DMF), and control (VEH-VEH). As a result, DMF-DMF, DMF-VEH, and VEH-DMF reduced allodynia and attenuated anhedonia measured at 4 weeks post-SNI, compared to VEH-VEH. VEH-DMF increased serum protein levels of anti-inflammatory markers, including IL-10 and G-CSF, and those pleiotropic, such as IL-6, IFN-g, and IL-17A. The leptin reduction seems to be a delayed effect of DMF. Meanwhile, other anti-inflammatory cytokines, IL-4 and IL-13, increased with relatively large effect sizes. The subsequent experiment shows that DMF pretreatment also alleviated anxiety- and cognitive dysfunction-like behaviors, measured at 6-7 weeks post-surgery. Additionally, this treatment significantly diminished SNI-induced protein ATF-3 - a neuronal injury marker - in L4-6 DRG at day 49 post-surgery. Nuclear factor E2-related factor 2 (Nrf2), a major regulator of the antioxidant and anti-inflammatory response, appears to be linked with DMF protective mechanisms, with trigonelline, an Nrf2 inhibitor, largely abolishing its effects. In conclusion, preexposure to an anti-inflammatory drug improved rats' resilience to long-term allodynia and pain-related manifestations. This suggests the immune system's involvement in the susceptibility to chronic pain and its comorbidities. Regarding mechanisms, Nrf2 and its inflammatory downstream effectors, as well as ATF-3, play a significant role, although potential contributions of other factors cannot be dismissed.

The association between C1q deficiency and the development of Systemic Lupus Erythematosus (SLE) is well established. Several studies have shown that deficiency in C1q is associated with failed apoptotic cleanup, leading to SLE progression. However, the magnitude of this correlation indicates that C1q may play a much more complex role in the development of lupus. This study provides further insight into the pathogenesis of SLE by investigating the consequences of the interaction between C1q and CD4+ T-cells in the breakdown of self-tolerance. Since the C1q/C1q receptor interaction is postulated to play a role, we first confirmed the presence of surface-expressed C1q and C1q receptors on CD4+ T-cells. Then, cell proliferation assays were performed in the presence and absence of purified C1q, gC1qR, and cC1qR. The supernatants of these cultures were used to determine the levels of immunoregulatory cytokines released. Our data confirm that increasing concentrations of C1q and gC1qR significantly inhibited cell proliferation. Furthermore, the CD4+ cells treated with either C1q or gC1qR secreted reduced inflammatory cytokines, such as IL-6 and TNF-alpha, compared to the untreated controls, suggesting that C1q deficiency facilitates the uncontrolled secretion of these critical cytokines, thus contributing to SLE. Although the role of pro-inflammatory cytokines in the induction of SLE is well documented, the mechanism by which C1q contributes to the disease is still a study in progress. Our data demonstrate that the interaction between C1q and its receptors on CD4+ T cells plays a critical role in the suppression of pro-inflammatory cytokines that cause tissue injury in SLE. Therefore, the C1q-C1qR axis may provide a rationally sound target for the design of novel therapeutic approaches for SLE treatment.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by parkinsonism, cerebellar dysfunction, and autonomic failure. Key pathological features of MSA include the formation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes (OLs), myelin loss, and neuroinflammation. Although both inflammation and myelination are known to be critical in MSA, the roles of myelin proteins and their relationship with inflammation have often been overlooked. In this study, we injected AAV-Olig001 vectors carrying either human SNCA (AAV-hSNCA) or eGFP (AAV-eGFP) into the striatum of TgM83 transgenic mice, which express the A53T mutant form of human alpha-synuclein (αSyn), as well as into wild-type (WT) mice. We then assessed myelin protein expression and inflammatory responses. TgM83 mice injected with AAV-hSNCA exhibited demyelination, increased activation of microglia and astrocytes, and altered cytokine and chemokine profiles (including IL-1α, IL-10, IL-12(p40), CCL2, CCL3, CCL4, and CCL5), compared to both WT mice and TgM83 mice injected with AAV-eGFP. Interestingly, myelin basic protein (MBP) levels were significantly elevated around the injection site in TgM83 mice injected with AAV-hSNCA. Notably, we observed a positive correlation between MBP expression and inflammatory markers, as indicated by Iba1 and GFAP staining. These findings suggest that hSNCA overexpression is associated with increased MBP levels and enhanced inflammatory responses, implicating that MBP and myelination processes may play previously underappreciated roles in the pathogenesis of MSA.

Hypertensive disorders of pregnancy (HDP) is assumed to be triggered by incomplete remodeling of the decidual spiral arteries. We examined the lymphocyte subsets and identified immune differences in the spiral arteries between HDP and normal pregnancies, and between remodeled and non-remodeled arteries such as the muscular artery and acute atherosis. One hundred seventy-three patients with HDP diagnosed at our hospital between 2008 and 2017 were included. Patients with a normal course of delivery and patients with premature birth after 34 weeks without pathological changes and abnormalities in the pregnancy course were included in the control group. The infiltrating lymphocytes were evaluated using immunohistochemistry. Acute atherosis was observed in 56 patients (32.4%) of all HDP patients. In patients that presented HDP with acute atherosis, the density of CD8+ T cells and CD4+ T cells was higher in the acute atherosis than those in the non-remodeled muscular artery. CD4+ T cells were more abundant in the non-remodeled muscular artery compared to the remodeled artery. In control patients, the density of CD4+ T cells was higher in the non-remodeled muscular artery than that in the remodeled artery; there was no difference in the density of CD56+ natural killer cells. There was no difference in the density of CD3+ T cells and CD56+ natural killer cells in the remodeled artery between patients presenting HDP with acute atherosis and control patients. These immune differences may cause changes in local cytokine balance around the spiral artery, contributing to the development of HDP.

Trypanosomatids constitute a family of parasitic protozoa that cause significant human and veterinary diseases that are classified as neglected zoonotic diseases (NZDs). In a rapidly evolving world, these diseases have the potential to become a world health problem no longer solely associated with low-income countries. Therefore, the development of new strategies to control and restrain the dissemination of trypanosomatids is imperative. Extracellular vesicles (EVs) are a heterogeneous group of membrane-enclosed vesicles released by prokaryotic and eukaryotic cells. They can be found in diverse body fluids that carry biologically active molecules, including proteins, nucleic acids, lipids, and carbohydrates. EVs participate in cell-to-cell communication by delivering their cargo content to recipient cells. Thus, EVs play a role in regulating normal physiological processes, including immune surveillance and tissue repair, as well as being involved in pathological conditions, like cancer. In recent years, EVs have attracted significant attention from the scientific community, mainly due to their immune regulatory properties. Therefore, this review examines the role played by trypanosomatid-derived EVs in leishmaniases and trypanosomiasis, highlighting their biological role in host-parasite communication and exploring their potential future applications in controlling NZDs, especially those caused by trypanosomatids.

The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) through pattern recognition receptors (PRRs). Inflammasomes, cytoplasmic protein complexes, are activated in response to PAMPs and DAMPs, leading to the release of inflammatory cytokines such as IL-1β and IL-18. NLRP3 inflammasome is one of the best characterized inflammasomes and recently its activation has been associated with granuloma formation, structures that aggregate immune cells in response to infections, such as those caused by bacteria, fungi and parasites, and autoinflammatory diseases, such as sarcoidosis. Activation of NLRP3 inflammasomes in macrophages induces the release of cytokines that recruit immune cells, such as monocytes and lymphocytes, to the site of infection. Neutrophils, monocytes, T and B lymphocytes are important in the formation and maintenance of granulomas. Although NLRP3 plays a key role in the immune response, cell recruitment and granuloma formation, many aspects of its function in different cell types remain to be elucidated. In this review, we aim to outline the NLRP3 inflammasome not only as a protein complex that aids innate immune cells in combating intracellular pathogens but also as a platform with broader implications in orchestrating immune responses. This underexplored aspect of the NLRP3 inflammasome presents a novel perspective on its involvement in immunity. Thus, we review the current understanding of the role of the NLRP3 inflammasome in immune cell infiltration and its significance in the organization and formation of granulomas in inflammatory diseases.

Alopecia areata (AA) is a complex, chronic inflammatory skin disorder characterized by unpredictable, nonscarring hair loss, affecting millions worldwide. Its pathogenesis remains poorly understood, driven by intricate interactions among immune dysregulation, genetic predisposition, and environmental triggers. Despite significant advances in identifying these contributing factors, substantial gaps persist in our understanding of the full spectrum of AA's molecular mechanisms and in the development of effective therapeutic approaches. This review aims to comprehensively explore the immunological, genetic, epigenetic, and environmental factors underlying AA, with a focus on immune-mediated mechanisms. We also evaluate diagnostic approaches and recent advancements in assessing disease severity. Furthermore, the review discusses evolving therapeutic options, including traditional therapies, biologics, small-molecule agents, and emerging treatments. The academic value of this work lies in its synthesis of current knowledge on the multifaceted nature of AA, providing insights for future research and clinical practice. By elucidating the interconnected factors underlying AA, this review seeks to advance both understanding and management of this prevalent, clinically challenging disorder.

Vaccine-induced protective immunity against SARS-CoV-2 has proved difficult to sustain. Robust T-cell responses are thought to play an important role, but T-cell responses against the SARS-CoV-2 spike protein (S-protein), the core vaccine antigen, following vaccination or natural infection are incompletely understood.

Herein, the reactivity of 170 putative SARS-CoV-2 S-protein CD8+ and CD4+ T-cell peptide epitopes in the same individuals prior to vaccination, after COVID-19 vaccination, and again following subsequent natural infection was assayed using a high-throughput reverse transcription-quantitative PCR (HTS-RT-qPCR) assay.

The profile of immunoreactive SARS-CoV-2 S-protein epitopes differed between vaccination and natural infection. Vaccine-induced immunoreactive epitopes were localised primarily into two extra-domanial regions. In contrast, epitopes recognised following natural infection were spread across the antigen. Furthermore, T-cell epitopes in naïve individuals were primarily recognised in association with HLA-A, while natural infection shifted epitope associations towards HLA-B, particularly the B7 supertype.

This study provides insight into T-cell responses against the SARS-CoV-2 S-protein following vaccination and subsequent natural infection.

Patients have a limited response rate to immune checkpoint inhibitors (ICIs) therapy. Although several biomarkers have been proposed, their ability to accurately predict the response to ICIs therapy remains unsatisfactory. In addition, mutational signatures were validated to be associated with ICIs therapy. Therefore, we developed a mutational signature-based biomarker (MS-bio) to predict the response to ICIs therapy. Based on differentially mutated genes, we extracted six mutational signatures (single-base substitution (SBS)-A, SBS-B, SBS-C, SBS-D, double-base substitution (DBS)-A, and DBS-B) as MS-bio, and constructed a random forest (RF) model to predict the response. Internal and external validations consistently demonstrated the excellent predictive capability of MS-bio, with an accuracy reaching up to 0.82. Moreover, MS-bio exhibited superior performance compared to existing biomarkers. To further validate the accuracy of MS-bio, we explored its performance in The Cancer Genome Atlas (TCGA) cohort and found that the predicted responders were immunologically "hot". Finally, we found that SBS-C had the highest importance in prediction and was related to T cell differentiation. Overall, here we introduced MS-bio as a novel biomarker for accurately predicting the response to ICIs therapy, thereby contributing to the advancement of precision medicine.

Pseudomonas aeruginosa (P. aeruginosa) is a multidrug-resistant opportunistic pathogen responsible for chronic obstructive pulmonary disease (COPD), cystic fibrosis, and ventilator-associated pneumonia (VAP), leading to cancer. Developing an efficacious vaccine remains the most promising strategy for combating P. aeruginosa infections. In this study, we employed an advanced in silico strategy to design a highly efficient and stable mRNA vaccine using immunoinformatics tools. Whole proteome data were utilized to identify highly immunogenic vaccine candidates using subtractive proteomics. Three extracellular proteins were prioritized for T- and linear B-cell epitope prediction. Beta-definsin protein sequence was incorporated as an adjuvant at the N-terminus of the construct. A total of 3 CTL, 3 HTL, and 3 linear B cell highly immunogenic epitopes were combined using specific linkers to design this multi-peptide construct. The 5' and 3' UTR sequences, Kozak sequence with a stop codon, and signal peptides followed by a poly-A tail were incorporated into the above vaccine construct to create our final mRNA vaccine. The vaccines exhibited antigenicity scores >0.88, ensuring high antigenicity with no allergenic or toxic. Physiochemical properties analysis revealed high solubility and thermostability. Three-dimensional structural analysis determined high-quality structures. Vaccine-receptor docking and molecular dynamic simulations demonstrated strong molecular interactions, stable binding affinities, dynamic nature, and structural stability of this vaccine, with significant immunogenic responses of the immune system against the vaccine. The immunological simulation indicates successful cellular and humoral immune responses to defend against P. aeruginosa infection. Validation of the study outcomes necessitates both experimental and clinical testing.

Salmonella enterica serovar Typhimurium is a Gram-negative bacterium that causes gastrointestinal infection and poses significant public health risks worldwide. This study aims to explore how S. Typhimurium manipulates B-cell function through outer membrane protein A (OmpA). We investigate the effect of OmpA on Raji human B-cells, leading to the induction of activation-induced cytidine deaminase (AID) protein, which plays an important role in generating antibody diversity in B-cells, via initiating the process of somatic hypermutation (SHM) and class switch recombination (CSR). Our key findings demonstrate that OmpA is crucial for inducing aberrant AID expression in B-cells, leading to increased CSR. Interestingly, the increased AID expression was likely due to overexpression of cMYC, an activator for AID expression. Not only was the expression of cMYC elevated, but its occupancy on the aicda locus was raised. Furthermore, increased AID expression induced CSR events, specifically switching to IgA. In summary, our study suggests that OmpA plays a potential role in modulating B-cell regulation and controlling the adaptive immune system. These functional attributes of OmpA implicate its potential as a therapeutic target for combating S. Typhimurium pathogenesis.

Cardiovascular diseases are the leading cause of death around the globe. In recent years, a crucial role of the immune system has been acknowledged in cardiac disease progression, opening the door for immunomodulatory therapies. To this ongoing change of paradigm, positron emission tomography (PET) imaging of the immune system has become a remarkable tool to reveal immune cell trafficking and monitor disease progression and treatment response. Currently, PET imaging of the immune system in cardiovascular disease mainly focuses on the innate immune system such as macrophages, while the immune cells of the adaptive immune system including B and T cells are less studied. This can be ascribed to the lack of radiotracers specifically binding to B and T cell biomarkers compatible with PET imaging within the cardiovascular system. In this review, we summarize current knowledge about the role of the adaptive immune system (e.g., B and T cells) in major cardiovascular diseases and introduce key biomarkers for specific targeting of these immune cells and their subpopulations. Finally, we present available radiotracers for these biomarkers and propose a pathway for developing probes or optimizing those already used in other fields (e.g., oncology) to make them compatible with the cardiovascular system.

Ischemic stroke (IS) is a significant contributor to disability and death worldwide, with limited treatments beyond early intervention. The importance of CD4+ T cells in the advancement of IS has been highlighted by recent studies, providing new insights into immunomodulatory strategies. This review describes the spatiotemporal dynamics of CD4+ T cells and their subsets at different stages of IS. The signaling pathways activated by IS regulate the distribution of CD4+ T cells and their subsets, which further influences the inflammatory response and disease progression. In the acute and subacute stages, CD4+ T cells exacerbate neuronal damage. In contrast, CD4+ T cells, which are predominantly composed of Treg cells (Tregs), promote tissue repair and neurological recovery in the chronic stage. In light of recent findings that challenge traditional views, we analyze the underlying mechanisms and potential explanations for these discrepancies. In addition, we summarize the potential of targeting CD4+ T cells as a therapeutic strategy for IS. Although no drugs specifically targeting CD4+ T cells have been developed, certain drugs that modulate CD4+ T cells show potential for IS treatment. Moreover, multitarget drugs integrated with nanomaterials are currently undergoing preclinical investigation. We further explore the challenges in the clinical translation of CD4+ T-cell-targeted therapies and discuss potential strategies to address these challenges. In conclusion, a deeper comprehension of the complex effects of CD4+ T cells and their subsets on IS will contribute to disease management and drug development, thereby improving the quality of life for IS patients.

Adaptive immunity after a stroke results in a shift of T cells between compartments, leading to peripheral lymphopenia and an increased number of T cells within the brain lesion. Stroke-associated infection (SAI) presents a clinically significant challenge in stroke units. The role of T-cell subsets in the post-stroke immune response and in SAI remains unclear. Thus, we aimed to observe the quantitative changes of circulating CD4+, CD8+, double-negative T cells, and the CD4+/CD8+ ratio in stroke and SAI.

We prospectively assessed circulating CD4+, CD8+, and double-negative T cells using flow cytometry in 52 patients on days 1, 3, 10, and 90 after ischemic stroke. We compared the results to those obtained from age-, sex-, and vascular risk factor-matched controls. We analyzed lymphocyte parameters in relation to clinical outcome, SAI, infarct lesion volume, and risk factor burden.

There were no differences in the studied parameters between stroke patients and controls, as well as between subjects with and without SAI. A higher percentage of CD4+ T cells and a higher CD4+/CD8+ ratio correlated with better clinical status in the acute and subacute phases, while CD8+ T cells showed the opposite correlation. The percentage of CD8+ T cells positively correlated with CRP levels during the acute and subacute phases of stroke, as well as in the control group. A negative correlation was noted between the percentage of CD4+ T cells on D1 and the serum CRP level on D10 after stroke. Similarly, the CD4+/CD8+ ratio on D1 negatively correlated with CRP on D1, D3, and D10. In patients with a history of hypertension (HT), there was a higher percentage of CD8+ T cells and a lower percentage of CD4+ T cells in the acute phase of stroke than those without HT.

Particulate matter (PM), a ubiquitous significant component of the ambient air pollution mixture, significantly contributes to increased global risk for chronic cardiopulmonary diseases, acute hospitalizations, and deaths. One of the causes of this increased risk is because PM exposure increases the incidence and severity of respiratory infections. The respiratory system is particularly vulnerable to air pollution and its impact on infection as it is a key site for exposure both to inhaled pollutants and infectious microbes or viruses. This review examines the current understanding of how PM affects antiviral host defense responses and possible underlying mechanisms.

While numerous studies have associated adverse health outcomes with combined or sequential exposure to inhaled pollutants and viruses, defining causal relationships and mechanisms remains limited. Particularly limited, are contemporary data focuses on low- and middle-income countries, including heavily polluted regions such as Ulaanbaatar, Mongolia. This manuscript focuses on how (1) PM, serving as a carrier for viruses, enhances the transmission of viruses; (2) PM impairs immune defense to viruses; and (3) PM impacts epithelial cell functions to exacerbate viral infections. Given the significant public health hazards on PM, particularly in heavily polluted regions such as Southeast Asia, Middle East and Africa, it is critical to define specific mechanisms of PM on respiratory infection and how their impact may differ in these highly polluted regions. Ultimately, this could devise future public health measures and interventions to limit this substantial public health risk.

Major histocompatibility complex class II (MHCII) molecules are antigen presentation proteins and increased in post-mortem Parkinson's disease (PD) brain. Attempts to decrease MHCII expression have led to neuroprotection in PD mouse models. Our group reported that a single nucleotide polymorphism (SNP) at rs3129882 in the MHCII gene Human Leukocyte Antigen (HLA) DRA is associated with increased MHCII transcripts and surface protein and increased risk for late-onset idiopathic PD. We therefore hypothesized that decreased MHCII may mitigate dopaminergic degeneration. During an ongoing α-synuclein lesion, mice with MHCII reduction in systemic and brain innate immune cells (LysMCre + I-Abfl/fl or CRE+) displayed brain T cell repertoire shifts and greater preservation of the dopaminergic phenotype in nigrostriatal terminals. Next, we investigated a human cohort to characterize the immunophenotype of subjects with and without the high-risk GG genotype at the rs3129882 SNP. We confirmed that the high-risk GG genotype is associated with peripheral changes in MHCII inducibility, frequency of CD4 + T cells, and differentially accessible chromatin regions within the MHCII locus. Although our mouse studies indicate that myeloid MHCII reduction coinciding with an intact adaptive immune system is insufficient to fully protect dopamine neurons from α-synuclein-induced degeneration, our data are consistent with the overwhelming evidence implicating antigen presentation in PD pathophysiology.

Acute dacryoadenitis is characterized by inflammation of the lacrimal gland, and is typically viral. Bacterial dacryoadenitis is rare, with Staphylococcus and Streptococcus species being the most common pathogens. The bilateral sequential onset of dacryoadenitis has not been described in the literature to date.

A 54-year-old immunocompetent female presented to the emergency department with a 1-week history of left-sided periorbital swelling, erythema, and pain. Orbital computed tomography demonstrated significant soft tissue thickening and swelling surrounding the left orbit and a lacrimal gland abscess. Culture swabs were negative for microorganisms. Despite initial management with intravenous antibiotics and surgical drainage, the condition recurred post-discharge. Three years later, the patient experienced similar symptoms in the right eye. Cultures were repeatedly negative for microorganisms. Despite courses of intravenous antibiotics and surgical drainage, the patient experienced recurrences of abscesses in the right eye, highlighting the challenges in managing this rare condition.

We describe a unique case of bilateral sequential bacterial dacryoadenitis with abscess formation. This case highlights the need for prompt diagnosis and management, including surgical intervention, to prevent complications and recurrences.

T cells play an important role in adaptive immune responses, providing antigen specificity for pathogen and tumor recognition. Recent studies have elucidated the complex interplay between T cell metabolism and broad epigenetic modifications in response to tumors, occurring at transcriptional, post-transcriptional, and post-translational levels. At the transcriptional level, gene expression is regulated through mechanisms such as DNA methylation, chromatin remodeling, and transcription factor activity. Post-transcriptionally, gene expression is further modulated by non-coding RNAs and RNA modifications, an area of increasing research interest. In addition, histone proteins are primarily regulated by well-established post-translational modifications (PTMs), including acetylation and methylation. Novel PTMs such as succinylation, glycosylation, glutamylation, and lactylation add complexity to the regulation and warrant further investigation. At present, the interaction between CD8+ T cell metabolism and epigenetic modifications in response to malignancies has been reported extensively. However, the interplay in CD4+ T cells remains less understood. In this review, we introduce the differentiation trajectories of T cells and critically evaluate existing interplay between metabolic activity and epigenetic modifications influences the functional dynamics in both CD8+ and CD4+ T cells, offering promising avenues for the development of novel cancer immunotherapies.

Exosomes are extracellular vehicles that facilitate intra-cellular communication via transport of critical proteins and genetic material. Every exosome is intrinsically reflective of the cell from which it was derived and can even mimic effector functions of their parent cells. In recent years, with the success of CAR-T therapies, there has been growing interest in characterizing exosomes derived from CAR-T cells. CAR exosomes contain the same cytotoxic granules as their parent cells and have demonstrated significant anti-tumor activity in vitro and in animal models. Moreover, infusion of CAR exosomes in animal models did not generate cytokine release syndrome. Conversely, there are also novel bispecific antibodies which target tumor-derived exosomes in hopes of derailing immunosuppressive pathways mediated by exosomes produced from malignant cells. The two most promising examples include (a) BsE CD73 x EpCAM which binds and inhibits exosomal CD73 to suppress production of immunosuppressant adenosine and (b) BsE CD3 x PD-L1 which targets exosomal PD-L1 within the tumor microenvironment to guide cytotoxic T-cells towards tumor cells. As our understanding of exosome biology continues to evolve, opportunities for advances in cellular therapies will grow in tandem.

Mus musculus, the house mouse, is the most widely used mammalian model in biomedical research. Mice frequently undergo injectable anesthesia for numerous research procedures, with the most common anesthetic protocol being ketamine-xylazine (K/X). 2,2,2-Tribromoethanol (TBE), a non-regulated chemical, is also used, but has been linked to peritonitis. The focus of this study was to directly compare these two anesthetic protocols by evaluating induction rates, recovery times, organ weight data, and immune endpoints. Forty-five CD-1 female (8-10 week-old) mice were divided into three experiments. Two anesthetic events were performed 2 weeks apart. For each experiment, mice received an intraperitoneal (IP) injection of sterile phosphate buffered saline, (PBS; n = 3 mice), an IP injection of K/X (n = 6 mice), or an IP injection of sterile TBE (n = 6 mice). In a separate third anesthetic event (n = 5 mice/treatment), post-treatment peripheral blood and peritoneal lavage samples were collected for a 9-plex cytokine analysis. Mice were euthanized 2 weeks after the last anesthetic event. Induction rates were non-significantly but numerically more rapid with TBE as compared to K/X, at 2.7 ± 0.6 min and 4.0 ± 0.7 min, respectively. TBE mice had significantly more rapid recovery time (∼25 min) compared to K/X (∼50 min), which also had 50 % anesthetic mortalities. Organ weight ratios, immune phenotype, cytology, serum and peritoneal lavage cytokine levels, and histopathology were unremarkable. TBE performed better and more safely as a murine anesthetic for light anesthesia compared to K/X based on recovery times, no mortalities, and an absence of local and systemic inflammation.

In the 100 years since isolation and administration of animal insulin to sustain life in Type 1 diabetes, there has been increasing progress in the administration of exogenous insulin to lower glucose levels.

We reviewed using standard search engines and PubMed present-day techniques of management of type 1 diabetes.

Long-acting insulin formulations have been developed to maintain basal glucose levels in the normal range, while rapid acting insulins have been synthesized to address the sharp rise in glucose levels after a meal. Insulin pumps administer insulin continuously subcutaneously guided by continuous glucose monitoring systems. These almost closed loop systems achieve near normal glucose levels other than at meal times where the rapid glucose rise and then fall pose a significant challenge due to the extended duration of subcutaneous insulin depots. Implanted insulin pumps with intraperitoneal delivery may eventually permit improved post meal glucose control. Type 1 diabetes has now been redefined as an autoimmune disease which may be diagnosed purely from the presence of anti-beta cell antibodies with no abnormality of glucose levels. The future will see an intensification of efforts to combat the immune process which destroys beta cells.

Prostate cancer (PC) remains a leading cause of morbidity and mortality among men worldwide, highlighting the need for novel therapeutic strategies. Our study investigates the therapeutic potential of targeting the heme degradation pathway through heme oxygenase-1 (HO-1) inhibition in PC. Using both in vitro and in vivo models, we explored the effects of combining HO-1 inhibition with chemotherapy, represented by docetaxel (Doc), on tumor growth and immune infiltration. In vitro experiments demonstrated that HO-1 inhibition, as well as HO-1 knockout (KO), significantly reduced tumor cell proliferation and enhanced chemosensitivity in RM-1 cells. Additionally, U937 cells co-cultured with HO-1 KO cells shifted cell polarization toward an M1 phenotype. In vivo, the combined treatment of the HO-1 inhibitor, tin protoporphyrin (SnPP), with Doc significantly enhanced anti-tumor efficacy in mouse models compared to chemotherapy or SnPP alone. This combination therapy not only reduced Ki67 expression and increased CC3 expression in tumor tissues but also shifted macrophage polarization toward an M1 phenotype and enhanced CD4+ and CD8+ T cells infiltration, indicating an augmented immune response. Further investigation using macrophage-specific HO-1 knockout mice revealed a direct role of HO-1 inhibition in driving macrophage polarization, confirming its involvement in promoting the shift toward an M1 phenotype. Although this response was significant, it was more robust with systemic HO-1 inhibition. Our findings indicate that HO-1 inhibition can potentiate the effects of chemotherapy, offering a promising avenue for improving PC treatment outcomes.

The immune system encounters a diverse array of antigens, both self and foreign, necessitating mechanisms to maintain tolerance and prevent harmful inflammatory responses. CD4＋ T cells, crucial in orchestrating immune responses, play a critical role in mediating tolerance to both self and foreign antigens. While the mechanisms of CD4＋ T cell-mediated tolerance to self-antigens are well-documented, the understanding of tolerance to foreign antigens, including those from commensal microbes and food, remains incomplete. This review discusses recent progress in the mechanisms underlying immune tolerance to foreign antigens, with a focus on the role of CD4＋ T cells. We explore how inflammatory and tolerogenic CD4＋ T cell subsets are developed and maintained. Moreover, we delve into the complexities of immune responses to commensal microbes and food antigens by reviewing recent findings, highlighting the immunological contexts that shape immune tolerance. Understanding these mechanisms enhances our comprehension of how immune tolerance is established and sustained, providing insights into potential therapeutic approaches for managing chronic inflammatory diseases resulting from a loss of immune tolerance to foreign antigens. [BMB Reports 2025; 58(4): 158-168].

The purpose of this study was to elucidate the role of the corneal lymphatic Prox1 gene in modulating limbal stem cell stemness and facilitating corneal injury repair.

The limbal Prox1 gene was knocked down by adeno-associated virus (AAV). The alkali burn model was induced in the naive group, the AAV-sham group, and the AAV-shProx1 group. Anterior segment photography, fluorescein sodium staining, and hematoxylin and eosin (H&E) staining were conducted immediately on days 1, 3, 7, 14, and 21 post-injury. Immunofluorescent (IF) staining was used to assess Ki67, ΔNp63, and K14. Additionally, seq-mRNA technology facilitated a comparative transcriptomic analysis between the AAV-sham and the AAV-shProx1 groups 7 days post-injury. Key regulated genes were verified by protein level. Furthermore, a co-culture model of lymphatic endothelial cells (LECs) and limbal stem cells (LSCs) was used to investigate the proliferation capacity and stemness expression of LSCs.

Fluorescein sodium staining revealed that the epithelial defect area was significantly larger in the AAV-shProx1 group than in the AAV-sham group on days 1 and 3 post-injury (P < 0.05). Ki67, ΔNp63, and K14 expressions were consistently lower in the AAV-shProx1 group than in the AAV-sham group at distinct time points. Additionally, seq-mRNA results demonstrated that genes (Prox1 and Lyve1) were downregulated while inflammatory factors (Ccl2, Ccl7, IL16, IL1R, and TNFsf11) were upregulated in the AAV-shProx1 group compared with the AAV-sham group. When Prox1 was silenced in LECs, the proliferation and stemness of LSCs were markedly downregulated.

The Prox1 and Lyve1 proteins in lymphatic vessels served as pivotal regulated proteins in corneal injury repair. The draining role of lymphatic vessels during corneal injury was indispensable.

Background and Objectives: The administration of oral vaccines offers a potential strategy for cancer immunotherapy; yet, the development of effective platforms continues to pose a difficulty. This study examines Escherichia coli Nissle 1917 (EcN) as a microbial vector for the precise delivery of Glypican-1 (GPC1), a tumor-associated antigen significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC).To evaluate the effectiveness of EcN as a vector for the delivery of GPC1 and assess its potential as an oral vaccination platform for cancer immunotherapy. Materials and Methods: EcN was genetically modified to produce a GPC1-flagellin fusion protein (GPC1-FL) to augment antigen immunogenicity. The expression and stability of GPC1 were confirmed in modified PANC02 cells using Western blot and flow cytometry, indicating that GPC1 expression did not influence tumor cell growth. A mouse model was employed to test immunogenicity post-oral delivery, measuring systemic IgG, IL-10, IL-2, and IFN-γ levels to indicate immune activation. Results: Oral immunization with EcN GPC1-FL elicited a robust systemic immune response, demonstrated by markedly increased levels of IgG and IL-10. IL-2 and IFN-γ concentrations were elevated in vaccinated mice relative to controls; however, the differences lacked statistical significance. Western blot examination of fecal samples verified consistent antigen expression in the gastrointestinal tract, indicating effective bacterial colonization and antigen retention. No detrimental impacts were noted, hence substantiating the safety of this methodology. Conclusions: These findings confirm EcN as a feasible and patient-friendly oral vaccination platform for cancer immunotherapy. The effective production of GPC1 in tumor cells, along with continuous antigen delivery and immune activation, underscores the promise of this approach for PDAC and other cancers. This study promotes microbial-based antigen delivery as a scalable, non-invasive substitute for traditional vaccine platforms.

Hypoxia-inducible factors (HIFs) are transcription factors that enable cells to adapt to low-oxygen environments. Viruses can exploit this pathway to enhance infection, making HIF modulation a potential antiviral strategy. In previous in vitro studies, we found that respiratory syncytial virus (RSV) stabilizes HIFs under normoxic conditions with inhibition of HIF-1α reducing replication. Despite several HIF-modulating compounds being tested or approved in other non-infectious models, little is known about their efficacy against respiratory viruses in relevant animal models. This study aimed to characterize the disease-modulating properties and antiviral potential of HIF-1α (PX478) and HIF-2α PT2385 inhibitors in RSV-infected BALB/c mice. We found that the inhibition of HIF-1α worsened clinical disease parameters while simultaneously improving airway function. Blocking HIF-1α also significantly reduced peak RSV replication in the lung. In contrast, the inhibition of HIF-2α was associated with improved clinical parameters, no changes in airway function, and reduced viral replication following RSV infection. The analysis of lung cells found significant modification in the T-cell compartment that correlated with changes in lung pathology and viral titers for each HIF inhibitor. This study underscores the differential roles of HIF proteins in RSV infection and highlights the need for further characterization of compounds currently in use or under therapeutic consideration.

Oxidative stress and inflammation are pivotal in linking COPD to NSCLC progression, with dysregulated cytokine levels in inflamed COPD airways correlating with disease severity and lung cancer advancement. CD4+ T helper cells, pivotal in the inflammatory response, exhibit altered gene expression patterns in COPD and NSCLC, emphasizing their role in disease pathogenesis. Mitochondrial transcription factor A (mtTFA) dysregulation is implicated in inflammation and oxidative stress, affecting COPD and NSCLC progression. CRISPR/Cas9-mediated mtTFA depletion heightens inflammatory transcription factor expression, whileitsoverexpression reduces inflammation and oxidative stress markers. Histone deacetylases (HDACs) exhibit elevated expression in COPD and NSCLC CD4+ T cells, with inhibition via TSA treatment showing decreased inflammation and oxidative stress. Patients progressing from COPD to NSCLC demonstrate distinct epigeneticsignatures,with altered acetylation and methylation markers. TSA treatment enhances methylation and acetylation at the VEGFA gene locus, mitigating disease progression effects. Overexpression of mtTFA downregulates HDACs, while knockout upregulates them, influencing oxidative stress levels. These findings underscore the interplay between transcription factors, cytokines, and epigenetic regulation in CD4+ T cells, providing insights into disease mechanisms and potential therapeutic avenues. Understanding these pathways and targets may lead to innovative epigenetic therapies for COPD and NSCLC, potentially preventing COPD progression to NSCLC.

Type 2 (T2)-high asthma with neutrophilic inflammation is characterized by airway eosinophilic and neutrophilic infiltration, hyperresponsiveness, remodeling, and insensitivity to steroid treatment. Sphingosine-1-phosphate (S1P), which has a crucial role in the development of asthma, promotes the proliferation and contraction of airway smooth muscle cells (ASMCs), contributing to the pathophysiological processes of asthma. However, the downstream mediator of S1P remains unclear, as does its role in T2-high asthma with neutrophilic inflammation.

Ovalbumin- and ozone-induced murine models were used to replicate T2-high asthma with neutrophilic inflammation and primary ASMCs were applied to explore the underlying effects. Through transcriptomic analysis, PLK1 was identified as a potential key molecule associated with S1P-induced proliferation and contraction. Functional studies were performed both in vitro and in vivo by pharmacological inhibition to validate the role of PLK1 and to evaluate the therapeutic effects of PLK1 inhibition.

S1P level was elevated in the bronchoalveolar lavage fluid (BALF) of T2-high asthma with neutrophilic inflammation model, and promoted ASMCs proliferation and contraction. PLK1 expression increased in S1P-stimulated ASMCs and asthmatic lung tissues. Inhibition of PLK1 blocked S1P-induced ASMCs proliferation and contraction. In vivo, PLK1 inhibition reduced airway inflammation (particularly neutrophilic infiltration), airway remodeling (airway smooth muscle proliferation and collagen deposition), and airway hyperresponsiveness and resistance, improving lung function (of both large and small airways), with superior therapeutic effects to those of dexamethasone. In addition, PLK1 inhibition markedly reduced the BALF levels of IL-17A, IL-21 and IL-6, suggesting that PLK1 might exert its effects mainly through the regulation of Th17 pathway.

PLK1 mediates S1P-induced ASMC proliferation and contraction, and plays an important part in T2-high asthma with neutrophilic inflammation model, making it a potential therapeutic target for treating T2-high asthma with neutrophilic inflammation.

Electroacupuncture (EA) is utilized to address various health conditions. Herein, we designed a systematic review and meta-analysis to evaluate the efficacy of EA on clinical and immunological factors in herpes zoster (HZ) based on randomized clinical trials.

Four international databases and 3 Chinese databases were searched until January 2024. We used RevMan 5.3 for meta-analysis and presented the data as standardized mean difference (SMD) or odds ratio (OR) and 95% confidence interval.

A total of 1361 records were identified in the databases and at last, 19 articles were entered into the meta-analysis. The result shows a negative pooled SMD of -2.55 (P < .00001) for the VAS score. The pooled SMD for cessation of pustules time in the case group compared to the control group was -0.69 (P = .0008), for pain relief time was -1.36 (P = .002), for the time to scab was -0.47 (P = .009), and for time to remove scab was -1.01 (P = .0003). The pooled OR for the incidence of postherpetic neuralgia was 0.11 (P < .00001), and the total effective rate was 4.25 (P < .00001). The pooled SMD for the cluster of differentiation (CD)3 count was 2.59 (P = .07), for the CD4 count was 2.81 (P = .04), for the CD8 count was -0.75 (P = .50), and for theCD4/CD8 ratio was 1.12 (P = .15).

The results indicate that the EA treatment had several significant benefits compared to Western medicine (WM) in HZ patients in terms of clinical and immunological factors. But, the combination of treatments of EA with WM had better effects compared to EA treatment alone.

Klebsiella pneumoniae is a pathogen that causes infections in various parts of the body, with high mortality rates reported in antibiotic-resistant cases. Treating at-risk individuals requires crucial vaccination efforts due to the challenges that exist. This research involved designing a multi-epitope vaccine from K. pneumoniae's fimbriae antigens. Optimal T-cell and B-cell epitopes were chosen through in silico studies including epitope-HLAs molecular docking. The multi-epitope was created, featuring antigenic T- and B-cell epitopes, β-defensin as an adjuvant, the PADRE sequence to boost immunogenicity and well-suited linkers. The tertiary structure of the multi-epitope was achieved through modeling and molecular dynamics-based refinements. The construct underwent scrutiny for structural traits, physicochemical properties, conformational B epitope prediction, immune responses simulation, in silico cloning, molecular docking for assay binding to toll-like receptors (TLRs), and deformability studies. The outcomes indicated the vaccine candidate's positive attributes, encompassing immunogenicity, structure, physicochemical properties, solubility, TLR binding, toxicity, stability, allergenicity, and cross-reactivity. The multi-epitope vaccine candidate exhibits the potential for provoking diverse immune responses against K. pneumoniae. Nevertheless, additional in vitro and in vivo experimental tests are necessary to substantiate its efficacy.

Complement-associated disorders are caused by the dysregulation and disbalance of the complement system, especially excessive activation. Most drugs that target the complement system are designed to inhibit the complement pathway at either the proximal or terminal levels. The use of a natural complement regulator such as factor H (FH) could provide a superior treatment option by restoring balance to an overactive complement system. We recently reported the moss-based production of an analog of human FH with an optimized glycan profile (CPV-104), which showed in vitro and in vivo characteristics comparable to its human counterpart. Here, we follow up our previous work, focusing in more detail on the time course and long-term efficacy of CPV-104 treatment in FH-deficient (FH -/-) mice. The analysis of long-term treatment effects following multiple injections of human FH into mice was previously hindered by the immune response, so we developed a protocol for the sustained depletion of CD20+ B-cells and CD4+ T-cells, preventing antibody formation without influencing the C3G phenotype. Using this dual-depletion method, we were able to complete dosing interval experiments in FH -/- mice, administering up to three injections of CPV-104 at different intervals. Repeated CPV-104 administration was able to lastingly resolve C3 deposits, offering additional rationale for the clinical testing of CPV-104 in human C3G patients. Moreover, our novel dual-depletion method has the potential for adaptation to different mouse models, allowing the testing of multiple doses of other therapeutic proteins.

Recent research has uncovered new mechanisms that disrupt the balance between the host and microbes in the middle ear, potentially leading to dysbiosis and chronic suppurative otitis media (CSOM). Dysbiotic microbial communities, including core pathogens such as persister cells, are recognized for displaying cooperative virulence. These microbial communities not only evade the host's immune defenses but also promote inflammation that leads to tissue damage. This leads to uncontrolled disorder and pathogen proliferation, potentially causing hearing loss and systemic complications. In this discussion, we examine emerging paradigms in the study of CSOM that could provide insights into other polymicrobial inflammatory diseases. Additionally, we underscore critical knowledge gaps essential for developing a comprehensive understanding of how microbes interact with both the innate and adaptive immune systems to trigger and maintain CSOM.

Encoding spatially resolved transcriptomics (SRT) data serves to identify the biological semantics of RNA expression within the tissue while preserving spatial characteristics. Depending on the analytical scenario, one may focus on different contextual structures of tissues. For instance, anatomical regions reveal consistent patterns by focusing on spatial homogeneity, while elucidating complex tumor micro-environments requires more expression heterogeneity. However, current spatial encoding methods lack consideration of the tissue context. Meanwhile, most developed SRT technologies are still limited in providing exact patterns of intact tissues due to limitations such as low resolution or missed measurements. Here, we propose STForte, a novel pairwise graph autoencoder-based approach with cross-reconstruction and adversarial distribution matching, to model the spatial homogeneity and expression heterogeneity of SRT data. STForte extracts interpretable latent encodings, enabling downstream analysis by accurately portraying various tissue contexts. Moreover, STForte allows spatial imputation using only spatial consistency to restore the biological patterns of unobserved locations or low-quality cells, thereby providing fine-grained views to enhance the SRT analysis. Extensive evaluations of datasets under different scenarios and SRT platforms demonstrate that STForte is a scalable and versatile tool for providing enhanced insights into spatial data analysis.

Major histocompatibility complex class II (MHCII) molecules are antigen presentation proteins and increased in post-mortem Parkinson's disease (PD) brain. Attempts to decrease MHCII expression have led to neuroprotection in PD mouse models. Our group reported that a SNP at rs3129882 in the MHCII gene Human leukocyte Antigen (HLA) DRA is associated with increased MHCII transcripts and surface protein and increased risk for late-onset idiopathic PD. We therefore hypothesized that decreased MHCII may mitigate dopaminergic degeneration. During an ongoing α-synuclein lesion, mice with MHCII reduction in systemic and brain innate immune cells (LysMCre+I-Abfl/fl or CRE+) displayed brain T cell repertoire shifts and greater preservation of the dopaminergic phenotype in nigrostriatal terminals. Next, we investigated a human cohort to characterize the immunophenotype of subjects with and without the high-risk GG genotype at the rs3129882 SNP. We confirmed that the high-risk GG genotype is associated with peripheral changes in MHCII inducibility, frequency of CD4+ T cells, and differentially accessible chromatin regions within the MHCII locus. Although our mouse studies indicate that myeloid MHCII reduction coinciding with an intact adaptive immune system is insufficient to fully protect dopamine neurons from α-synuclein-induced degeneration, our data are consistent with the overwhelming evidence implicating antigen presentation in PD pathophysiology.

Globally, periodontal diseases, mainly driven by polymicrobial biofilms, are a widespread concern of social medicine due to their considerable incidence and tie-up to systemic disorders like diabetes, cardiovascular diseases, and complications during pregnancy. Traditional treatments focus on mechanical debridement and antimicrobial therapies, but these approaches have limitations, including recurrence and antibiotic resistance. Periodontal vaccines offer a promising alternative by targeting the immunological mechanisms underlying periodontal disease. This review explores the current state of periodontal vaccine development, highlighting key antigens, vaccine delivery systems, and preclinical and clinical advancements. Special emphasis is placed on antigen selection, host variability, immune tolerance, and future directions to overcome these barriers. This article highlights the advancements and challenges in periodontal vaccine research, offering insights into the capability of immunoprophylaxis as a groundbreaking way to manage periodontal diseases.