Immuno

Pandemics in the last two centuries have been initiated by causal pathogens that include Severe Acute Coronavirus 2 (SARS-CoV-2) and Influenza (e.g., the H1N1 pandemic of 2009). The latter is considered to have initiated two prior pandemics in 1918 and 1977, known as the “Spanish Flu” and “Russian Flu”, respectively. Here, we discuss other emerging infections that could be potential public health threats. These include Henipaviruses, which are members of the family Paramyxoviridae that infect bats and other mammals. Paramyxoviridae also include Parainfluenza and Mumps viruses (Rubulavirus) but also Respiratory Syncytial virus (RSV) (Pneumovirus). Additionally included is the Measles virus, recorded for the first time in writing in 1657 (Morbillivirus). In humans and animals, these may cause encephalitis or respiratory diseases. Recently, two more highly pathogenic class 4 viral pathogens emerged. These were named Hendra Henipavirus (HeV) and Nipah Henipavirus (NiV). Nipah virus is a negative-sense single-stranded ribonucleic acid ((−) ssRNA) virus within the family Paramyxoviridae. There are currently no known therapeutics or treatment regimens licensed as effective in humans, with development ongoing. Nipah virus is a lethal emerging zoonotic disease that has been neglected since its characterization in 1999 until recently. Nipah virus infection occurs predominantly in isolated regions of Malaysia, Bangladesh, and India in small outbreaks. Factors that affect animal–human disease transmission include viral mutation, direct contact, amplifying reservoirs, food, close contact, and host cell mutations. There are different strains of Nipah virus, and small outbreaks in humans limit known research and surveillance on this pathogen. The small size of outbreaks in rural areas is suggestive of low transmission. Person-to-person transmission may occur. The role that zoonotic (animal–human) or host immune system cellular factors perform therefore requires analysis. Mortality estimates for NiV infection range from 38–100% (averaging 58.2% in early 2019). It is therefore critical to outline treatments and prevention for NiV disease in future research. The final stages of the disease severely affect key organ systems, particularly the central nervous system and brain. Therefore, here we clarify the pathogenesis, biochemical mechanisms, and all research in context with known immune cell proteins and genetic factors. Full article

The production of pro-inflammatory and anti-inflammatory cytokines, as well as adipocyte differentiation and fat accumulation in the 3T3-L1 mouse embryo fibroblast cell line and the human monocytic cell line THP-1 were measured to determine the anti-inflammatory and antiadipogenic effects of ethanolic extracts of verjuice (unripe grape juice (Vitis vinifera L.)), Salvia officinalis L., and Alchemilla vulgaris L. On both cell lines, the three extracts had much greater cytostatic effects than cytotoxic effects. With an IC50 of 505 μg/mL, S. officinalis had the highest cytostatic effect on THP-1-derived macrophages. After treatment with 125 μg/mL, the three extracts dramatically reduced the LPS-induced NO generation in THP-1-derived macrophages from 80 μM to control values after treatment with 125 µg/mL. Furthermore, the extracts reduced the levels of TNF-α and IL-6 production in a dose-dependent manner with the highest effects reached at 250 µg/mL. The production of TNF-α decreased at higher levels compared to IL-6 production. V. vinifera, S. officinalis, and A. vulgaris extracts improved the production levels of IL-10 from 32 pg/mL to 86 pg/mL, 98 pg/mL, and 80 pg/mL at an extract concentration of 125 µg/mL, respectively. The adipocyte differentiation and fat accumulation in 3T3-L1 were decreased to 20% of control values after treatment with plant extracts. Taken together, these results suggest that V. vinifera, S. officinalis, and A. vulgaris likely exert their anti-obesity effects through cytostatic actions and modulation of pro-inflammatory and anti-inflammatory cytokine production, as well as by reducing adipocyte differentiation and fat accumulation. Full article

Modulation of the immune system has been demonstrated as a powerful approach to treating cancer. Immunotherapies are generally classified as active or passive according to their ability to trigger the immune system. During the last decades, information regarding the relevance of aberrant glycosylation as a major player in tumour biology encouraged expectations for the development of new therapeutic strategies directed at glycans. Several tumour-associated carbohydrate antigens (TACAs) have been identified and validated as suitable immunotherapeutic targets, leading to promising therapeutic developments. It is known that TACAs are poorly immunogenic since they are unable to trigger a proper immune response. Given that they are not presented by major histocompatibility complex (MHC) molecules and that they induce immune tolerance, the development of active immunotherapeutic strategies against TACAs is a real challenge. However, antitumor strategies based on mimetics of TACAs have been developed and show promising results. Active immunotherapies based on TACAs mimicry can currently be grouped into strategies based on the use of mimetic peptides and anti-idiotype (Id) antibodies. In this review, we discussed the scientific basis on which these strategies are based and the available therapeutic options that have shown the best results in preclinical studies and in clinical practice. Full article

COVID-19 has presented itself as a challenging task to medical teams and researchers throughout the world, since the outbreak of SARS-CoV-2 started in the Chinese city of Wuhan. To this day, there are still new variants emerging, and the knowledge about the mechanisms used by the virus to infect cells and perpetuate itself are still not well understood. The scientific community is still trying to catch up with the velocity of new variants and, consequently, the new physiological pathways that appear along with it. It is known that the new coronavirus plays a role in changing many molecular pathways to take control of the infected cells. Many of these pathways are related to control genomic expression of certain genes by epigenetic ways, allowing the virus to modulate immune responses and cytokines production. The let-7 family of microRNAs, for instance, are known to promote increased viral fusion in the target cell through a mechanism involving the transmembrane serine protease 2 (TMPRSS2). It was also demonstrated they are able to increase the inflammatory activity through the NF-κB/IL-6/let-7/LIN-28 axis. In addition, let-7 overexpression led to a reduction in inflammatory cytokines and chemokines expression (IL-6, IL-8 and TNF-α). Interestingly, the cytokines modulated by the let-7 family are related to COVID-19-induced cytokine storm observed in patients undergoing clinical phase three. Thus, let-7 can be considered a novel and attractive biomarker for therapeutic purpose. Based on that, the present study aims to critically analyze the immunopathological mechanisms of the microRNA let-7 in the infection caused by SARS-CoV-2. Full article

COVID-19 is a viral disease that has caused millions of deaths around the world since 2020. Many strategies have been developed to manage patients in critical conditions; however, comprehension of the immune system is a key factor in viral clearance, tissue repairment, and adaptive immunity stimulus. Participation of immunity has been identified as a major factor, along with biomarkers, prediction of clinical outcomes, and antibody production after infection. Immune cells have been proposed not only as a hallmark of severity, but also as a predictor of clinical outcomes, while dynamics of inflammatory molecules can also induce worse consequences for acute patients. For convalescent patients, mild disease was related to higher antibody production, although the factors related to the specific antibodies based on a diversity of antigens were not clear. COVID-19 was explored over time; however, the study of immunological predictors of outcomes is still lacking discussion, especially in convalescent patients. Here, we propose a review using previously published studies to identify immunological markers of COVID-19 outcomes and their relation to antibody production to further contribute to the clinical and laboratorial management of patients. Full article

Since the momentous discovery of X-rays, high-dose radiotherapy (H-XRT) has been a cornerstone for combating cancer. The high-energy electromagnetic waves induce direct damage to tumor-cells’ DNA, thereby halting cell growth and proliferation, and eventually leading to tumor eradication. Furthermore, recent evidence suggests that H-XRT may have immunomodulatory properties which arise from its ability to induce the release of neoantigens, which in turn prime T-cells and contribute to T-cell repertoire diversity. Throughout the years, there have been different treatment modalities introduced as complements to H-XRT that have yielded greater results than monotherapy alone. In this review, we will discuss preclinical and clinical data related to the recently introduced low-dose radiotherapy (L-XRT) modality. We will also explore the justification for combining L-XRT and H-XRT, which became known as the “RadScopal Technique”, as a novel immune adjuvant to treat cancer. In this analysis, we detail and dissect the physiological mechanisms of action of each modality and describe the synergistic amalgamation effect observed on primary and metastatic tumors. Finally, we will explore the impetus for further studies to investigate combinations of the “RadScopal Technique” with various immune-oncology drug candidates. Full article

Mastic oil (MO) is extracted from the resin of the bark of Pistacia lentiscus var. chia, a tree abundantly grown in the Greek island of Chios. Various biological activities, such as antimicrobial, anticancer and antioxidant, have been associated with the dietary intake of MO. However, little is known about MO’s potential anti-inflammatory effects, while some of its main chemical constituents were reported to exert significant anti-inflammatory activity. This study aims to assay the bioactivity of MO on in vitro and in vivo experimental inflammation models, in particular on LPS-stimulated RAW264.7 macrophages, murine primary peritoneal macrophages and a model of zymosan-induced peritonitis in BALB/c mice. The per os administration of MO inhibited the recruitment of macrophages into the peritoneal cavity of zymosan-treated mice, but did not affect neutrophil mobilisation or the levels of IL-6 or TNF-α in the peritoneal fluid. Similarly, IL-6 and TNF-α secretion in primary LPS-stimulated macrophages was not affected by MO, but the levels of phosphoproteins that activate inflammation in macrophages were differentially regulated. Finally, MO and some of its individual constituents reduced nitric oxide (NO), prostaglandin E2 and TNF-α levels in supernatants of LPS-stimulated RAW264.7 cells and inhibited their phagocytosis rate. Our data imply that MO may promote an anti-inflammatory transition in macrophages due to the combined bioactivities of its individual constituents. Thus, as a mixture of various compounds, MO seems to affect multiple molecular mechanisms that are involved in the development of inflammation. Therefore, more research, focusing on MO’s individual constituents and employing various pre-clinical inflammation models that activate different mechanisms, is required for a detailed investigation of the oil’s potential anti-inflammatory activity. Full article

Despite advances in treatment options, the clinical outcomes of pediatric patients with advanced solid tumors have hardly improved in decades, and alternative treatment options are urgently needed. Innovative therapies, such as chimeric antigen receptor (CAR) T cells and oncolytic viruses (OVs), are currently being evaluated in both adults and children with refractory solid tumors. Because pediatric solid tumors are remarkably diverse and biologically different from their adult counterparts, more research is required to develop effective treatment regimens for these patients. Here, we first summarize recent efforts and advances in treatments for pediatric solid tumors. Next, we briefly introduce the principles for CAR T cell therapy and oncolytic virotherapy and clinical trials thereof in pediatric patients. Finally, we discuss the basis for the potential benefits of combining the two approaches in pediatric patients with advanced solid tumors. Full article

Differences in the baseline levels of serum cytokines or in single-nucleotide polymorphisms (SNPs) in cytokine genes may be useful to predict outcomes for patients being treated for metastatic breast cancer. We have measured the plasma levels and characterized individual SNPs for IL-1RA, IL-1β, IL-2, IL-6 and TNFα in 130 patients with metastatic breast cancer treated with high-dose chemotherapy. Patients were treated with high-dose cyclophosphamide (Group 1, 74 patients) or high-dose paclitaxel-containing regimens (Group 2, 56 patients). A high plasma level of IL-1RA and a SNP in the IL-1RA gene indicated a better prognosis for patients in Group 1 (but not Group 2). However, the level of plasma IL-1RA did not correlate with the SNP genotype. A high plasma level of IL-6 or TNFα indicated a poorer outcome for patients in Group 1 although the SNP genotypes for the IL-6 and TNFα SNPs were not associated with differences in outcome. The plasma levels of IL-1β and IL-2 and the genotype of the IL-1β SNPs did not indicate differences in outcome. Although, individually, plasma levels of cytokine or “risk” SNP genotypes may not indicate outcome, in combination there was an increased trend to predict outcome for patients treated with high-dose cyclophosphamide but not high-dose paclitaxel. These results suggest that the immune cytokines may be useful as prognostic biomarkers in the treatment of patients with metastatic breast cancer treated with different types of chemotherapy. Full article

Interceding nutrients have been acquiring increased attention and prominence in the field of healing and deterrence of various disorders. In this light, the present article encompasses several facets of ketogenic diet as an immunomodulator with respect to its expansive clinical applications. Accordingly, several scientific records, models, and case histories, including viral infections, cancer, chronic diseases, e.g., cardiovascular diseases, epilepsy, as well as numerous other neuro-disorders, are assembled, revealing a profound influence of KD in favor of improvement in the patient’s condition. We accentuate possible manifold mechanisms of KD that require further exploration. Full article

In the chronic phase of chikungunya virus (CHIKV) infection, excessive inflammation manifests as incapacitating joint pain and prolonged arthritis. Arthritis resulted from a large influx of infiltrating immune cells driven by pro-inflammatory cytokines and chemokines originating from the toll-like receptor (TLR)-mediated innate antiviral response. This study investigated fisetin’s ability to modulate TLR-mediated antiviral responses against CHIKV in Huh7 cells. The CHIKV inhibitory potential of fisetin was assessed by plaque-forming unit assay, virus yield reduction assay, and bright-field microscopy (cytopathic effect, immunofluorescence). Fisetin’s modulatory potential on TLR-mediated antiviral response was evaluated by immunofluorescence assay (expression of TLR proteins), qRT-PCR (mRNA level of antiviral genes), human cytokine array, and the immunoblotting of key transcription factors. The present study showed fisetin induced the expression of the antiviral genes at an early time-point by promoting the phosphorylation of IRF3 and IRF7. Fisetin reduced excessive inflammatory cytokine responses in CHIKV-infected Huh7 cells by impeding the over-phosphorylation of NF-κB. Fisetin also reduced CHIKV-induced cytopathic effects in CHIKV-infected Huh7 cells. Altogether, our study suggests that fisetin modulates TLR-mediated antiviral responses by affecting the CHIKV-induced inflammatory responses. Full article

The pathogenesis and refractory nature of inflammatory bowel disease (IBD) are related to multiple factors, including genetic factors, environmental factors, and abnormalities in gut microbial diversity, which lead to decreased levels of short-chain fatty acids (SCFAs). Among SCFAs, butyrate plays an important role in mucosal barrier maintenance, serves as an energy source in intestinal epithelial cells (IECs), and exhibits anti-inflammatory effects; therefore, it is a particularly important factor in gut homeostasis. Changes in gut microbiota and butyrate levels affect the outcomes of drug therapy for IBD. Butyrate is mainly absorbed in the large intestine and is transported by monocarboxylate transporter 1 (MCT1) and sodium-coupled monocarboxylate transporter 1 (SMCT1). During gut inflammation, butyrate utilization and uptake are impaired in IECs. Dysbiosis and low abundance of butyrate affect fecal microbiota transplantation and anticancer immunotherapy. Although butyrate administration has been reported as a treatment for IBD, its effects remain controversial. In this review, we discuss butyrate absorption and metabolism in patients with IBD and their relationship with drug therapy. Full article

Prolonged survival and durable responses in several late-stage cancers such as melanoma and lung cancer have been made possible with the use of immune checkpoint inhibitors targeting the programmed cell-death protein 1 (PD-1) or its ligand PD-L1. While it is prudent to focus on the unprecedented and durable clinical responses, there are subsets of cancer patients that do not respond to immunotherapies or respond early and then relapse later. Many pathways of resistance have been characterized, and more continue to be uncovered. To overcome the development of resistance, an in-depth investigation is necessary to identify alternative immune receptors and signals with the overarching goal of expanding treatment options for those with demonstrated resistance to PD1 checkpoint immunotherapy. In this mini-review, we will discuss the mechanisms by which tumors exhibit resistance to anti-PD-1/PD-L1 immunotherapy and explore strategies to overcome such resistances. Full article

AVR-48 is a structural derivative of chitin previously shown by our laboratory to significantly decrease lung injury parameters in LPS, hyperoxia and sepsis-induced rodent models. The current study objectives are to determine the cellular mechanism of action and demonstrate efficacy in a mouse bacterial lung infection model. For in vitro receptor binding and macrophage polarization studies, C57Bl/6J mouse derived spleens and human peripheral blood mononuclear cells (hPBMCs) were treated with AVR-48 ± LPS or biotin conjugated AVR-48. Different macrophage types were determined using flow cytometry and secreted cytokines were measured using ELISA. In vivo, a CD-1 mouse Pseudomonas aeruginosa lung infection was treated with AVR-48, assessing bacterial colony forming unit (CFU), IL-10 and IL-17A levels in lung and blood samples. AVR-48 binds to both the toll-like receptor 4 (TLR4) and the CD163 receptor on mouse monocytes. In hPBMCs, frequency of intermediate macrophages increased upon AVR-48 treatment for 72 h. Increased bacterial phagocytosis/intracellular killing were observed in THP-1 cells and reduction in CFU in CD-1 mouse lungs. Binding of AVR-48 to both TLR4 and CD163 receptors bring the macrophages to an intermediary stage, resulting in increased phagocytosis and decreased inflammation, altogether providing an optimal immune balance for treating lung injury and infection. Full article

Inflammatory processes represent a pivotal element in the development and complications of cardiovascular diseases (CVDs). Targeting these processes can lead to the alleviation of cardiomyocyte (CM) injury and the increase of reparative mechanisms. Loss of CMs from inflammation-associated cardiac diseases often results in heart failure (HF). Evidence of the crosstalk between nuclear factor-kappa B (NF-κB), Hippo, and mechanistic/mammalian target of rapamycin (mTOR) has been reported in manifold immune responses and cardiac pathologies. Since these signaling cascades regulate a broad array of biological tasks in diverse cell types, their misregulation is responsible for the pathogenesis of many cardiac and vascular disorders, including cardiomyopathies and atherosclerosis. In response to a myriad of proinflammatory cytokines, which induce reactive oxygen species (ROS) production, several molecular mechanisms are activated within the heart to inaugurate the structural remodeling of the organ. This review provides a global landscape of intricate protein–protein interaction (PPI) networks between key constituents of NF-κB, Hippo, and mTOR signaling pathways as quintessential targetable candidates for the therapy of cardiovascular and inflammation-related diseases. Full article

Obesity, defined by excessive fat mass and its associated low-grade chronic inflammation, leads to insulin resistance, diabetes, and metabolic dysfunctions. The immunomodulatory properties of natural agents have gained much interest in recent decades. Some of the plant-derived agents are known to be immunomodulators that can affect both innate and adaptive immunity, e.g., thymoquinone, curcumin, punicalagin, resveratrol, quercetin, and genistein. Natural immunomodulators may contribute to the treatment of a number of inflammatory diseases, as they have significant efficacy and safety profiles. The immunomodulatory effects of traditional Greco-Arab and Islamic diets and medicinal plants are well acknowledged in abundant in vitro studies as well as in animal studies and clinical trials. This review highlights the role of Greco-Arab and Islamic diets and medicinal plants in the management of inflammation associated with obesity. Although previously published review articles address the effects of medicinal plants and phytochemicals on obesity-related inflammation, there is no systematic review that emphasizes clinical trials of the clinical significance of these plants and phytochemicals. Given this limitation, the objective of this comprehensive review is to critically evaluate the potential of the most used herbs in the management of obesity-related inflammation based on clinical trials. Full article

Among other systemic autoimmune diseases, primary Sjögren syndrome (pSS) bears the highest risk for lymphoma development. In pSS, chronic antigenic stimulation gradually drives the evolution from polyclonal B-cell expansion to oligoclonal/monoclonal B-cell predominance to malignant B-cell transformation. Thus, most pSS-related lymphomas are B-cell non-Hodgkin lymphomas (NHLs), with mucosa-associated lymphoid tissue (MALT) lymphomas predominating, followed by diffuse large B-cell lymphomas (DLBCLs) and nodal marginal zone lymphomas (NMZLs). Since lymphomagenesis is one of the most serious complications of pSS, affecting patients’ survival, a plethora of possible predisposing factors has been studied over the years, ranging from classical clinical, serological, hematological, and histological, to the more recently proposed genetic and molecular, allowing clinicians to timely detect and to closely follow-up the subgroup of pSS patients with increased risk for lymphoma development. Overall predisposing factors for pSS-related lymphomagenesis reflect the status of B-cell hyperactivity. Different clinical features have been described for each of the distinct pSS-related B-cell NHL subtypes. While generally pSS patients developing B-cell NHLs display a fairly good prognosis, outcomes in terms of treatment response and survival rates seem to differ depending on the lymphoma subtype, with MALT lymphomas being characterized by a rather indolent course and DLBCLs gravely affecting patients’ survival. Full article

The nasal cavity is a primary checkpoint for the invasion of respiratory pathogens. Numerous pathogens, including SARS-CoV-2, S. pneumoniae, S. aureus, etc., can adhere/colonize nasal lining to trigger an infection. Secretory IgA (sIgA) serves as the first line of immune defense against foreign pathogens. sIgA facilitates clearance of pathogenic microbes by intercepting their access to epithelial receptors and mucus entrapment through immune exclusion. Elevated levels of neutralizing IgA at the mucosal surfaces are associated with a high level of protection following intranasal immunizations. This review summarizes recent advances in intranasal vaccination technology and challenges in maintaining nominal IgA levels at the mucosal surface. Overall, the review emphasizes the significance of IgA-mediated nasal immunity, which holds a tremendous potential to mount protection against respiratory pathogens. Full article