Immuno, Volume 2, Issue 4 (December 2022) – 9 articles

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

Advances over the last decades have made renal transplantation an important therapy for patients with end-stage renal disease, as the incidences of acute rejection and short-term transplant loss have been significantly reduced. However, long-term transplant survival remains a challenge in the renal transplantation community. The main causes of long-term graft loss are acute and chronic rejection, as well as the complications related to immunosuppression therapy. In spite of the breakthroughs achieved in recent years, histology is the gold standard technique to confirm the activation of the immune system against the graft with all the ensuing problems that taking biopsies brings to immunosuppressed patients. For this reason, several assays have been developed to try to monitor the immune function, but they show serious constraints owing to the fact that they require substantial laboratory work, they are not clinically available and they provide controversial results, so the combination of multiple assays is often needed to obtain a reliable diagnosis. Thus, the aim of this review is to perform a retrospective study of the immune system in renal transplantation, with special emphasis on the cutting-edge technological developments for monitoring, classification and early detection of rejection episodes in order to contribute to a better adjustment of immunosuppressive therapies and, hence, to a more personalized medicine that improves the quality of life of patients. Full article