Immuno

Social behavior restrictions, social distancing, and promotion of non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic have significantly reduced the incidence of many epidemic infections in the world, especially in children. Resurges of infectious diseases vary depending on the biological characteristics of each infectious pathogen and differences in culture, lifestyle, and infection control mitigation policies by country or region. Although the gapping of infectious disease outbreaks can cause children who were uninfected during that period to become more susceptible to infection after the pandemic, resulting in a slightly older age of infected children, there are no conclusive reports that suggest a definite impact on the development of children’s immune maturation or its balance. Insufficient immune challenges in early life may influence the risk of developing immune-mediated conditions such as allergies or autoimmune diseases later in life, though evidence for this is still emerging. Future observational studies are needed to determine the long-term impact of the epidemic gap caused by the COVID-19 pandemic as well as the long-term impact of COVID-19 infection itself on the immune function or balance of children. Full article

Sex-based differences in innate immunity may play a crucial role in susceptibility to and progression of tuberculosis (TB), a disease that disproportionately affects men. This study aimed to examine whether early host–pathogen interactions contribute to the heightened vulnerability of males to Mycobacterium tuberculosis (Mtb) infection. Using recombination activating gene 2 knockout (RAG2 KO) mice, which lack adaptive immunity, we were able to isolate and analyze innate immune responses to Mtb without the influence of T and B cells. Surprisingly, and in stark contrast to wild-type mice that reflect the male bias as observed in humans, female RAG2 KO mice were more susceptible to Mtb than their male counterparts. Increased lung CFU in females was accompanied by a significant rise in inflammation, indicated by elevated levels of inflammatory cytokines and chemokines, as well as a massive influx of neutrophils into the lungs. In contrast, male mice exhibited higher levels of IFN-γ and CCL5, along with a greater presence of NK cells in their lungs, suggesting that, in the absence of adaptive immunity, males benefit from a more robust NK cell response, potentially offering greater protection by better controlling inflammation and slowing disease progression. Full article

Lawsonia intracellularis is a Gram-negative, intracellular bacterium that can infect several animal species. In pigs, the bacteria cause porcine proliferative enteropathy, or ileitis. The wide spread of the pathogen produces a large impact on pig production worldwide. Saliva is a source of biomarkers that can help to monitor changes in the immune system after vaccination. The purpose of this study was to study the changes in haptoglobin (Hp), immunoglobulin G (IgG), and adenosine deaminase (ADA) in saliva after vaccination against Lawsonia intracellularis. In addition, productivity parameters were analysed to evaluate if vaccination and changes in salivary analytes could be associated with changes in these parameters. The pigs vaccinated against Lawsonia showed an improvement in the productive parameters and a reduction in food conversion and frequency of diseases. In addition, they showed lower values of Hp (p = 0.011), IgG (p < 0.01), and ADA (p < 0.003) in saliva during the first two months of the fattening period compared to non-vaccinated pigs. It could be concluded that in our experimental conditions, the vaccination against Lawsonia intracellularis produced a significant decrease in biomarkers of the immune response in saliva compared with the non-vaccinated pigs. This would indicate a reduction in the activation of the immune system, which could be postulated to be due to the increased defence ability of the organism against pathogens. This reduced activation of the immune system can lead to better food conversion and an increase in the productive parameters of these pigs. Overall, this report opens a new window for the possible use of saliva for non-invasive evaluation of the immune system after vaccination in pigs. Full article

Dendritic cells (DCs) play a crucial role in controlling viral infections. Little is known about the changes in frequencies of the DC subsets in patients with chronic hepatitis C (CHC), particularly in the era of interferon-free regimens. We aimed to evaluate the impact of sofosbuvir/daclatasvir on the frequency of different peripheral DC subsets, the expression of the inhibitory CD200R and its ligand CD200 on DC, and their relation to the treatment outcome. A total of 1000 patients with CHC were enrolled and treated with a fixed oral dose of 400 mg of sofosbuvir and 60 mg of daclatasvir for 12 weeks. A total of 940 patients achieved sustained virologic response (SVR), and only 60 patients were non-responders (NRs). The frequencies of the peripheral plasmacytoid (pDC) and myeloid (mDCs) subsets and their surface expressions of CD200R and CD200 molecules were analyzed using flow cytometry. This analysis included 60 non-responders (NR group), 60 randomly selected sustained virologic responders (SVR group) at baseline, and at the end of treatment, and 60 healthy controls. HCV infection was associated with a down-regulation in the frequency of mDC, compared to healthy controls. In addition, mDC in HCV-infected patients showed lower levels of CD200R. However, neither the pDC frequency nor their CD200R expression was significantly altered. Interestingly, by the end of therapy, the frequencies of circulating mDCs and CD200R⁺mDC increased significantly in the SVR group and were even comparable to healthy controls. The levels of these cells were not normalized in the NR group. Percentages of mDCs and CD200R⁺mDC subsets showed good prognostic accuracy for predicting virologic response to therapy. Our results showed that HCV infection was associated with modulation of the mDC frequency and their surface expression of CD200R. Successful daclatasvir and sofosbuvir combined therapy was associated with the normalization of the percentages of mDC and CD200R⁺mDC. Full article

Exostosin 1 (EXT1) encodes a type II transmembrane glycosyltransferase residing in the endoplasmic reticulum and plays an essential role in the elongation of heparan sulfate chain biosynthesis. Additionally, EXT1 may act as an oncogene that could promote cell proliferation as well as cancer cell metastasis. Herein, we investigated EXT1’s expression pattern and prognostic value in breast cancer, along with its immunological implications. Immunohistochemical staining of EXT1 was assessed in 85 breast cancer patients. Patients were categorized into molecular subtypes, namely luminal A, luminal B, and human epidermal growth factor receptor 2 (HER2), along with triple-negative breast cancer (TNBC). Correlations of EXT1 immunostaining with clinicopathological parameters were evaluated. Furthermore, the correlations of EXT1 expression with tumor immune infiltration and immune cell surface markers were assessed using TIMER. Moreover, survival analysis was conducted to reveal EXT1’s prognostic value. EXT1 expression was markedly associated with the status of the estrogen receptor (ER), molecular subtypes, and recurrence status. In addition, high levels of EXT1 expression were associated with worse overall survival (OS) and relapse-free survival (RFS). Analysis of immune infiltration indicated that EXT1 expression was positively correlated with dendritic cells (DCs), macrophages, neutrophils, CD4⁺ T cells, and CD8⁺ T cells, although it showed a negative correlation with the tumor purity. Overall, this study suggests that the elevated EXT1 expression, particularly in TNBC, has a positive correlation with poor prognosis and with immune-infiltrated cells in breast cancer. Therefore, it may emerge as an independent prognostic biomarker, immunological marker, and potential future therapeutic target for the most aggressive TNBC subtype. Full article

Background: Chronic rhinosinusitis (CRS) is a disease characterized by persistent sinonasal mucosal inflammation. Fibroblasts play a crucial role in extracellular matrix production and inflammation. We investigated the heterogeneity of fibroblasts in patients with CRS. Methods: Fibroblasts were isolated from nasal polyp tissues. RNA sequencing was then performed. We also analyzed the GSE136825 dataset obtained from the Gene Expression Omnibus database. Alternatively, fibroblasts were stimulated in vitro. Results: Hierarchical clustering of samples indicated ADGRB3-high and POSTN-high fibroblasts. A Gene Set Enrichment Analysis (GSEA) revealed that cytotoxic immune responses were enriched in ADGRB3-high fibroblasts, while cell cycle pathways were enriched in POSTN-high fibroblasts. Similar GSEA results were observed in the GSE136825 dataset. Additionally, type 1 and type 3 inflammation-related genes were highly expressed in ADGRB3-high samples, whereas type 2-related genes were highly expressed in POSTN-high samples. In vitro, ADGRB3 expression increased in fibroblasts stimulated with IFN-γ, while POSTN increased in those stimulated with IL-4 and IL-13. Conclusions: Our study demonstrates that type 1 inflammation induces ADGRB3-high fibroblasts, associated with the cytotoxic immune response, while type 2 inflammation induces POSTN-high fibroblasts, linked to CRS progression via an elevated cell cycle. The further characterization of fibroblasts could provide insights into the stromal networks in the CRS microenvironment. Full article

Dengue fever is currently a major global issue, especially in tropical and subtropical countries. The absence of specific antiviral medications supports alternative dengue treatment strategies. South Asian countries have been using Carica papaya leaves as a traditional remedy for dengue for many years. Carica papaya possesses several biological features, including anti-inflammatory, antiviral, cancer-fighting, anti-diabetic, and antioxidant qualities. Additionally, numerous studies have demonstrated that bioactive compounds found in papaya leaf extracts, including carpaine, dehydrocarpaine I and II, chymopapain, and papain, significantly influence platelet counts, while phenolic compounds, such as chlorogenic acid, kaemferol, protocatechuic acid, quercetin, and 5,7-dimethoxycoumarin significantly inhibit viral replication in dengue patients, with negligible side effects. Carica papaya may be considered a viable pharmacological candidate with several targets for treating dengue. It has been shown to prevent infections, reduce oxidative stress, control cytokine storms and the immune system, lessen thrombocytopenia, and increase the body’s protein and hemoglobin levels. This literature review highlights the pathophysiological mechanism of dengue, as well as the pharmacological action of Carica papaya, both of which combat this debilitating disease. Despite these findings, additional investigation, including clinical studies, is necessary to confirm the effectiveness and safety of papaya-based treatments. It is necessary to address issues like standardizing papaya extracts, figuring out the best dosages, and assessing any drug interactions. Full article

Antiphospholipid syndrome (APS) is a thrombo-inflammatory disease propelled by circulating autoantibodies that recognize cell surface phospholipids and phospholipid-binding proteins. APS is an autoimmune disorder associated with recurrent thrombosis of arterial or venous vessels and/or recurrent obstetric complications as miscarriages. APS can be divided into primary or secondary clinical syndrome because of the possible association with other autoimmune systemic diseases as systemic lupus erythematosus (SLE). Vitamin K antagonists remain the mainstay of treatment for most patients with APS and, based on current data, appear superior to the more targeted direct oral anticoagulants. However, the choice of the type of antithrombotic drug is based on the anamnesis of affected patients: patients with previous arterial or venous thrombosis may benefit from anticoagulants, while patients with previous obstetric diseases may benefit from aspirin, but several clinical exceptions may be evaluated. This short review is dedicated to underlining the main clinical evidence for patients affected by APS or CAPS (catastrophic antiphospholipid syndrome) in order to prevent recurrent thrombosis. Full article

Human immunodeficiency virus (HIV) has troubled humankind for many years. The rate of new HIV cases is decreasing steadily, mostly because of safer sexual practices and scientific advances in medicine. However, the number of HIV-related trials has significantly increased, as the search for a definite cure for HIV is still fruitless. Our current treatment options involve antiretroviral therapy (ART) with various drug combinations that lower the patients’ viral load in order for the immune system to reconstitute itself. This way, adherent patients achieve a life expectancy similar to the general population. Besides the established treatment protocols, the focus has currently shifted towards secondary pharmaceutical regimen programs that enhance a patient’s immune system and response to opportunistic infections. Vitamins C and D are easily obtainable even in the developing world and are known to improve an individual’s daily life, with vitamin D enhancing the human immune response and vitamin C having an assisting role in both the immune response and as an important antioxidant. Recently, many studies assessing the effect of these vitamins on the progression of HIV have been performed. We aimed to collect and review these studies in order to determine the necessity of the supplementation of these vitamins in HIV-infected patients, which might complement the existing ART. To this day, the scientific community is conflicted, and more studies must be conducted before a definite conclusion about these vitamins’ effects on HIV patients can be reached. Full article

Background and Aim: Monkeypox (Mpox) is a viral disease mainly found in central and western Africa, with symptoms similar to variola virus (smallpox) but distinguished by the early lymph node swelling specific to Mpox. This review summarizes the neuropsychiatric manifestations of Mpox infection and vaccination, along with management approaches. Method: We searched different databases such as PubMed, Scopus, WoS, and Google Scholar about the neuropsychiatric manifestations of Mpox disease and the associated strategies of management. Results and conclusions: Mpox can cause a wide range of neurological symptoms. These range from mild symptoms like headaches, muscle aches, fatigue, and pain to severe symptoms, including seizures, blindness, photophobia, delirium, coma, encephalitis, and transverse myelitis. It is essential to distinguish Mpox from smallpox and other orthopox viruses. Psychiatric issues, such as stigma, disfigurement, isolation, and physical pain, are common in Mpox patients. To address these, healthcare providers should provide accurate information, counseling, and virtual support. Neurological side effects were associated with the previous smallpox vaccine, which offered cross-protection against Mpox. This vaccine has since been replaced by JYNNEOS, which does not pose any neurological risks. Mpox-related neurological symptoms are generally managed with supportive care, including NSAIDs, antibiotics, antiepileptics, and sedatives for seizures. Antivirals like acyclovir are also used. Severe cases may require hospitalization or intubation. So, we recommend early diagnosis, isolation, and prompt treatment, as Mpox spreading to the central nervous system can lead to serious and potentially fatal complications. Full article

DENV belongs to the Flaviviridae family and possesses a single-stranded RNA genome of positive polarity. DENV infection manifests in mild subclinical forms or severe forms that may be dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Despite a lot of effort worldwide, the exact mechanism underlying the pathogenesis of severe DENV infection remains elusive. It is believed that both host and viral factors contribute to the outcome of dengue disease. The host factors are age at the time of infection, sex, nutrition, and immune status, including the presence of pre-existing antibodies or reactive T cells. Viral factors include the serotype, genotype, and mutation(s) due to error-prone RNA-dependent polymerase leading to the development of quasispecies. Accumulating bodies of literature have depicted that DENV has many ways to invade and escape the immune system of the host. These invading strategies are directed to overcome innate and adaptive immune responses. Like other viruses, once the infection is established, the host also mounts a series of antiviral responses to combat and eliminate the virus replication. Nevertheless, DENV has evolved a variety of mechanisms to evade the immune system. In this review, we have emphasized the strategies that DENV employs to hijack the host innate (interferon, IFN; toll-like receptors, TLR; major histocompatibility complex, MHC; autophagy; complement; apoptosis; RNAi) and adaptive (antibody-dependent enhancement, ADE; T cell immunity) immune responses, which contribute to the severity of DENV disease. Full article

The metabolism of T-lymphocytes has recently emerged as a pivotal area of investigation, offering insights into the supra-genic modulations that can influence the genetic mechanisms underlying lymphocyte clustering processes. Furthermore, it has become a crucial aspect in understanding lymphocyte plasticity within the immune microenvironment, both in physiological and pathological contexts. T-lymphocyte metabolism has recently emerged as a pivotal factor in both targeted therapy and the genetic signature of the T-lymphocyte, as a result of its influence on gatekeeper processes. From this perspective, the interconnections between the metabolic processes traditionally associated with energy production and the capacity to influence the genetic fate of the T lymphocyte have identified purine metabolism and nuclear/cytoplasmic signaling as pivotal elements in comprehending the intricacies of these molecular phenomena. The two aspects of purine metabolism and metabolic/molecular control of the nuclear envelope have been the subject of a number of significant studies published in recent years. However, from a certain perspective, the existing evidence remains sparse and inconclusive, hindering a comprehensive understanding of the subject matter. In this review, we endeavor to establish a connection between these aspects for the first time and to present a review of the molecular, immunological and genetic events that determine how these aspects, which have hitherto received insufficient attention, may represent a new avenue for lymphocyte reprogramming in the therapeutic field. This will be achieved by understanding the connections between nuclear control and purine flux within and outside the cell. Full article

Background. Several research findings suggest that sodium–glucose co-transporter 1 (SGLT1) is implicated in the progression and control of infections and inflammation processes at the pulmonary level. Moreover, our previous works indicate an engagement of SGLT1 in inhibiting the inflammatory response induced in intestinal epithelial cells by TLR agonists. In this study, we report the anti-inflammatory effects observed in the lung upon engagement of the transporter, and upon the use of glucose and BLF501, a synthetic SGLT1 ligand, for the treatment of animal models of lung inflammation, including a model of allergic asthma. Methods. In vitro experiments were carried out on human pneumocytes stimulated with LPS from Pseudomonas aeruginosa and co-treated with glucose or BLF501, and the production of IL-8 was determined. The anti-inflammatory effect associated with SGLT1 engagement was then assessed in in vivo models of LPS-induced lung injury, as well as in a murine model of ovalbumin (OVA)-induced asthma, treating mice with aerosolized LPS and the synthetic ligand. After the treatments, lung samples were collected and analyzed for morphological alterations by histological examination and immunohistochemical analysis; serum and BALF samples were collected for the determination of several pro- and anti-inflammatory markers. Results. In vitro experiments on human pneumocytes treated with LPS showed significant inhibition of IL-8 production. The results of two in vivo experimental models, mice exposed to aerosolized LPS and OVA-induced asthma, revealed that the engagement of glucose transport protein 1 (SGLT1) induced a significant anti-inflammatory effect in the lungs. In the first model, the acute respiratory distress induced in mice was abrogated by co-treatment with the ligand, with almost complete recovery of the lung morphology and physiology. Similar results were observed in the OVA-induced model of allergic asthma, both with aerosolized and oral BLF501, suggesting an engagement of SGLT1 expressed both in intestinal and alveolar cells. Conclusions. Our results confirmed the engagement of SGLT1 in lung inflammation processes and suggested that BLF501, a non-metabolizable synthetic ligand of the co-transporter, might represent a drug candidate for therapeutic intervention against lung inflammation states. Full article

The aim of this review was to gather pieces of information from available critically evaluated published articles concerning any interplay in which the spleen could be involved. For many years, the spleen has been alleged as an unnecessary biological structure, even though splenomegaly is an objective finding of many illnesses. Indeed, the previous opinion has been completely changed. In fact, the spleen is not a passive participant in or a simple bystander to a relationship that exists between the immune system and other organs. Recently, it has been evidenced in many preclinical and clinical studies that there are close associations between the spleen and other parts of the body, leading to various spleen–organ axes. Among them, the gut–spleen axis, the liver–spleen axis, the gut–spleen–skin axis, the brain–spleen axis, and the cardio-splenic axis are the most explored and present in the medical literature. Such recent sources of evidence have led to revolutionary new ideas being developed about the spleen. What is more, these observations may enable the identification of novel therapeutic strategies targeted at various current diseases. The time has come to make clear that the spleen is not a superfluous body part, while health system operators and physicians should pay more attention to this organ. Indeed, much work remains to be performed to assess further roles that this biological structure could play. Full article

Rheumatoid arthritis (RA) is an autoimmune disorder causing chronic inflammation primarily due to collagen regulation and transport imbalances. Collagen VII A1(COL7A1), a major component of anchoring fibrils, regulates inflammation via interacting with its transporter protein Transport and Golgi organization 2 homologs (TANGO1). The study revealed a significant increase in COL7A1 levels in both the plasma and PBMCs of RA patients. Additionally, a positive correlation between COL7A1 and ACCPA (anti-cyclic citrullinated peptide antibody) levels was observed among RA patients. TANGO1 mRNA expression was also found to be elevated in PBMCs. The knockdown of COL7A1 in RA synoviocytes using siRNA affected the expression of TANGO1 and inflammatory genes. Western blot analysis showed that COL7A1 si-RNA in TNF-α-induced SW982 cells reduced the expression of COL7A1, TANGO1, and NF-kBp65. The mRNA expression of inflammatory genes TNF-α, NF-kB p65, and IL-6 simultaneously decreased after the knockdown of COL7A1, as measured by qRT-PCR. An in silico analysis found 20 common interacting proteins of COL7A1 and TANGO1, with pathway enrichment analysis linking them to antigen presentation, class I and II MHC, and adaptive immunity pathways in RA. Among the common proteins, The DisGeNET database depicted that COL1A1, MIA3, SERPINH1, and GORASP1 are directly linked to RA. The molecular docking analysis of COL7A1 and TANGO1 revealed strong interaction with a −1013.4 energy-weighted score. Common RA-used drugs such as Adalimumab, Golimumab, and Infliximab were found to inhibit the interaction between COL7A1 and TANGO1, which can further impede the transport of COL7A1 from ER exit sites, indicating COL7A1 and TANGO1 as potential therapeutic targets to diminish RA progression. Full article

PTEN (phosphatase and tensin homolog) is a frequently lost tumor suppressor gene in prostate cancer, leading to aggressive tumor behavior and poor clinical outcomes. PTEN loss results in aberrant activation of the PI3K/AKT/mTOR pathway, promoting oncogenesis. These alterations also lead to an immunosuppressive tumor microenvironment with altered immune cell infiltration, cytokine profiles, and immune checkpoint regulation. This review aims to provide a comprehensive overview of the mechanisms underlying PTEN loss in prostate cancer and the consequent immune alterations observed in this subtype, thus underscoring the importance of understanding PTEN-mediated immune modulation for the development of effective therapeutic interventions in prostate cancer. Full article

Propolis, a complex natural product that honey bees produce by mastication to protect and maintain their hive structures, comprises various bioactive constituents, including phenolic acids, flavonoids, diterpenes, sesquiterpenes, lignans, vitamins, minerals, etc. The objective of the current research was to extract crude propolis to enrich the total polyphenolic and flavonoid content, conduct preliminary phytochemical screening, and develop and evaluate dosage form to improve formulation characteristics and immunomodulatory potential. Total balsam, polyphenols, and flavonoids were found to be 46% w/w, 34.82 ± 0.078 mg equivalent of gallic acid/g, and 23.61 ± 0.045 mg equivalent of quercetin/g, respectively. DSC and FTIR studies demonstrated molecular dispersion of the propolis extract. Formulation was optimized with a 3² factorial design, and an optimized batch showed 92.20 ± 1.72% drug release in 1 h, an elevated hypersensitivity (DTH) response (p < 0.0001), increased phagocytic activity (p < 0.01), and a significantly (p < 0.001) higher total leukocyte count ((5.015 ± 0.19) × 10³/mm³). The developed formulation showed significantly modulated immune modulatory potential compared with the propolis extract and conventional levamisole. This study can be further extended for clinical evaluations. Full article

Inflammatory bowel disease (IBD) is a chronic complicated inflammatory gut pathological disorder and is categorized into ulcerative colitis (UC) and Crohn’s disease (CD). Although the cause of IBD is unclear, dysbiosis of the gut microbiota is thought to be a key factor in the disease’s progression. The gut microbiome serves as a metabolic organ and promotes wellness by carrying out several biological activities. Any modification in the makeup of the gut microbiome leads to several pathological conditions, including IBD. In this review, we emphasize the key metabolic processes that control host–microbiome interaction and its impact on host health. We also discuss the association between microbiome dysbiosis (bacteriome, virome, and mycobiome) and the progression of IBD. Finally, we will highlight microbiome-based therapy as a novel and promising strategy to treat and manage IBD. Full article

Background: Previous research has suggested that modulated electro-hyperthermia (mEHT) can be used to induce anti-tumor immune effects and to extend patient survival. The use of mEHT in advanced pancreatic cancer is beneficial; however, its immune-mediating effects were never investigated. Methods: A retrospective observational study was conducted. Leukocyte counts, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and granulocyte-to-lymphocyte ratio (GLR) were measured at baseline, midpoint, and after mEHT treatment. Results: A total of 73 mEHT treated pancreatic cancer patients were included. The time elapsed between tumor diagnosis and the first mEHT treatment was 4.40 ± 5.70 months. While no change could be observed between the baseline and the first follow-up visits, the total white blood cell (WBC), neutrophil, and granulocyte count, CRP, NLR, and GLR were significantly higher at the second follow-up compared to both previous visits. Higher levels of the latter parameters following the last mEHT treatment were signaling significantly poor prognostic signs, and so were their longitudinal changes. Conclusions: After the initiation of mEHT, immune markers stabilize with the treatment, but this positive effect is eroded over time by progressive disease. Monitoring the changes in these markers and the occurrence of their increase is a prognostic marker of shorter survival. Full article