Search Results (2,758)

Rheumatoid arthritis is a chronic systemic autoimmune disease that arises from complex interactions among genetic susceptibility, environmental factors, and immune dysregulation. Growing evidence indicates that microorganisms residing in the oral cavity and gastrointestinal tract, together with dietary factors, play a central role in shaping inflammatory and autoimmune responses in rheumatoid arthritis, forming an interconnected microbiome–immune–nutrition axis. Alterations in the composition and function of oral and intestinal microbial communities are associated with disruption of mucosal barrier integrity, activation of innate and adaptive immune pathways, increased differentiation of proinflammatory T lymphocyte subsets, and loss of immune tolerance that promotes autoantibody production. In addition, microbially derived metabolites, particularly short-chain fatty acids, provide a mechanistic link between microbial ecology, immune regulation, and bone metabolism. Diet represents a key upstream modulator of this axis. Dietary patterns rich in anti-inflammatory nutrients support microbial diversity and immunoregulatory metabolite production, whereas diets high in processed foods and saturated fats favor proinflammatory microbial profiles. Accumulating clinical evidence suggests that nutritional strategies and microbiome-targeted dietary interventions may reduce systemic inflammation and disease-related comorbidities when used alongside standard pharmacological treatments. Taken together, the microbiome–immune–nutrition axis represents a modifiable and clinically meaningful target in rheumatoid arthritis, emphasizing the need for interdisciplinary research and well-designed clinical trials to translate these insights into personalized approaches for disease management. The aim of this review is to integrate current mechanistic and clinical evidence on the interactions between the microbiome, immune system, and nutrition in rheumatoid arthritis, with a focus on their pathogenic relevance, therapeutic potential, and implications for personalized, diet-based interventions. Full article

Plastic pollutants, including phthalates, bisphenol A (BPA), per- and polyfluoroalkyl substances (PFAS), and microplastics (MPs), are increasingly recognized as emerging environmental cofactors that intersect with infectious disease dynamics. These compounds, once considered inert, can alter immune function, reshape host–pathogen interactions, and directly influence viral survival and transmission. In this review, we compile current evidence on the chemistry, environmental occurrence, and biological activity of major plastic-associated pollutants with emphasis on their role in viral infections. Phthalates such as di(2-ethylhexyl) phthalate (DEHP) and its metabolite MEHP modulate innate immune signaling and have been shown to exacerbate infections, including Dengue and Coxsackievirus B3. Other DEHP-like phthalates, such as dibutyl phthalate (DBP), exhibit consistent infection-enhancing effects, while high molecular weight or cyclical phthalates such as polyvinyl acetate phthalate (PVAP) display conflicting results in their modulation of viral infections. BPA, widely detected in human tissues, acts through endocrine and immune disruption, worsening viral myocarditis, and altering influenza outcomes. PFAS, persistent “forever chemicals,” reshape adaptive immune responses and are associated with increased susceptibility, viral persistence, or severity of infection of herpesvirus (HCMV, EBV, HSV-1), hepatitis virus, and influenza infection. Microplastics represent a distinct risk by acting as physical carriers for viruses and bacteria, stabilizing viral RNA, enhancing host cell uptake, and skewing immune responses. Together, these pollutants extend beyond toxicology into virology, providing novel insights into how environmental exposures converge with viral pathogenesis. We highlight mechanistic advances and critical knowledge gaps and propose future directions for integrating environmental health and infectious disease research. Full article

Staphylococcus aureus (S. aureus) is the most prevalent pathogen associated with subclinical mastitis, which significantly impacts dairy farming worldwide. Fluctuations in reproductive hormones, such as bovine prolactin (bPRL) and 17β-estradiol (E2), are known to compromise the innate immune response (IIR) of the mammary gland (MG). In this study, we evaluated the effects of bPRL and E2 on the effector response of primary bovine macrophages, isolated from lactating Holstein cows, challenged with S. aureus. We demonstrated that physiological concentrations of bPRL (5 ng/mL) and E2 (50 pg/mL) induced differential changes in the expression of pro-inflammatory (TNF-α, IL-6, and IL-1β) and anti-inflammatory (IL-10) cytokines, chemokines (IL-8), antimicrobial peptides (BNBD10 and S100A7), and miRNAs (miR-451, miR-155, miR-7863, miR-146a, miR-21a, Let-7a-5p, miR-30b, and miR-23a) in S. aureus-challenged macrophages. Moreover, these hormones promoted global histone H3 acetylation and the epigenetic H3K9ac mark without affecting H3K9me2 levels. Hormonal treatment also modulated histone deacetylase (HDAC) activity. Furthermore, hormonal treatment altered macrophage chemotaxis and phagocytosis. In conclusion, bPRL and E2 modulate the effector functions of bovine macrophages during S. aureus infection. This process could be associated with the regulation of histone H3 modifications, such as H3K9ac, in IIR-related genes. Full article

Food allergies are increasing worldwide, yet the early epithelial mechanisms that initiate allergic sensitization remain incompletely defined. As the intestinal epithelium governs both allergen translocation and epithelial–immune crosstalk, it constitutes a critical but underutilized model for predicting allergenicity. In this study, we used Caco-2 and T84 intestinal epithelial monolayers cultured on Transwell^® inserts to compare barrier properties and responses to peanut protein extract. Phenotypic characterization included biomarker profiling, transepithelial electrical resistance (TEER) measurements, tight junction integrity assessment, and analysis of cytokine levels as well as oxidative and nitrosative stress. Peanut exposure caused moderate TEER reductions without overt tight junction disruption while allowing translocation of the major allergen, Arachis hypogaea allergen 1 (Ara h 1), likely via transcellular pathways. Peanut protein extracts also induced epithelial stress responses, characterized by increased reactive oxygen species and nitric oxide production, alongside time-dependent secretion of innate and type 2-associated mediators, including IL-1β, TSLP, IL-25, and IL-33, indicating epithelial activation in the absence of complete barrier breakdown. Notably, basolateral supernatants from peanut-exposed epithelial monolayers activated THP-1-derived macrophages and enhanced IL-6 secretion, demonstrating that limited allergen passage across an otherwise intact epithelial barrier is sufficient to elicit early innate immune responses. Collectively, these findings indicate that peanut extract induce subtle functional perturbations in the intestinal epithelium while promoting downstream immune activation, highlighting Caco-2 and T84 cells as complementary in vitro platforms for studying barrier-dependent mechanisms of allergic sensitization. Full article

Classical swine fever virus (CSFV) remains a significant threat to the global swine industry, causing a highly contagious and often fatal disease in pigs. This review comprehensively examines the molecular biology of CSFV and the intricate mechanisms it employs to establish infection. We detail the structure and functions of viral proteins, highlighting their roles in virus entry, replication, and immune evasion. A major focus is placed on the virus–host interaction, specifically how CSFV subverts host innate immune responses and hijacks critical cellular processes, including metabolism and cell death pathways. The virus strategically manipulates host cell death programs (apoptosis, mitophagy, necroptosis) and exploits intracellular transport systems to promote its propagation. Furthermore, we summarize recent advances in understanding the cellular receptors involved in CSFV entry and the role of exosomes in viral spread. This synthesis of current knowledge aims to provide a deeper insight into the pathogenesis of CSFV and identify potential vulnerabilities that could be targeted for the development of novel antiviral strategies. Full article

The unprecedented success of mRNA vaccines during the COVID-19 pandemic marks a fundamental paradigm shift in vaccinology, moving the field from empirical pathogen modification toward the rational engineering of host immunity. This review synthesizes recent breakthroughs to construct a conceptual framework for understanding how modern vaccines function as programmable immune instructions. We first analyze the innate immune system as an instructional center, where recognition of vaccine components dictates the quality of ensuing adaptive responses. We then examine the germinal center (GC) as a micro-evolutionary engine for antibody maturation, the output of which can be tuned by vaccine design. The discussion centers on three integrated pillars of next-generation vaccines: computationally designed immunogens, spatiotemporally controlled adjuvant systems, and intelligent delivery platforms, emphasizing that their synergy is essential for achieving broad, durable protection against complex pathogens. Finally, we explore how the convergence of systems vaccinology, artificial intelligence, and personalized medicine is guiding the field toward a more predictable and rapid-response future, while also outlining key advances and persistent challenges. Full article

Necroptosis is a regulated form of programmed cell death that helps the body defend itself against infections and cellular stress, especially when apoptosis is blocked. At the center of this process is mixed lineage kinase domain-like (MLKL) protein, the final effector of necroptosis, which is activated downstream of receptor-interacting protein kinase 3 (RIPK3). Once phosphorylated, MLKL changes shape, assembles into oligomers, moves to cellular membranes, and disrupts membrane integrity, ultimately causing cell death. While this RIPK3-MLKL pathway has been well described, it is becoming increasingly clear that MLKL regulation is more complex than originally thought. Recent findings show that MLKL can be modified and activated through alternative mechanisms, even in the absence of RIPK3, and that post-translational modifications such as ubiquitination further fine-tune its activity. Notably, deleting RIPK3 or MLKL does not consistently resolve inflammatory phenotypes in experimental models, suggesting that MLKL has context-dependent functions that extend beyond its role in necroptosis. In line with this idea, MLKL has been implicated in inflammatory signaling, interferon responses, and innate immunity, and is frequently targeted by viruses seeking to evade host defenses. Beyond infections, aberrant MLKL activation contributes to a wide range of chronic diseases, including atherosclerosis, cardiometabolic disorders, liver disease, neurodegeneration, and cancer. In these settings, sustained MLKL-mediated membrane damage and release of danger signals drive ongoing inflammation and tissue injury rather than protective cell elimination. In this review, we provide an overview of MLKL structure, activation, and regulation in both necroptotic and non-necroptotic contexts. We also discuss emerging therapeutic strategies aimed at targeting MLKL activation, membrane engagement, and stability, and highlight key unanswered questions that must be addressed to translate MLKL biology into effective clinical interventions. Full article

Helminths infect a quarter of the human population and are controlled in the frame of a canonical type-2 immune response. Interleukin-9 is a cytokine with pleiotropic functions during type-2 immunity that can be produced by many different cells. Accumulating evidence suggest that IL-9 is of particular relevance in controlling intestinal helminth infections. Using mice infected with the parasitic nematode Strongyloides ratti, we showed previously that ejection from the intestine depends on IL-9 and IL-9-mediated activation of mucosal mast cells. Here we use IL-9 reporter mice to identify the relevant cellular sources of IL-9 in vivo. We report that predominantly CD4⁺ T cells and group 2 innate lymphoid cells (ILC2s) produced IL-9 in S. ratti-infected or IL-33-treated mice. Interestingly, the IL-33-mediated induction of IL-9 and subsequent mast cell degranulation was modulated by concurrent S. ratti infection. While the IL-33-mediated expansion of IL-9-producing ILC2s was supressed by S. ratti infection, IL-9-producing CD4⁺ T cells were proportionally increased. Finally, we show that S. ratti-derived E/S products interfered with IL-9 production by BM-derived ILC2 in vitro. In conclusion, we have identified that ILC2 and CD4⁺ T cells produce IL-9 during S. ratti infection, and that ILC2 responses are suppressed by S. ratti products. Full article

Intestinal bacteria play crucial roles in maintaining host health and regulating disease. While much of the current research has focused on how changes in the gut microbiota affect various physiological functions of the host, little is known about how the host’s genetic factors shape gut microbiota diversity or how gut-dominant bacteria influence host innate immunity and lifespan. In this study, we demonstrated that a mutation in the Caenorhabditis elegans ERK-encoding gene, mpk-1, promotes the enrichment of Raoultella planticola in the gut of worms, and the bacterium confers resistance to infection by the pathogenic bacterium Pseudomonas aeruginosa PA14 (PA14) in worms. Mechanistically, a compromised immune response, which is dependent on the let-60–mpk-1 pathway, promotes the colonization of R. planticola in mpk-1 mutants. Importantly, R. planticola induces autophagy, thereby enhancing nematode resistance to PA14 infection and extending its lifespan. Our findings shed light on how immune-compromised mpk-1 mutants increase colonization permissiveness and utilize R. planticola to bolster their antibacterial immunity against pathogenic P. aeruginosa, offering new insights into the regulatory mechanisms of host–microbiota interactions. These results emphasize the complex interplay between host genetics, the microbiota, and immune responses, providing potential therapeutic strategies to modulate the microbiota for improved health outcomes. Full article

Background and Objectives: Traumatic hemorrhage is a leading cause of death. Our aim was to examine the effect of adenosine, lidocaine and magnesium (ALM) resuscitation therapy with and without fresh frozen plasma (FFP) or fresh whole blood (FWB) in a rat model of non-compressible hemorrhage. Materials and Methods: Anesthetized adult male Sprague-Dawley rats (439 ± 46 g) randomly assigned to (1) Shams (surgical trauma and liver isolation only without hemorrhage) (n = 34), (2) Saline controls (n = 34), or (3) ALM therapy (n = 34), underwent liver resection and uncontrolled bleeding. After 5 h 3% NaCl ± ALM bolus and 0.9% NaCl ± ALM drip fluid resuscitation, each group was randomized to receive no transfusion (NT) (n = 10 per treatment group), FFP (n = 12), or FWB (n = 12), and monitored for 72 h. Survival, hemodynamics, lactate, hematology, coagulation, platelet function, and lung histopathology were measured. Results: Sham, Saline and ALM NT survival were 50%, 0% and 100%. Sham survival increased to 75% with FFP, but not FWB (50%), and only marginally in the Saline group (8% and 17%, respectively). ALM protection was lost after 1–2 days with FFP and FWB (8% and 0% survival). Mortality was associated with acute lung injury, inflammation, activation of innate immunity, intrinsic hypocoagulopathy, and metabolic acidosis. Survival was associated with maintained platelet count and aggregation. Acute phase protein fibrinogen increased ~2.5 times in both survivors and non-survivors. Conclusions: ALM therapy without FFP or FWB transfusion significantly improved survival, reduced lung injury, preserved platelet function, and decreased immune and metabolic dysfunction. Blood products administered 5 h after injury did not significantly improve survival after non-compressible hemorrhage. Surgical trauma (laparotomy and liver isolation) also contributed to poor outcomes. The trauma and transfusion-related multi-system failure requires further investigation. Full article

Aging is accompanied by profound alterations in immune function that collectively drive increased susceptibility to infection, reduced vaccine efficacy, impaired tissue repair, and heightened risk of age-related diseases (ARDs). These alterations are characterized by the coexistence of immunosenescence and inflammaging. Rather than reflecting isolated cellular defects, immune aging emerges as a systems-level reprogramming of immune networks that disrupts the initiation, resolution, and regenerative phases of inflammatory responses. In particular, aging is associated with impaired resolution of inflammation, defective efferocytosis, reduced responsiveness to pro-resolving signals, and diminished regenerative capacity, leading to persistent inflammatory milieus and tissue damage. This review summarizes recent advances in the mechanisms underlying immune dysfunction in aging, with a focus on how chronic inflammation, failed resolution, and defective repair reinforce one another. We discuss how alterations in innate and adaptive immunity, immunometabolism, cellular senescence, and immune–tissue interactions drive inflammaging and contribute to major ARDs, including cancer, neurodegenerative, and cardiometabolic diseases. Finally, we highlight emerging therapeutic strategies aimed at restoring immune balance and resolution. By adopting a systems-level and network-based perspective, this review underscores immune aging as a modifiable driver of ARDs and identifies key knowledge gaps and future directions toward interventions that promote healthy aging and extended healthspan. Full article

Diabetes mellitus is one of the most common health problems worldwide; however, increased blood glucose alone cannot adequately explain its pathophysiology. Although high blood glucose is a defining feature, evidence increasingly proves that diabetes arises from systemic disturbances involving the gut microbiome, immune system, and metabolic control. From this perspective, diabetes can be viewed as a systemic condition shaped by the dynamic interactions between the gut microbiome, the immune system, and metabolic pathways. Alterations in gut microbiome composition and function can influence nutrient metabolism, microbial metabolite production, bile acid signaling, and intestinal barrier integrity. Any damage of the gut barrier allows movement of microbiome-derived molecules that activate innate immune pathways and provoke chronic low-grade inflammation. This inflammatory state interferes with insulin signaling, contributes to immune maladaptation, and exacerbates metabolic dysfunction. Over time, these processes contribute to the advance of multisystem complications, including cardiovascular disease, diabetic nephropathy, neuropathy with cognitive impairment, delayed wound healing, and increased susceptibility to infection. The review also integrates environmental and public health factors, demonstrating how diet, antibiotic exposure, circadian disruption, and social conditions shape the microbiome, immune function, metabolic regulation, and disease risk across the life course. By bringing together clinical, experimental, and population-based evidence, this review illustrates the limitations of care models that concentrate only on glucose. It also points out how integrated approaches targeting the microbiome, immune system, and metabolic pathways can improve diabetes prevention, management, and guide future research. Full article

For decades, immunology has followed a clear paradigm: immunological memory resides only within the adaptive immunity, as a unique property of lymphocytes giving the host the ability to recognize specific antigens and offer long-term protection. However, this raises an important question: how valid is this belief in light of new evidence? The discovery of trained immunity shows that innate immune cells can also develop lasting functional changes. This finding prompts a profound reconsideration of the traditional framework. Trained immunity is a functional reprogramming of the innate immune cells driven by long-term epigenetic and metabolic reprogramming, resulting in enhanced responses upon subsequent exposure to the same pathogen or even to unrelated stimuli. The presence of pattern recognition receptors (PRRs) on innate immune cells already suggested a certain level of specificity in this compartment thanks to the engagement of a PRR by a pathogen-associated molecular pattern (PAMP) inducing memory-like properties in the responding cell. While such partial specificity can enhance protection, it may also amplify aberrant inflammatory circuits, thereby contributing to the initiation or worsening of autoimmune and chronic inflammatory diseases. This dual nature of trained immunity raises important questions for the field: is trained immunity ultimately harmful or beneficial in autoimmunity, and can its mechanisms be harnessed therapeutically rather than pathologically? The present Perspective will address these issues by examining recent findings that reveal the specificity, pathogenic potential, and translational opportunities in given examples of autoimmune diseases (ADs). Full article

Cooperation between neutrophils and macrophages is essential to innate immunity. Though they share origins, their distinct roles make them complementary in fighting pathogens and regulating inflammation. However, dysregulation can drive chronic inflammation and autoimmune disease, making therapeutic targeting highly challenging. Broad suppression of these cells is risky; instead, precision strategies are needed to modulate their dual roles in promoting and resolving inflammation. Aging further complicates this balance, as impaired neutrophil and macrophage functions—alongside microbiota alterations—contribute to inflammaging and immune dysfunction. Recent advances in technology offer opportunities to explore these interactions in physiologically relevant contexts, paving the way for targeted interventions that restore immune homeostasis without compromising defense mechanisms. This article highlights the need for nuanced approaches to harness neutrophil–macrophage cooperation for therapeutic benefit. Full article

Metapneumoviruses comprise a genus of negative-sense RNA viruses that cause significant respiratory disease across human and avian hosts. Human metapneumovirus (hMPV) is a globally prevalent pathogen associated with acute lower respiratory tract infections in infants, older adults, and immunocompromised individuals. Avian metapneumovirus (aMPV) imposes substantial economic losses on the poultry industry through respiratory disease, reproductive impairment, and high mortality in the presence of secondary infections. Despite their distinctive host ranges, hMPV and aMPV share a conserved genomic architecture and encode homologous structural and non-structural proteins that mediate viral entry, replication, assembly, and evasion of host innate immunity. Comparative analysis highlights that both have deeply conserved polymerase and nucleocapsid functions, and yet have a wide range of diversity in the attachment glycoprotein (G) and small hydrophobic protein (SH), reflecting divergent evolutionary pressures in human versus avian hosts that have led to such distinctive differences. The recent emergence and detection of aMPV/A and aMPV/B across the previously aMPV-free United States beginning in late 2023, combined with rising cases globally of hMPV post-SARS-CoV-2 pandemic, underscore the continued challenges of metapneumovirus surveillance and control in humans and animals. This review aims to highlight the current knowledge on the history, molecular virology, pathogenesis, epidemiology, diagnostics, and control strategies for aMPV while drawing mechanistic parallels to hMPV. By contextualizing shared biology and structure alongside host-specific adaptations, we aim to identify key gaps that shape vaccine design, antiviral development, and future research priorities aimed at mitigating the health and economic burden posed by metapneumoviruses found in both birds and humans. Full article