Search Results (323)

Chronic pain conditions are debilitating and have an enormous impact on quality of life, yet underlying biological mechanisms remain poorly understood, hindering the development of diagnostic tools and effective treatments. Emerging evidence suggests a role for immune dysfunction in chronic pain. Among the various forms of immune dysfunction, T cell exhaustion and senescence, well-characterized in cancer and chronic infections, remain largely unexplored in chronic pain research. At the same time, lifestyle factors such as sleep, stress, physical activity, and diet are increasingly recognized as modulators of both pain and immune function. This review explores the potential interplay between these behavioural factors, immune exhaustion/senescence, and chronic pain. Critical gaps in current knowledge are identified, and future directions are outlined to clarify immune dysfunction and the influence of lifestyle factors in chronic pain conditions. Full article

Porcelain-fused-to-metal (PFM) crowns continue to serve as a cornerstone of restorative dentistry owing to their strength, affordability, and esthetics. However, late-onset complications such as oral burning and lichenoid reactions have been observed in long-serving PFMs, suggesting complex host–material interactions that extend beyond simple mechanical wear. This Perspective introduces the Nallan–Nickel Effect, a theoretical model proposing that a host- and environment-dependent threshold of bioavailable nickel ions (Ni²⁺), once exceeded, may trigger a neuro-immune cascade culminating in a burning phenotype. Within this framework, slow corrosion at exposed PFM interfaces releases Ni²⁺ into saliva and crevicular fluid, facilitating epithelial uptake and activation of innate immune sensors such as TLR4 and NLRP3. The resulting cytokine milieu (IL-1β, IL-6, TNF-α) drives NF-κB, mediated inflammation and T-cell activation, while neurogenic mediators—including nerve growth factor (NGF), substance P, and CGRP—sensitize TRPV1/TRPA1 nociceptors, establishing feedback loops of persistent burning and neurogenic inflammation. Modifying factors such as low salivary flow, acidic oral pH, mixed-metal galvanic coupling, and parafunctional stress can lower this threshold, whereas replacement with high-noble or all-ceramic materials may restore tolerance. The model generates testable predictions: elevated local free Ni²⁺ levels and increased expression of TLR4 and TRPV1 in symptomatic mucosa, along with clinical improvement following substitution of nickel-containing restorations. Conceptually, the Nallan–Nickel Effect reframes PFM-associated burning and lichenoid lesions as threshold-governed, neuro-immune phenomena rather than nonspecific irritations. By integrating corrosion chemistry, mucosal immunology, and sensory neurobiology, this hypothesis offers a coherent, testable framework for future translational research and patient-centered management of PFM-related complications. Full article

Mycotoxins are toxic secondary metabolites produced by filamentous fungi that contaminate agricultural commodities, posing risks to food safety, animal productivity, and human health. The gastrointestinal tract is the first and most critical site of exposure, where the intestinal epithelium functions as both a physical and immunological barrier against luminal toxins and pathogens. While extensive research has demonstrated that mycotoxins disrupt epithelial integrity through tight junction impairment, oxidative stress, apoptosis, and inflammation, their effects on the intestinal stem cell (ISC) compartment and epithelial regeneration remain insufficiently understood. This review integrates recent findings from in vivo, cell culture, and advanced 3D intestinal organoid and gut-on-chip models to elucidate how mycotoxins such as deoxynivalenol and zearalenone impair ISC proliferation, alter Wnt/Notch signaling, and compromise mucosal repair. We also discuss dose relevance, species differences, and the modulatory roles of the microbiome and short-chain fatty acids, as well as emerging evidence of additive or synergistic toxicity under co-exposure conditions. By bridging well-established mechanisms of barrier disruption with the emerging concept of ISC-driven regenerative failure, this review identifies a critical knowledge gap in mycotoxin toxicology and highlights the need for integrative models that link epithelial damage to impaired regeneration. Collectively, these insights advance understanding of mycotoxin-induced intestinal dysfunction and provide a foundation for developing nutritional, microbial, and pharmacological strategies to preserve gut integrity and repair. Full article

Background: Lichen planus (LP) is a common inflammatory disease affecting skin, mucous membranes, hairs, and nails, with an unpredictable course involving remissions and relapses. LP is a Type-I-Inflammation disease involving IFN-γ and IL-17 as key inflammatory mediators. Materials and Methods: We searched PubMed/MEDLINE and Google Scholar search engines for studies on the esophageal manifestation of lichen planus over an unlimited time frame. Articles were searched with combinations of Medical Subject Heading (MeSH) terms. Given the limited number of publications, no exclusion criteria were applied. Results: Esophageal lichen planus (ELP) is an underreported manifestation of LP that primarily affects middle-aged women. Its prevalence among LP patients remains to be defined. Though potentially clinically silent, ELP can significantly impact patient wellbeing and serve as a precursor to esophageal squamous cell carcinoma. While dysphagia is the primary symptom, the condition may also remain subclinical. The endoscopic hallmarks of ELP are mucosal denudation and tearing, trachealization, and hyperkeratosis. Chronic disease progression may lead to scarring esophageal stenosis. Histologically, ELP shows mucosal detachment, T-lymphocytic infiltrations, epithelial cell apoptosis (Civatte bodies), dyskeratosis, and hyperkeratosis. Fibrinogen deposits along the basement membrane zone distinguish ELP from various immunological esophageal diseases. There is currently no standardized therapy available. Topical steroids lead to symptomatic and histologic improvements in two-thirds of patients. Severe or refractory cases require immunosuppressive therapy, whereas JAK-inhibitors represent a promising emerging option. Endoscopic dilation helps symptomatic stenosis. Considering ELP’s precancerous potential, timely diagnosis and treatment are crucial in preventing complications, such as stenosis or invasive esophageal squamous cell carcinoma. Conclusions: ELP is an underdiagnosed and underreported manifestation of LP. While it may remain clinically silent, it can nevertheless significantly affect patients’ wellbeing and life expectancy. This narrative review aims to initiate multidisciplinary cooperation among gastroenterologists, dermatologists, oral health professionals, and histopathologists to support clinical diagnosis and management. Full article

Polyethylene terephthalate glycol-modified (PETG) is a transparent, stable copolymer commonly used in biomedical devices such as surgical guides, clear aligners, and anatomical models. Its biocompatibility must be assessed not only for cytotoxicity, but also for subtle molecular and immunological responses, especially when in contact with mucosal or hormone-sensitive tissues. This study evaluated the biological safety of PETG processed via CNC milling and CO₂ laser cutting, two methods that preserve bulk chemistry but may alter surface properties. PETG diskettes were analyzed by FT-IR, ¹H-NMR, and GC–MS to confirm chemical integrity and absence of degradation products. Biocompatibility was tested using MCF-7 epithelial cells and THP-1 monocytes. Cell viability remained above 90% over seven days. Inflammatory (COX-2, TNFα, IL-8, IL-1α, IL-4, IL-10, IFNγ) and hormone-related (ERα, ERβ) gene expression was analyzed by qRT-PCR. Gene profiling revealed only modest, non-significant changes: COX-2 was upregulated 1.8-fold after laser processing, and ERα increased 1.6-fold following milling—both below thresholds considered biologically active. These findings indicate that mechanical surface treatments induce minimal bioactivity, with no meaningful immune or hormonal stimulation. PETG remains functionally inert under the tested conditions, supporting its continued safe use in intraoral and hormone-sensitive biomedical applications. Full article

Chlamydia invades multiple mucosal tissues in humans and animals. The body’s first line of defense against chlamydial infection is provided by innate immunity, whereas adaptive immunity plays a crucial role in managing the infection’s progression and preparing the immune system to combat reinfection. Host resistance to chlamydial infection necessitates a coordinated effort between innate and adaptive immune cells. Numerous cell types are capable of producing interferon gamma (IFN-γ) as a defense mechanism against chlamydial infection, thereby effectively mediating the clearance of infection. However, the distinct roles of various immune cell populations in responding to chlamydial infection, as well as their functions during infection progression, remain poorly understood. Therefore, we will discuss the various roles of IFN-γ released by different immune cells in chlamydial infection, focusing primarily on experimental animal models and a review of available data from in vivo cellular immunological studies in humans. Full article

Antibodies are a cornerstone of the adaptive immune response, serving as key defenders against viral infections; however, they can also act as a double-edged sword, contributing to immune-mediated pathologies. This review advances a “Yin-Yang” framework to integrate the dual activities of antibodies. The protective ‘Yin’ functions are driven by high-affinity antibodies generated through processes like somatic hypermutation and class-switch recombination. These antibodies execute viral neutralization, activate the complement system, and engage Fc receptors (FcRs) to drive antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. These mechanisms form the immunological basis of effective vaccines, which aim to elicit durable and functionally specialized antibody isotypes like IgG and mucosal IgA. Conversely, the pathogenic ‘Yang’ of the response can be detrimental. This includes antibody-dependent enhancement (ADE) of infection, notably observed with flaviviruses, and the development of autoimmunity through mechanisms like molecular mimicry and bystander activation, which can lead to conditions such as multiple sclerosis and Guillain-Barré Syndrome. The balance between protection and pathology is tipped by a confluence of factors. These include viral evasion strategies like antigenic mutation and glycan shielding, as well as host-based determinants such as genetic polymorphisms in FcRs, immune history, and the gut microbiome. Understanding these molecular determinants informs the rational design of next-generation interventions. Promising strategies, such as Fc-region glyco-engineering and the design of tolerogenic vaccines, aim to selectively promote protective functions while minimizing pathological risks, offering a clear path forward in combating viral threats. Full article

Background/Objectives: Innovative intranasal delivery systems have emerged as a strategy to overcome the limitations of conventional COVID-19 vaccines, including suboptimal mucosal immunity, limited antigen retention, and vaccine hesitancy. This study aimed to evaluate physicochemical properties and murine safety of a novel COVID-19 intranasal vaccine candidate based on CHIVAX 2.1 (CVX)-loaded chitosan nanoparticles (CNPs). Methods: The CVX recombinant protein was encapsulated into CNPs using the ionic gelation method. The nanoparticles were characterized by their physicochemical properties (mean size, zeta potential, morphology, and encapsulation efficiency) and spectroscopic profiles. Mucin adsorption and in vitro release profiles in simulated nasal fluid were also assessed. In vivo compatibility was evaluated through histopathological analysis of tissues in male C-57BL/6J mice following intranasal administration. Results: CNPs exhibited controlled size distribution (38.5–542.5 nm) and high encapsulation efficiency (65.4–92.2%). Zeta potential values supported colloidal stability. TEM analysis confirmed spherical morphology and successful CVX encapsulation, and immunogenic integrity was also demonstrated. Mucin adsorption analysis demonstrated effective nasal retention, particularly in particles ≈90 nm. In vitro release studies revealed a biphasic protein profile, where ≈80% of the recombinant protein was released within 2 h. Importantly, histopathological analyses and weight monitoring of intranasally immunized mice revealed no signs of adverse effects related to toxicity. Conclusions: The ionic gelation encapsulation process preserved the physical and immunological integrity of CVX antigen. Furthermore, the intranasal administration of the CVX-loaded CNPs demonstrated a favorable safety profile in vivo. These findings support the potential of the CVX intranasal vaccine formulation for further immunogenicity studies, with no apparent biosafety concerns. Full article

Globally, Parkinson’s disease (PD) is the neurodegenerative condition with the most rapidly increasing prevalence, and a growing body of evidence associates its pathology with impairments in the gut–brain axis. Traditionally viewed as a disease marked by the loss of dopaminergic neurons, emerging evidence emphasizes that chronic neuroinflammation is a driver of neurodegeneration, with gut-originating inflammation playing a crucial role. Increased intestinal permeability, often called “leaky gut,” allows harmful substances, toxins, and misfolded α-synuclein into the systemic circulation, potentially exacerbating neuroinflammation and spreading α-synuclein pathology to the brain through the vagus nerve or compromised blood–brain barrier (BBB). This review synthesizes current insights into the relationship between gut health and PD, emphasizing the importance of gut permeability in disrupting intestinal barrier function. This paper highlights innovative therapeutic approaches, particularly personalized therapies involving gut microbiome engineering, as promising strategies for restoring gut integrity and improving neurological outcomes. Modulating specific gut bacteria to enhance the synthesis of certain metabolites, notably short-chain fatty acids (SCFAs), represents a promising strategy for reducing inflammatory responses and decelerating neurodegeneration in Parkinson’s disease. Full article

Despite growing recognition of the role of the gut microbiome in host health and in modulating pathogen activity, the dynamic and reciprocal relationship between enteric viruses and the gut microbial ecosystem remains insufficiently defined and requires further exploration. This comprehensive review examines the bidirectional interplay between the gut microbiome and enteric viral infections by addressing (i) viruses associated with gastrointestinal alterations, (ii) how enteric viral infections alter the composition and function of the gut microbiome, (iii) how the gut microbiome modulates viral infectivity and host susceptibility, and (iv) current microbial-based approaches for preventing or treating enteric viral infections. Gastrointestinal viral infections induce gut microbiome dysbiosis, marked by reductions in beneficial bacteria and increases in potentially pathogenic populations. Specific gut microorganisms can modulate host susceptibility, with certain bacterial genera increasing or decreasing infection risk and disease severity. Pattern recognition receptors in the intestinal epithelium detect microbial signals and trigger antimicrobial peptides, mucus, and interferon responses to control viral replication while maintaining tolerance to commensal bacteria. The gut microbiome can indirectly facilitate viral infections by creating a tolerogenic environment, suppressing antiviral antibody responses, and modulating interferon signaling, or directly enhance viral replication by stabilizing virions, promoting host cell attachment, and facilitating coinfection and viral recombination. In turn, commensal gut bacteria can inhibit viral entry, enhance host antiviral responses, and strengthen mucosal barrier function, contributing to protection against gastrointestinal viral infections. Probiotics and fecal microbiota transplantation constitute potential microbial-based therapeutics that support antiviral defenses, preserve epithelial integrity, and restore microbial balance. In conclusion, the role of the gut microbiome in modulating enteric viral infections represents a promising area of future investigation. Therefore, integrating microbiome insights with virology and immunology could enable predictive and personalized strategies for prevention and treatment. Full article

Vaccines remain one of the most powerful tools in modern medicine, having revolutionized public health by preventing millions of deaths and controlling the spread of infectious diseases worldwide. However, conventional needle-based vaccines face several limitations, including pain and discomfort, the need for cold-chain infrastructure, reliance on trained healthcare personnel, risk of cross-contamination, and limited accessibility in low-resource settings. These challenges have spurred the development of non-invasive vaccination approaches that promise safer, more accessible, and patient-friendly immunization. Non-invasive immunizations not only eliminate the need for needles but may also enhance compliance and enable mucosal immune responses. To harness the full potential of these innovative delivery routes, a comprehensive understanding of their formulation strategies and mechanism of action is essential. This review aims to comprehensively discuss recent advancements in oral, intranasal, microneedle, buccal, sublingual, and vaginal vaccinations and highlight their underlying immunological mechanisms, formulation strategies in preclinical studies, examples of marketed products, and ongoing clinical trials. Full article

Background: Inflammatory bowel disease (IBDs) are chronic, immune-mediated disorders of the gastrointestinal tract, encompassing ulcerative colitis (UC) and Crohn’s disease (CD), and primarily affecting individuals with genetic susceptibility. IBDs are characterized by dysregulated mucosal immune responses to intestinal microbiota, leading to sustained inflammation and tissue damage. These conditions not only pose a significant burden on healthcare systems but are also frequently associated with distinct comorbidities. Rationale: Given the immunological nature of both IBDs and type 2 diabetes (T2D)—each involving a complex interplay between genetic predisposition and environmental triggers—an increasing number of studies have suggested a pathophysiological link between the two. Both diseases involve chronic low-grade inflammation and alterations in immune signaling pathways, such as cytokine dysregulation, T-cell imbalance, and aberrant innate immune activation. Methods: To investigate this association more robustly, we conducted a cohort study involving 49 consecutive patients diagnosed with both IBD and T2D. Results: Our findings revealed a strong correlation between the two conditions, with UC emerging as the predominant IBD subtype linked to T2D. Notably, the highest prevalence was observed in patients aged 65–74 years, suggesting age-related immune modulation may play a role. In a matched case-control analysis (48 cases vs. 96 controls), 70.8% of the IBD–T2D cases were diagnosed with UC, 25.0% with CD, and 4.2% with indeterminate colitis. Similarly, in the cohort study, UC accounted for 73.81% of cases, CD for 21.43%, and non-determined colitis for 4.76%. Conclusions: These data support the hypothesis that UC, more so than CD, exhibits a stronger immunological and clinical association with T2D. Interestingly, CD was absent in the 55–64 age group, potentially indicating age-specific immunological trajectories or differential environmental exposures. The observed patterns reinforce the concept that immune dysregulation is a shared underpinning of both IBD and T2D, and that UC may serve as an immunological bridge linking gastrointestinal and metabolic inflammation. Full article

Background: The COVID-19 pandemic provided a unique opportunity to evaluate how the human immune system responded to a novel pathogen and to determine whether immune responses initiated through natural infection differ from those elicited by vaccination against the same antigen. Here, we provide a comprehensive analysis of SARS-CoV-2 Spike (S-antigen)-reactive memory B cells (B_mem) elicited in previously immunologically naïve subjects following their first infection with the original Wuhan-Hu-1 (WH1)-like strain or their initial COVID-19 mRNA prime-boost regimen encoding the same WH1-S-antigen. In particular, we tested the hypothesis that the primary encounter of SARS-CoV-2 S-antigen in lung mucosal tissues during infection vs. intramuscular COVID-19 mRNA injection would elicit different B_mem responses. Methods: Cryopreserved peripheral blood mononuclear cell (PBMC) samples collected following primary infection with the WH1 strain or completion of the initial prime-boost vaccination regimen were tested in ImmunoSpot^® assays to assess the frequency, Ig class/subclass usage, and cross-reactivity of the S-antigen-reactive B_mem compartment; pre-pandemic blood draws served as naïve controls. Results: The B_mem repertoires generated post-infection vs. post-vaccination were found to be quite similar but with some subtle differences. In both cases, the prevalent induction of IgG1-expressing B_mem in similar frequencies was seen, ~30% of which targeted the receptor binding domain (RBD) of the WH1-S-antigen. Also, the extent of cross-reactivity with the future Omicron (BA.1) RBD was found to be similar for both cohorts. However, IgA⁺ B_mem were preferentially induced after infection, while IgG4⁺ B_mem were detected only after vaccination. Conclusions: B_mem elicited in naïve human subjects following SARS-CoV-2 infection or after WH1-S encoding mRNA vaccination were only subtly different, although the relevance of these differences as it relates to immune protection warrants further investigation. Our findings serve to illustrate the usefulness and feasibility of performing comprehensive monitoring of antigen-specific B cell memory in larger cohorts using the ImmunoSpot^® technique. Full article

Burning mouth syndrome (BMS) and oral lichen planus (OLP) are two chronic oral diseases/disorders that continue to pose a challenge for conventional diagnosis and treatment. Both diseases do not occur in isolation but rather appear to reflect a broader interplay of psychological, neurological, endocrine, and immunological factors, i.e., complex disorders in interconnected biological and psychological systems. In BMS, patients often suffer from persistent burning sensations without visible lesions, which may be related to altered pain processing, emotional stress, and dysregulation in the brain regions responsible for interoception and perception. Although OLP is primarily characterised by immune-mediated mucosal damage, it often has significant psychological comorbidity, particularly in the erosive form. Common features such as cortisol imbalance, disturbed cytokine patterns, and high levels of anxiety and depression suggest that these conditions may be due to overlapping systemic disorders. It is no longer sufficient to focus only on the visible lesions or symptom relief. Understanding these diseases/disorders through a more comprehensive psychoneuroendocrine immune system (PNEI) opens up new opportunities for early intervention, improved diagnostics, and more personalised therapeutic strategies that go beyond treating symptoms. Ultimately, these diseases/disorders require a more integrated and patient-centred approach, where understanding the whole system is as important as treating its individual parts. Full article

Background/Objectives: Food protein-induced enterocolitis syndrome (FPIES) is a food-related hypersensitivity disorder characterized by delayed repeated vomiting that typically presents within the first years of life. Although FPIES has traditionally been considered a pediatric condition, it has more recently been observed also in teenagers and adults. Adult FPIES may be a continuation of childhood-onset disease or new-onset forms developing later in life. This review aims to describe the peculiarities of FPIES across the lifespan and to provide an update from the last years on the studies focused on FPIES in adolescence. Methods: Papers focusing on FPIES in adolescents, in English and published in PubMed, were reviewed. Results: There is less data available in the literature on FPIES in adolescents. Multiple sensitizations to food can compromise nutritional status in patients with FPIES. Several potential diagnostic biomarkers related to genomic susceptibility, altered immunologic response, mucosal inflammation and intestinal microbiota are under study/validation. The lack of age-specific diagnostic algorithms makes it difficult to understand the clinical features of persistent forms of FPIES. Conclusions: Shared transition medicine protocols tailored to adolescents could help us better understand the clinical, pathophysiological, diagnostic, and therapeutic characteristics of this delicate phase of life. Full article