Search Results (1,419)

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infections (ALRIs) in young children, especially bronchiolitis, with significant global health and economic impact. Increasing evidence links early-life RSV infection to long-term respiratory complications, notably recurrent wheezing and asthma. This narrative review examines these associations, emphasizing predictive factors and emerging biomarkers for risk stratification. Early RSV infection can trigger persistent airway inflammation and immune dysregulation, increasing the likelihood of chronic respiratory outcomes. Risk factors include severity of the initial infection, age at exposure, genetic susceptibility, prematurity, air pollution, and tobacco smoke. Biomarkers such as cytokines and chemokines are showing promise in identifying children at higher risk, potentially guiding early interventions. RSV-related bronchiolitis may also induce airway remodeling and promote Th2/Th17-skewed immune responses, mechanisms closely linked to asthma development. Advances in molecular profiling are shedding light on these pathways, suggesting novel targets for early therapeutic strategies. Furthermore, passive immunization and maternal vaccination offer promising approaches to reducing both acute and long-term RSV-related morbidity. A deeper understanding of RSV’s prolonged impact is essential to develop targeted prevention, enhance risk prediction, and improve long-term respiratory health in children. Future studies should aim to validate biomarkers and refine immunoprophylactic strategies. Full article

Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders. Full article

Considering the high plasticity of FoxP3⁺ regulatory T (Treg) cells and Interleukin (IL)-17-producing Th17 cells, we hypothesized that a Th17 inflammatory milieu may impair the functional properties of Treg cells in chronic inflammatory arthritides. Therefore, a cross-sectional explorative analysis was set up in patients with psoriatic arthritis (PsoA), rheumatoid arthritis, or spondyloarthritis to investigate the features of Th17 and Treg cells. T cell subpopulation counts, FOXP3 mRNA expression, CpG methylation of the FOXP3 gene, and the suppressive capacity of isolated Treg cells were determined. Ex vivo analysis of PsoA-derived peripheral blood lymphocytes showed a Th17-mediated inflammation. It was accompanied by demethylation of the FOXP3 promotor and Treg-specific demethylated region (TSDR) in Treg cells which, however, resulted neither in elevated FOXP3 mRNA expression nor in increased suppressive Treg cell capacity. To clarify this conundrum, in vitro stimulation of isolated Treg cells with Th17-inducing cytokines (IL-1β, IL-6, IL-23, TGFβ), recombinant IL-17, or the anti-IL-17A antibody secukinumab was performed, demonstrating that cell culture conditions polarizing towards Th17, but not IL-17 itself, impair the suppressive function of Treg cells, accompanied by diminished FOXP3 mRNA expression due to hypermethylation of the FOXP3 promotor and TSDR. This potential causal relationship between Th17 inflammation and impaired Treg cell function requires attention regarding the development of immunomodulatory therapies. Full article

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder characterized by immune dysregulation and skin barrier impairment. This study evaluated the anti-inflammatory and immunomodulatory effects of Camellia japonica extract in a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model using SKH-1 hairless mice. Topical application of Camellia japonica extract for four weeks significantly alleviated AD-like symptoms by reducing epidermal thickness, mast cell infiltration, and overall skin inflammation. Hematological analysis revealed a marked decrease in total white blood cell (WBC) and neutrophil counts. Furthermore, the Camellia japonica extract significantly decreased oxidative stress, as evidenced by reduced serum reactive oxygen species (ROS) and nitric oxide (NO) levels, while enhancing the activity of antioxidant enzymes such as catalase. Importantly, allergic response markers including serum immunoglobulin E (IgE), histamine, and thymic stromal lymphopoietin (TSLP), were also downregulated. At the molecular level, Camellia japonica extract suppressed the expression of key pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and T helper 2 (Th2)-type cytokines such as IL-4 and IL-5, while slightly upregulating the anti-inflammatory cytokine IL-10. Collectively, these findings suggest that Camellia japonica extract effectively modulates immune responses, suppresses allergic responses, attenuates oxidative stress, and promotes skin barrier recovery. Therefore, application of Camellia japonica extract holds the promising effect as a natural therapeutic agent for the prevention and treatment of AD-like skin conditions. Full article

Background: The study evaluates the immunomodulatory potential of secukinumab (SECU) and honokiol (HONK) in a murine model of allergic asthma complicated by acute lung injury (ALI), with an emphasis on modulating key inflammatory pathways. The rationale is driven by the necessity to attenuate Th17-mediated cytokine cascades, wherein IL-17 plays a critical role, as well as to explore the adjunctive anti-inflammatory effects of HONK on Th1 cytokine production, including IL-6, TNF-α, and Th2 cytokines. Methods: Mice were sensitized and challenged with ovalbumin (OVA) and lipopolysaccharide (LPS) was administrated to exacerbate pulmonary pathology, followed by administration of SECU, HONK (98% purity, C₁₈H₁₈O₂), or their combination. Quantitative analyses incorporated OVA-specific IgE measurements, differential cell counts in bronchoalveolar lavage fluid (BALF), and extensive cytokine profiling in both BALF and lung tissue homogenates, utilizing precise immunoassays and histopathological scoring systems. Results: Both SECU and HONK, when used alone or in combination, display significant immunomodulatory effects in a murine model of allergic asthma concomitant with ALI. The combined therapy synergistically reduced pro-inflammatory mediators, notably Th1 cytokines, such as TNF-α and IL-6, as measured in both BALF and lung tissue homogenates. Conclusions: The combined therapy showed a synergistic attenuation of pro-inflammatory mediators, a reduction in goblet cell hyperplasia, and an overall improvement in lung histoarchitecture. While the data robustly support the merit of a combinatorial approach targeting multiple inflammatory mediators, the study acknowledges limitations in cytokine diffusion and the murine model’s translational fidelity, thereby underscoring the need for further research to optimize clinical protocols for severe respiratory inflammatory disorders. Full article

The intranasal delivery of exogenous mitochondria is a potential therapy for Parkinson’s disease (PD). The regulatory mechanisms and effectiveness in genetic models remains uncertain, as well as the impact of modulating the mitochondrial permeability transition pore (mPTP) in grafts. Utilizing UQCRC1 (p.Tyr314Ser) knock-in mice, and a cellular model, this study validated the transplantation of mitochondria with or without cyclosporin A (CsA) preloading as a method to treat mitochondrial dysfunction and improve disease progression through intranasal delivery. Liver-derived mitochondria were labeled with bromodeoxyuridine (BrdU), incubated with CsA to inhibit mPTP opening, and were administered weekly via the nasal route to 6-month-old mice for six months. Both treatment groups showed significant locomotor improvements in open-field tests. PET imaging showed increased striatal tracer uptake, indicating enhanced dopamine synthesis capacity. The immunohistochemical analysis revealed increased neuron survival in the dentate gyrus, a higher number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and striatum (ST), and a thicker granule cell layer. In SN neurons, the function of mitochondrial complex III was reinstated. Additionally, the CsA-accumulated mitochondria reduced more proinflammatory cytokine levels, yet their therapeutic effectiveness was similar to that of unmodified mitochondria. External mitochondria were detected in multiple brain areas through BrdU tracking, showing a 3.6-fold increase in the ST compared to the SN. In the ST, about 47% of TH-positive neurons incorporated exogenous mitochondria compared to 8% in the SN. Notably, GFAP-labeled striatal astrocytes (ASTs) also displayed external mitochondria, while MBP-labeled striatal oligodendrocytes (OLs) did not. On the other hand, fewer ASTs and increased OLs were noted, along with lower S100β levels, indicating reduced reactive gliosis and a more supportive environment for OLs. Intranasally, mitochondrial transplantation showed neuroprotective effects in genetic PD, validating a noninvasive therapeutic approach. This supports mitochondrial recovery and is linked to anti-inflammatory responses and glial modulation. Full article

Background: Chitosan, a family of polysaccharides composed of glucosamine and N-acetyl glucosamine, is a promising adjuvant candidate for eliciting potent immune response. Methods: This study compared the adjuvant effects of chitosan to those of empty lipid nanoparticles (eLNPs) and aluminum hydroxide (alum) following administration of recombinant SARS-CoV-2 spike immunogen in adult mice. Mice received the adjuvanted recombinant protein vaccine in a prime-boost regimen with four weeks interval. Subsequent analyses included serological assessment of antibody responses, evaluation of T cell activity, immune cell recruitment and cytokine profiles at injection site. Results: Compared to alum, chitosan induced a more balanced Th1/Th2 response, akin to that observed with eLNPs, demonstrating its ability to modulate both the humoral and cellular immune pathways. Chitosan induced a different proinflammatory cytokine (e.g., IL-1⍺, IL-2, IL-6, and IL-7) and chemokine (e.g., Eotaxin, IP-10, MIP-1a) profile compared to eLNPs and alum at the injection site and in the draining lymph nodes. Moreover, chitosan potentiated the recruitment of innate immune cells, with neutrophils accounting for about 40% of the infiltrating cells in the muscle, representing a ~10-fold increase compared to alum and a comparable level to eLNPs. Conclusions: These findings collectively indicate that chitosan has the potential to serve as an effective adjuvant, offering comparable, and potentially superior, properties to those of currently approved adjuvants. Full article

Background: Mycosis fungoides (MF), the most prevalent cutaneous T cell lymphoma, features clonal CD4⁺ T cell proliferation within a Th2-dominant microenvironment. Interleukin-4 (IL-4) promotes disease progression while Brentuximab Vedotin (BV), an anti-CD30 antibody–drug conjugate, shows efficacy but faces resistance challenges. Methods: We conducted a narrative literature review (2010–2024) synthesizing evidence on IL-4 signaling and BV’s efficacy in MF to develop a theoretical framework for combination therapy. Results: IL-4 may modulate CD30 expression and compromise BV’s effectiveness through immunosuppressive microenvironment remodeling. Theoretical mechanisms suggest that IL-4 pathway inhibition could reprogram the microenvironment toward Th1 dominance and restore BV sensitivity. However, no direct experimental evidence validates this combination, and safety concerns including potential disease acceleration require careful evaluation. Conclusions: The proposed IL-4/BV combination represents a biologically compelling but unproven hypothesis requiring systematic preclinical validation and biomarker-driven clinical trials. This framework could guide future research toward transforming treatment approaches for CD30-positive MF by targeting both malignant cells and their immunologically permissive microenvironment. Full article

Human leukocyte extract (HLE), a non-immunogenic dialyzable leukocyte preparation (<10 kDa), may serve as a safe adjuvant in immunotherapy. We investigated the effects of albendazole (ABZ), HLE, and their combination in Mesocestoides vogae infected mice, focusing on lymphoid cells in the peritoneal cavity, the site of larval proliferation and parasite-induced immunosuppression. Peritoneal lymphoid cells were analysed by flow cytometry and qPCR. Cells proliferative responses to ConA, LPS, and parasite excretory/secretory (E/S) antigens, cytokine production (ELISA), IgM and IgG isotypes in exudates and parasite antigen recognition (Western blot) were assessed. Efficacy was measured by larval burden and 14-3-3 gene expression in larvae. HLE combined with ABZ enhanced larval clearance and suppressed 14-3-3 gene expression in larvae. HLE and combination therapy increased CD3⁺ T cell frequencies, especially CD3^+high, reduced regulatory CD3+/IL-10 Tregs and expression of Foxp3⁺. All treatments diminished CD19⁺/IL-10⁺ Bregs, correlating with lower CD9 and Atf3 mRNA levels compared to infected mice. Transcription factors T-bet expression was strongly upregulated, while GATA3 was moderately elevated. IFN-γ production and T/B cell proliferation were restored after HLE and combination therapy, partially, even in the presence of E/S antigens. IgM and total IgG levels against parasite antigens declined, while Th1-associated IgG2a increased in ABZ+HLE and HLE-treated groups. Albendazole failed to reverse the immunosuppressive Treg-type immunity but was more effective in reducing Breg populations and their functions. HLE enhanced ABZ efficacy by restoring Th1 responsiveness, reducing Treg/Breg activity, and modulating antibody profiles. It represents a promising immunomodulatory adjuvant in the treatment of the infections associated with Th2/Treg-driven immunosuppression. Full article

Background: Psoriasis, an inflammatory skin disorder, involves pyroptosis—a pro-inflammatory cell death process. However, cell-specific pyroptosis dynamics and immune microenvironment interactions remain unclear. Objective: To investigate cell-type-specific pyroptosis patterns in psoriasis and their immunoregulatory mechanisms. Methods: We integrated 21 transcriptomic datasets (from 2007 to 2020) obtained from the GEO database and two single-cell RNA sequencing datasets to quantify pyroptotic activity using Gene Set Variation Analysis and AUCell algorithms. Immune cell infiltration profiles were evaluated via CIBERSORT, while cell-cell communication networks were analyzed by CellChat. In vitro and in vivo experiments were performed to validate key findings. Results: Our analysis revealed that psoriasis patients exhibited significantly elevated levels of pyroptosis compared to healthy controls, with pyroptotic activity reflecting treatment responses. Notably, monocyte-derived macrophages (MDMs) in psoriatic lesions displayed markedly heightened pyroptotic activity. In vitro experiments confirmed that MDMs derived from psoriasis patients overexpressed pyroptosis-related molecules (Caspase 1 and Caspase 4) as well as pro-inflammatory cytokines (TNFα, IL6, IL1β) when compared to healthy controls. Furthermore, these cells showed increased expression of CXCL16, which might potentially activate Th17 cells through CXCR6 signaling, thereby driving skin inflammation. Inhibition of monocyte migration in an imiquimod-induced psoriasiform dermatitis model significantly alleviated skin inflammation and reduced the proportion of M1 macrophages and Th17 cells in lesional skin. Conclusions: This study revealed that MDMs in psoriatic lesions exhibited a hyperactive pyroptotic state, which contributed to disease progression through CXCL16-mediated remodeling of the immune microenvironment. These findings highlight pyroptosis as a potential therapeutic target for psoriasis. Full article

The therapeutic target of COVID-19 is focused on controlling inflammation and preventing fibrosis. Collagen–polyvinylpyrrolidone (collagen-PVP) and pirfenidone both have the ability to control the cytokine storm observed in rheumatic and fibrotic disorders. In this work, our aim was to understand the benefits of treatment with each of these drugs in patients with severe COVID-19. In total, 36 patients were treated with dexamethasone and enoxaparin, but 26 were allocated collagen-PVP or pirfenidone (n = 15 and 11, respectively); the clinical and metabolic effects were compared among them. Since pirfenidone works via transcriptional mechanisms, we performed a human genome microarray assay using RNA isolated from fibroblast and monocyte cultures treated with the biodrug, with the aim of hypothesising a possible mechanism of action for collagen-PVP. Our results showed that hospital stay duration, quick COVID-19 severity index (qCSI), and admission to the intensive care unit were statistically significantly lower (p < 0.02) in patients treated with collagen-PVP or pirfenidone when compared with the control group, and that only collagen-PVP normalised serum glucose at discharge. Ingenuity Pathway Analysis showed that the cell cycle, inflammation, and cell surface–extracellular matrix interactions could be regulated with collagen-PVP via the downmodulation of proinflammatory cytokines, while Th2 anti-inflammatory response signalling could be upregulated. Furthermore, the downregulation of some of the genes involved in nitric oxide production showed a possible control for JAK in the IFN-γ pathway, allowing for the possibility of controlling inflammation through the JAK/STAT pathway, as has been observed for pirfenidone and other immunomodulators, such as ruxolitinib. Full article

Autoimmune CD8⁺ T cell-driven melanocyte destruction constitutes a key pathogenic mechanism in the development of vitiligo. Therefore, the pharmacological inhibition of CD8⁺ T cell effector functions and skin trafficking is a clinically viable therapeutic strategy. This study investigates leflunomide (LEF), an immunomodulatory drug with established safety in autoimmune diseases, for its therapeutic potential in a tyrosine-related protein (TRP) 2-180-induced vitiligo mouse model. Through flow cytometry, immunofluorescence, ELISA, and histopathological analyses, we systematically evaluated LEF’s effects on T cell regulation, chemokine expression, and cytokine profiles. Key findings demonstrated that LEF (20 mg/kg/day) significantly attenuated depigmentation by reducing CD8⁺ T cell infiltration and suppressing the IFN-γ-driven expression of CXCL9/10. Furthermore, LEF restored CD4⁺/CD8⁺ T cell homeostasis and rebalanced pro-inflammatory (IFN-γ, TNF-α, IL-2) and anti-inflammatory (IL-4, IL-10) cytokines, inducing a shift from Th1 to Th2. These results position LEF as an effective immunomodulator that disrupts the IFN-γ-CXCL9/10 axis and re-establishes immune balance, offering a promising repurposing strategy for halting vitiligo progression. Full article

IgG antibodies, signaling via the inhibitory receptor, FcγRIIb, are potent inhibitors of IgE-mediated mast cell activation. We have previously reported that in addition to blocking mast cell degranulation, inhibitory IgG signals shut down a proinflammatory transcriptional program in which mast cells produce cytokines and chemokines known to drive type 2 tissue inflammation. To determine whether such effects of allergen-specific IgG can modulate allergic inflammation in vivo, we examined the airways of mice sensitized to ovalbumin (OVA) by intraperitoneal injection and then challenged with intranasal OVA. Pretreatment with allergen-specific IgG significantly reduced the recruitment of inflammatory cells, including macrophages and eosinophils, into the lungs of OVA-sensitized mice. The bronchoalveolar lavage fluid of OVA-challenged mice contained elevated levels of chemokine ligands (CCL2 and CCL24) and interleukin-5, a response that was markedly blunted in animals receiving allergen-specific IgG. IgG-treated animals exhibited attenuated allergen-induced production of IgE, IL-4, and IL-13, along with impaired OVA-induced goblet cell hyperplasia and Muc5ac expression and suppressed airway hyperresponsiveness, consistent with a shift away from a Th2 response. Using mice with a lineage-specific deletion of FcγRIIb, we demonstrated that each of these protective effects of IgG was dependent upon the expression of this receptor on mast cells. Overall, our findings establish that allergen-specific IgG can reduce allergen-driven airway inflammation and airway hyperresponsiveness and point to a mechanistic basis for the therapeutic benefit of aeroallergen-specific IgG therapy. Full article

The two probiotic bacteria Lactobacillus helveticus MIMLh5 and L. acidophilus NCFM exhibit homology, are both equipped with an S-layer made up of highly homologous proteins and are capable of stimulating Th1-inducing signals in dendritic cells. In this study, we aimed to compare the two strains as regards the thickness of the S-layer and their capacity to induce the production of the two Th1-inducing cytokines IL-12 and IFN-β. For both bacteria, stimulation with an increasing number of bacteria led to the higher and prompter production of IL-12 and IFN-β, but at all MOIs tested, the IL-12 response induced by NCFM was always the strongest. For both bacteria, the induction of IL-12 peaked at a multiplicity of infection (MOI) of 2–5, while IL-10, known to inhibit the induction of IL-12 cytokines, was induced more slowly and continued to increase at a higher MOI. By employing specific inhibitors, MIMLh5 and NCFM were also shown to activate different MAP kinase pathways. Endocytosed MIMLh5 showed higher survival in the DCs compared to NCFM. In the presence of mannan, previously shown to accelerate endosomal killing of Gram-positive bacteria, the survival of MIMLh5 was strongly decreased, and IL-12 increased to a level close to that induced by NCFM without the addition of mannan, indicating the importance of rapid endosomal degradation for a strong IL-12 response. When measuring the S-layer thickness, MIMLh5’s S-layer appeared to be more than twice the thickness of NCFM and exhibited an elastic modulus approximately twice as high, which is a measure of a cell’s resistance to an applied mechanic stress. When the two strains were depleted of S-layer protein, the elastic modulus was comparable. Together, our data suggests that the thicker S-layer of MIMLh5 compared to NCFM may contribute to its endosomal survival, thus reducing its capacity to induce IL-12. This may constitute an important parameter in the selection of probiotic bacteria for specific purposes. Full article

Toxoplasma gondii, a parasitic protozoan, causes zoonotic infections with severe health impacts in humans and warm-blooded animals, underscoring the urgent need for effective vaccines to control these infections. In this study, a DNA vaccine encoding TgROP5, TgROP18, TgGRA7, TgGRA15, and TgMIC6 was formulated using the eukaryotic expression vector pVAX I. IL-24 was delivered as a molecular adjuvant using plasmid pVAX-IL-24. BALB/c, C57BL/6, and Kunming mouse strains received the DNA immunization, after which antibody levels, cytokine production, and lymphocyte surface markers were analyzed to assess immune responses. Additionally, survival rates and brain cyst counts were measured 1 to 2 months post-vaccination in experimental models of toxoplasmosis. As a result, compared to controls, the DNA vaccine cocktail significantly increased serum IgG levels, Th1 cytokine production, and proportions of CD4+/CD8+ T cells, leading to extended survival and reduced brain cyst counts post-challenge with T. gondii ME49. Furthermore, the five-gene DNA vaccine cocktail conferred greater protection compared to single-gene immunizations. Co-administration of IL-24 significantly enhanced the immune efficacy of the multi-gene DNA vaccination. Our findings suggest that IL-24 is an effective molecular adjuvant, enhancing the protective immunity of DNA vaccines against T. gondii, supporting its potential role in vaccine strategies targeting other apicomplexan parasites. Full article