Asthma is a chronic disease affecting millions of children worldwide, and in severe cases requires hospitalization. The etiology of asthma is multifactorial, caused by both genetic and environmental factors. In recent years, the role of the early-life gut microbiome in relation to asthma has become apparent, supported by an increasing number of population studies, in vivo research, and intervention trials. Numerous early-life factors, which for decades have been associated with the risk of developing childhood asthma, are now being linked to the disease through alterations of the gut microbiome. These factors include cesarean birth, antibiotic use, breastfeeding, and having siblings or pets, among others. Association studies have highlighted several specific microbes that are altered in children developing asthma, but these can vary between studies and disease phenotype. This demonstrates the importance of the gut microbial ecosystem in asthma, and the necessity of well-designed studies to validate the underlying mechanisms and guide future clinical applications. In this review, we examine the current literature on the role of the gut microbiome in childhood asthma and identify research gaps to allow for future microbial-focused therapeutic applications in asthma.

The dynamics of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infections remain unclear, particularly when compared to responses in naive individuals. In this longitudinal prospective cohort study, 13 participants were recruited. Peripheral blood samples were collected every other day until day 7 after symptom onset. Transcriptome sequencing, single-cell sequencing, T-cell receptor (TCR) sequencing, B-cell receptor (BCR) sequencing, Olink proteomics, and antigen-antibody binding experiments were then performed. During the incubation periods of breakthrough infections, peripheral blood exhibited type 2 cytokine response, which shifted to type 1 cytokine response upon symptom onset. Plasma cytokine levels of C-X-C motif chemokine ligand 10, monocyte chemoattractant protein-1, interferon-γ, and interleukin-6 show larger changes in breakthrough infections than naïve infections. The inflammatory response in breakthrough infections rapidly subsided, returning to homeostasis by day 5 after symptom onset. Notably, the levels of monocyte-derived S100A8/A9, previously considered a marker of severe disease, physiologically significantly increased in the early stages of mild cases and persisted until day 7, suggesting a specific biological function. Longitudinal tracking also revealed that antibodies anti-Receptor Binding Domain (anti-RBD) in breakthrough infections significantly increased by day 7 after symptom onset, whereas cytotoxic T lymphocytes appeared by day 5. This study presents a reference for interpreting the immunological response to breakthrough infectious disease in humans.

Allergic asthma in children is typically associated with house dust mites (HDM) as the key allergen. Nevertheless, the diagnostic rate remains below 60% due to the absence of specific symptoms and diagnostic markers, which hinders the implementation of targeted personalized therapies. This study investigates immunological features of asthma with house dust mite (HDM) sensitisation in children, aiming to uncover diagnostic markers at single-cell resolution. The cohort comprised 8 children with physician-diagnosed asthma (age range: 4-11 years), stratified into groups based on HDM sensitization status. Single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) was conducted, employing Seurat for cell identification and differential gene expression analysis. Enrichment analyses and LASSO regression identified signature genes related to cellular origin, with protein-protein interaction networks elucidating cellular communication differences between groups. A total of 11 distinct cell types were identified, with classical monocytes and monocytes being the predominant cell types that differentiated the two groups. Among these, 12 genes were up-regulated, and 40 down-regulated, mainly involving MHC-II complex and antigen presentation pathways, as validated by Gene Ontology and Gene Set Enrichment Analysis. The machine learning model accurately predicted cellular groupings, evidenced by an area under the curve of 0.83. Enhanced communication signals in HDM allergy cases involved monocytes, contrasting with reduced interactions in naive CD8 + cells. HLA-DR and HLA-DP were identified as the primary hallmark receptors, and the innate immunity differences with non-dust mite allergic asthma were characterized by 18 genes including top candidates MT-ND4 and RPS3A. Individuals with HDM-sensitized asthma exhibited altered expression of MHC-II complex genes in their PBMCs and distinct gene expression patterns in antigen-presenting cells, highlighting the critical role of HLA-DR and HLA-DP in the HDM allergen presentation.

Pore-forming toxins (PFTs) are exotoxins secreted by bacteria that aggregate and perforate cell membranes through mechanisms such as binding to specific membrane proteins, thereby killing cells and promoting bacterial invasion, migration, and proliferation. In this study, an anti-virulence factor strategy and vaccine were combined to develop folic acid-modified red blood cell membrane-hybrid liposomes (FA-RCM-Lips). By utilizing the aggregation and perforation mechanism of pore-forming toxins on red blood cell membranes, Vibrio vulnificus hemolysin A (VvhA) was efficiently loaded as the antigenic protein, thereby neutralizing the toxicity of the toxin while maximizing the retention of its antigenic activity and constructing a toxoid nanovaccine (FA-RCM-Lips(VvhA)). The nanocarrier served as an adjuvant to enhance antigen uptake by antigen-presenting cells, while folic acid molecules adsorbed natural IgM, enhancing antigen uptake and presentation by B cells through the IgM-complement pathway. FA-RCM-Lips reduced the hemolysis rate of VvhA by 98.78 % and simultaneously inhibited VvhA-induced skin and tissue toxicity. Subcutaneous and intravenous immunization with FA-RCM-Lips(VvhA) induced stronger IgG titers, improved antigen presentation, enhanced immune responses, and provided immunoprotection in mice.

Adjuvants, as a critical component of vaccines, are capable of eliciting more robust and sustained immune responses. Nanomaterials have shown unique advantages and broad application prospects in adjuvant development due to their high adjustability and distinctive physicochemical properties. This review focuses on nanoadjuvants and their immunological mechanisms. First, various types of adjuvants are introduced with an emphasis on metal and metal oxide nanoparticles, coordination polymers, liposomes, polymer nanoparticles, and other inorganic nanoparticles that can serve as vaccine adjuvants. Second, this review describes the current status of the clinical applications of nanoadjuvants. Next, the mechanisms of action for nanoadjuvants have been thoroughly elucidated, including the depot effect, NLRP3 inflammasome activation, targeting C-type lectin receptors, activation of toll-like receptors, and activation of the cGAS-STING signaling pathway. Finally, the challenges and opportunities associated with the development of nanoadjuvants have also been addressed.

Chronic rhinosinusitis with nasal polyps (CRSwNP) often requires multiple treatments. When topical steroids prove insufficient, endoscopic sinus surgery (ESS) is the primary intervention. Among surgical options, reboot surgery is an innovative approach that offers the potential for prolonged disease control in rapidly recurring cases, delaying the need for monoclonal antibody (mAb) therapy. Our study investigates the histological and ultrastructural aspects of mucosal regeneration post-reboot surgery, providing evidence beyond clinical observations.

Five adult patients with recurrent CRSwNP, having undergone previous ESS, were enrolled in our study along with one control patient. All underwent partial reboot surgery, and biopsies were taken at pretreatment, 3-, 12-, and 24-months post-op. Analysis included clinical history, demographics, nasal polyps score, CT scans, and ACCESS score. All biopsies were analyzed using light (LM) and electron microscopy (both in transmission and scanning mode [TEM and SEM], respectively). Clinical response was assessed with Sinonasal Outcome Test-22 (SNOT-22) and Visual Analog Scale (VAS).

Difference of means of SNOT-22 and VAS scores, pre versus at 24 months, were statistically significant (69.8 vs. 18.6, p = 0.043; 9.2 vs. 1.2, p = 0.038, respectively). The histological and ultrastructural analysis revealed significant changes in mucosal morphology, collagen composition, vascularity, and cell adhesion, with gradual restoration of normal epithelium and ciliary structure over time.

Evidence of mucosal regeneration was provided at LM and electron microscopy. Reboot surgery is an innovative procedure that may be considered a valid alternative to mAbs, especially in younger patients, considering costs of medication and long-term safety.

Level 4.

Bordetella pertussis infects human upper airways and deploys an array of immunosuppressive virulence factors, among which the adenylate cyclase toxin (CyaA) plays a prominent role in disarming host phagocytes. CyaA binds the complement receptor-3 (CR3 aka αMβ2 integrin CD11b/CD18 or Mac-1) of myeloid cells and delivers into their cytosol an adenylyl cyclase enzyme that hijacks cellular signaling through unregulated conversion of cytosolic ATP to cAMP. We found that the action of as little CyaA as 22 pM (4 ng/mL) blocks macrophage colony-stimulating factor (M-CSF)-driven transition of migratory human CD14+ monocytes into macrophages. Global transcriptional profiling (RNAseq) revealed that exposure of monocytes to 22 pM CyaA for 40 hours in culture with 20 ng/mL of M-CSF led to upregulation of genes that exert negative control of monocyte to macrophage differentiation (e.g., SERPINB2, DLL1, and CSNK1E). The sustained CyaA action yielded downregulation of numerous genes involved in processes crucial for host defense, such as myeloid cell differentiation, chemotaxis of inflammatory cells, antigen presentation, phagocytosis, and bactericidal activities. CyaA-elicited signaling also promoted deacetylation and trimethylation of lysines 9 and 27 of histone 3 (H3K9me3 and H3K27me3) and triggered the formation of transcriptionally repressive heterochromatin patches in the nuclei of CyaA-exposed monocytes. These effects were partly reversed by the G9a methyltransferase inhibitor UNC 0631 and by the pleiotropic HDAC inhibitor Trichostatin-A, revealing that CyaA-elicited epigenetic alterations mediate transcriptional reprogramming of monocytes and play a role in CyaA-triggered block of monocyte differentiation into bactericidal macrophage cells.IMPORTANCETo proliferate on host airway mucosa and evade elimination by patrolling sentinel cells, the whooping cough agent Bordetella pertussis produces a potently immunosubversive adenylate cyclase toxin (CyaA) that blocks opsonophagocytic killing of bacteria by phagocytes like neutrophils and macrophages. Indeed, chemotactic migration of CD14+ monocytes to the infection site and their transition into bactericidal macrophages, thus replenishing the exhausted mucosa-patrolling macrophages, represents one of the key mechanisms of innate immune defense to infection. We show that the cAMP signaling action of CyaA already at a very low toxin concentration triggers massive transcriptional reprogramming of monocytes that is accompanied by chromatin remodeling and epigenetic histone modifications, which block the transition of migratory monocytes into bactericidal macrophage cells. This reveals a novel layer of toxin action-mediated hijacking of functional differentiation of innate immune cells for the sake of mucosal pathogen proliferation and transmission to new hosts.

Chronic wounds, such as diabetic foot ulcers, venous leg ulcers, and post-surgical wound healing disorders pose a significant challenge due to prolonged healing, risk of infection, and impaired quality of life. Persistent inflammation and impaired tissue remodeling are common in these wounds. Traditional diagnostic methods, including visual inspection and microbiological cultures, offer limited insight into the wound micro-environment. Immunomarker profiling could provide a deeper understanding of the molecular mechanisms underpinning wound healing, offering potential biomarkers for infection status and healing progression.

This observational, multi-center cohort study, part of the 'Wound-BIOME' project, analyzed 110 swab samples from patients with acute and chronic wounds using multiplex immunoassays. Clinical parameters such as wound type, healing status, regeneration stage, and microbial burden were recorded. Total protein concentration was assessed, and 35 key immunomarkers, including cytokines (e.g. IL- 1α, IL- 1β), chemokines (CCL2, CXCL8, CXCL10), growth factors (FGF- 2, VEGF) and matrix metalloproteinases (MMP- 7, MMP- 9, MMP- 13), were quantified. Statistical analyses were performed to correlate immunomarker levels with clinical outcomes.

Pro-inflammatory markers, such as IL- 1β, IL- 18 and chemokines like CCL2 and CXCL8, were significantly elevated in non-healing and infected wounds compared to healing wounds. The study identified two new immunomarker ratios - IL- 1β/IL- 1RA and CXCL8/CXCL10 - as potential predictors of wound healing status. The IL- 1β/IL- 1RA ratio showed the highest accuracy for distinguishing healing from non-healing wounds (AUC = 0.6837), while the CXCL8/CXCL10 ratio was most effective in identifying infection (AUC = 0.7669).

Immunomarker profiling via wound swabbing offers valuable insights into the wound healing process. Elevated levels of pro-inflammatory cytokines and MMPs are associated with chronic inflammation and impaired healing. The IL- 1β/IL- 1RA and CXCL8/CXCL10 ratios emerge as promising biomarkers to distinguish between infection and inflammation, with potential in targeted wound care. Further studies are needed to validate these findings and implement them in clinical practice.

This study aims to explore potential adverse events (AEs) related to Dupilumab using data from the US FDA Adverse Event Reporting System (FAERS) database. The FAERS database from Q2 2017 to Q4 2023 was mined for AEs related to Dupilumab. The types of AEs reported, along with gender, age distribution, and severity, were evaluated. Signal detection methods including Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Empirical Bayesian Geometric Mean were used. A total of 11,547,571 AE reports were collected, with 5335 reports suspected of being related to Dupilumab, identifying 307 Preferred Terms involving 27 System Organ Classes. Reports from female patients outnumbered males (56.08% vs. 34.65%). Patients aged 45-65 years reported the most events (21.34%). The number of reports increased significantly in 2023 (34.25%) compared to 2017 (0.42%), with the highest reporting rate from the US (98.07%). Common AEs included Pruritus, Product use in unapproved indication, and Rash, with Product dose omission issue indicating widespread misuse of Dupilumab. High signal strength AEs included Rebound atopic dermatitis, Rebound eczema, Dermatitis atopic, and Dry skin; injection site AEs like Injection site dryness and eczema; new potential AEs such as Dry eye, Eye pruritus, Ocular hyperaemia, Eye irritation, Conjunctivitis, Vision blurred, and Sleep disorder. This study reveals various potential AEs associated with Dupilumab, including newly identified risks. Future research needs to delve deeper into the safety of Dupilumab to better guide its clinical application.

Radiation-induced fibrosis (RIF) is a progressive pathology deleteriously impacting cancer survivorship. CXCL12 is an immune-stromal signal implicated in fibrosis and innate response. We hypothesized that modulation of CXCL12 would phenotypically mitigate RIF. CXCL12 expression was characterized in a rodent model of RIF and its expression modulated by the intravascular delivery of lentiviral vectors encoding small hairpin RNA to silence (LVShCXCL12) or overexpress (LVOeCXCL12) CXCL12. Multimodal fibrotic outcomes were quantified, and flow cytometry and Y-chromosome lineage-tracking studies performed to examine cellular recruitment and activation after radiotherapy. Whole-tissue RNA sequencing was used to examine matrisomal response. MATBIII tumors were engrafted within tissues with differing levels of CXCL12 expression, and tumoral response to RT was evaluated. CXCL12 was upregulated in irradiated fibroblasts demonstrating DNA damage after radiotherapy, which led to the recruitment of CD68+ macrophages. Silencing CXCL12 with LVShCXCL12 demonstrated reduced RIF phenotype as a result of decreased macrophage recruitment. Transcriptomic profiling identified osteopontin (OPN; SPP1) as being highly differentially expressed in LVShCXCL12-treated tissues. Tumors growing in tissues devoid of CXCL12 expression responded better after RT because of reductions in peritumoral fibrosis as a result of decreased CXCL12 and OPN expression at the tumor/normal tissue interface. This was also associated with greater CD8+ T-cell infiltration in tumors with less fibrosis. Antibody-mediated OPN blockade slowed tumor growth by increased intratumoral CD8+ T-cell activation. The CXCL12/OPN axis is an important node of immune/matrisomal cross-talk in the development of fibrosis. Therapeutic manipulation of this axis may offer greater antitumor efficacy while also reducing adverse effects.

Asthma, a chronic respiratory condition that has seen a dramatic rise in prevalence over the past few decades, now affects more than 300 million people globally and imposes a significant burden on healthcare systems. The key pathological features of asthma include inflammation, airway hyperresponsiveness, mucus cell metaplasia, smooth muscle hypertrophy, and subepithelial fibrosis. Cytokines released by lung epithelial cells, stromal cells, and immune cells during asthma are critical to pathological tissue remodeling in asthma. Over the past few decades, researchers have made great strides in understanding key cells involved in asthma and the cytokines that they produce. Epithelial cells as well as many adaptive and innate immune cells are activated by environmental signals to produce cytokines, namely, type 2 cytokines (IL-4, IL-5, IL-13), IFN-γ, IL-17, TGF-β, and multiple IL-6 family members. However, the precise mechanisms through which these cytokines contribute to airway remodeling remain elusive. Additionally, multiple cell types can produce the same cytokines, making it challenging to decipher how specific cell types and cytokines uniquely contribute to asthma pathogenesis. This review highlights recent advances and provides a comprehensive overview of the key cells involved in the production of cytokines and how these cytokines modulate airway remodeling in asthma.

Allergic rhinitis (AR) is a common chronic inflammatory airway disease caused by inhaled allergens, and its prevalence has increased in recent decades. AR not only causes nasal leakage, itchy nose, nasal congestion, sneezing, and allergic conjunctivitis but also induces asthma, as well as sleep disorders, anxiety, depression, memory loss, and other phenomena that seriously affect the patient's ability to study and work, lower their quality of life, and burden society. The current methods used to diagnose and treat AR are still far from ideal. Multi-omics technology can be used to comprehensively and systematically analyze the differentially expressed DNA, RNA, proteins, and metabolites and their biological functions in patients with AR. These capabilities allow for an in-depth understanding of the intrinsic pathogenic mechanism of AR, the ability to explore key cells and molecules that drive its progression, and to design personalized treatment for AR. This article summarizes the progress made in studying AR by use of genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics in order to illustrate the important role of multi-omics technologies in facilitating the precise diagnosis and treatment of AR.

The multifaceted biological defense system modulating complex immune responses against pathogens and foreign materials plays a critical role in tissue homeostasis and disease progression. Recently developed biomaterials that can specifically regulate immune responses, nanoparticles, graphene, and functional hydrogels have contributed to the advancement of tissue engineering as well as disease treatment. The interaction between innate and adaptive immunity, collectively determining immune responses, can be regulated by mechanobiological recognition and adaptation of immune cells to the extracellular microenvironment. Therefore, applying immunomodulation to tissue regeneration and cancer therapy involves manipulating the properties of biomaterials by tailoring their composition in the context of the immune system. This review provides a comprehensive overview of how the physicochemical attributes of biomaterials determine immune responses, focusing on the physical properties that influence innate and adaptive immunity. This review also underscores the critical aspect of biomaterial-based immune engineering for the development of novel therapeutics and emphasizes the importance of understanding the biomaterials-mediated immunological mechanisms and their role in modulating the immune system.

Inflammaging, a state of chronic low-grade inflammation associated with aging, has been linked to the development and progression of various disorders. Cellular senescence, a state of irreversible growth arrest, is another characteristic of aging that contributes to the pathogenesis of cardiovascular pathology. Senescent cells accumulate in tissues over time and secrete many inflammatory mediators, further exacerbating the inflammatory environment. This senescence-associated secretory phenotype can promote tissue dysfunction and remodeling, ultimately leading to the development of age-related cardiovascular pathologies, such as mitral valve myxomatous degeneration. The species-specific form of canine myxomatous mitral valve disease (MMVD) provides a unique opportunity to investigate the early causes of induction of ECM remodeling in mitral valve leaflets in the human form of MMVD. Studies have shown that in both humans and dogs, the microenvironment of the altered leaflets is inflammatory. More recently, the focus has been on the mechanisms leading to the transformation of resting VICs (qVICs) to myofibroblast-like VICs (aVICs). Cells affected by stress fall into a state of cell cycle arrest and become senescent cells. aVICs, under the influence of TGF-β signaling pathways and the mTOR complex, enhance ECM alteration and accumulation of systemic inflammation. This review aims to create a fresh new view of the complex interaction between aging, inflammation, immunosenescence, and MMVD in a canine model, as the domestic dog is a promising model of human aging and age-related diseases.

Keloids are a common skin disorder characterized by excessive fibrous tissue proliferation, which can significantly impact patients' health. Ferroptosis, a form of regulated cell death, plays a crucial role in the development of fibrosis; however, its role in the mechanisms of keloid formation remains poorly understood.

This study aimed to identify key genes associated with ferroptosis in keloid formation. Data from the NCBI GEO database, including GSE145725, GSE7890, and GSE44270, were analyzed, comprising a total of 24 keloid and 17 normal skin samples. Additionally, single-cell data from GSE181316, which included 8 samples with complete expression profiles, were also evaluated. Differentially expressed genes were identified, and ferroptosis-related genes were extracted from the GeneCards database. LASSO regression was used to select key genes associated with keloids. Validation was performed using qRT-PCR and Western blot (WB) analysis on tissue samples from five keloid and five normal skin biopsies.

A total of 471 differentially expressed genes were identified in the GSE145725 dataset, including 225 upregulated and 246 downregulated genes. Five ferroptosis-related genes were selected through gene intersection and LASSO regression. Two of these genes were upregulated, while three were downregulated in keloid tissue. Further analysis through GSEA pathway enrichment, GSVA gene set variation, immune cell infiltration analysis, and single-cell sequencing revealed that these genes were primarily involved in the fibrotic process. The qRT-PCR and WB results confirmed the expression patterns of these genes.

This study provides novel insights into the molecular mechanisms of ferroptosis in keloid formation. The identified ferroptosis-related genes could serve as potential biomarkers or therapeutic targets for treating keloids.

The aim of this study was to investigate the role of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exo) in regulating the intestinal type 2 immune response for either protection or therapy.

hUCMSC-Exo was considered a novel cell-free therapeutic product that shows promise in the treatment of various diseases. Type 2 immunity is a protective immune response classified as T-helper type 2 (Th2) cells and is associated with helminthic infections and allergic diseases. The effect of hUCMSC-Exo on intestinal type 2 immune response is not clear.

C57BL/6 mice were used to establish intestinal type 2 immune response by administering of H. poly and treated with hUCMSC-Exo before or after H. poly infection. Intestinal organoids were isolated and co-cultured with IL-4 and hUCMSC-Exo. Then, we monitored the influence of hUCMSC-Exo on type 2 immune response by checking adult worms, the hyperplasia of tuft and goblet cells Result: hUCMSC-Exo significantly delays the colonization of H. poly in subserosal layer of duodenum on day 7 post-infection and promotes the hyperplasia of tuft cells and goblet cells on day 14 post-infection. HUCMSC-Exo enhances the expansion of tuft cells in IL-4 treated intestinal organoids, and promotes lytic cell death.

Our study demonstrates hUCMSC-Exo may benefit the host by increasing the tolerance at an early infection stage and then enhancing the intestinal type 2 immune response to impede the helminth during Th2 priming. Our results show hUCMSC-Exo may be a positive regulator of type 2 immune response, suggesting hUCMSC-Exo has a potential therapeutic effect on allergic diseases.

It is believed that oncolytic viruses (OVs) exert both direct anti-tumor effects by intratumoral injection as well as indirect anti-tumor effects by activating systemic immunity. In phase III clinical trials, OV and anti-programmed cell death-1 (aPD-1) antibody combination therapy showed no significant differences in overall survival and progression-free survival in patients with unresectable advanced melanoma. In the study, OVs can exert only indirect anti-tumor effects in non-injected, systemic lesions. If the tumor is at a stage where both direct and indirect anti-tumor effects of OVs can be expected, OVs may further enhance the therapeutic effect, in addition to the clinically expected therapeutic effect. Therefore, we investigated whether canerpaturev (C-REV) and aPD-1 antibody combination therapy suppresses tumor progression in a murine melanoma model. Our findings showed that the C-REV and aPD-1 antibody combination therapy suppressed tumor progression in a murine melanoma model. The combination therapy stimulated systemic immunity in lymphoid tissues by activating helper T cells and B cells to enhance adaptive and humoral immunity, as well as by increasing effector/memory T cell fractions. Synergistically enhanced systemic anti-tumor effects suppressed lymph node and lung metastases. These findings suggest that direct anti-tumor effects by infecting and destroying cancer cells from within and indirect anti-tumor effects enhanced by the combination therapy worked simultaneously to suppress tumor progression. Our results may provide evidence to support the usefulness of OV and aPD-1 antibody combination therapy as a neoadjuvant therapy in the surgical treatment of melanoma.

Food allergies affect approximately 2.5% of the global population, with a notable increase in prevalence observed each year. Terpenoids, a class of natural bioactive constituents, have been widely utilized in the management of immune- and inflammation-related disorders, and their potential in alleviating food allergies is increasingly being recognized. This article summarizes various terpenoids derived from plant, fungal, and marine sources. Among them, triterpenoids, such as oleanolic acid, ursolic acid, and lupeol, possess the highest proportion and bioactivity in alleviating food allergy. Additionally, the mechanisms by which terpenoids may mitigate allergic diseases were categorically outlined, focusing on their roles in epithelial mucosal barrier function, immunomodulatory effects during the sensitization phase, inhibition of effector cells, oxidative stress, and regulation of microbial homeostasis. Finally, the advantages and limitations of natural extraction and artificial synthesis methods were compared, and the application of terpenoids in the food industry were also discussed. This article serves as a useful reference for the development of methods or functional foods based on terpenoids, which could represent a promising avenue for alleviating food allergy.

Neutrophils have a critical role in inflammation. Recent studies have identified their distinctive presence in certain types of atopic dermatitis (AD), yet their exact function remains unclear. This review aims to compile studies elucidating the role of neutrophils in AD pathophysiology. Proteins released by neutrophils, including myeloperoxidase, elastase, and lipocalin, contribute to pruritus progression in AD. Neutrophilic oxidative stress and the formation of neutrophil extracellular traps may further worsen AD. Elevated neutrophil elastase and high-mobility group box 1 protein expression in AD patients' skin exacerbates epidermal barrier defects. Neutrophil-mast cell interactions in allergic inflammation steer the immunological response toward Th2 imbalance and activate the Th17 pathway, particularly in response to allergens or infections linked to AD. Notably, drugs alleviating pruritic symptoms in AD inhibit neutrophilic inflammation. In conclusion, these findings underscore that neutrophils may be therapeutic targets for AD symptoms, emphasizing their inclusion in AD treatment strategies.

Menopause is an age-related change that persists for around one-third of a woman's life. Menopause increases the risk of metabolic illnesses such as diabetes, osteoporosis (OP), and nonalcoholic fatty liver disease (NAFLD). Immune mediators (pro-inflammatory cytokines), such as interleukin-1 (IL-1), IL-6, IL-17, transforming growth factor (TGF), and tumor necrosis factor (TNF), exacerbate the challenges of a woman undergoing menopause by causing inflammation and contributing to the development of these metabolic diseases in postmenopausal women. Furthermore, studies have shown that anti-inflammatory cytokines such as interleukin-1 receptor antagonists (IL-1Ra), IL-2, and IL-10 have a double-edged effect on diabetes and OP. Likewise, several interferon (IFN) members are double-edged swords in the OP. Therefore, addressing these immune mediators precisely may be an approach to improving the health of postmenopausal women. Hence, considering the significant changes in these cytokines, the present review focuses on the latest findings concerning the molecular mechanisms by which pro- and anti-inflammatory cytokines (interleukins) impact postmenopausal women with diabetes, OP, and NAFLD. Furthermore, we comprehensively discuss the therapeutic approaches that identify cytokines as therapeutic targets, such as hormonal therapy, physical activities, natural inhibitors (drugs), and others. Finally, this review aims to provide valuable insights into the role of cytokines in postmenopausal women's diabetes, OP, and NAFLD. Deeply investigating the mechanisms and therapeutic interventions involved will address the characteristics of immune mediators (cytokines) and improve the management of these illnesses, thereby enhancing the general quality of life and health of the corresponding populations of women.

High glucose level, bacterial infection, and persistent inflammation within the microenvironment are key factors contributing to the delay of diabetic ulcers healing, while traditional therapeutic methods generally fail to address these issues simultaneously. Here, we present a spatiotemporally responsive cascade bilayer microneedle (MN) patch for accelerating diabetic wound healing via local glucose depletion and sustained nitric oxide (NO) release for long-term antibacterial and anti-inflammatory effects. The MN patch (G/AZ-MNs) possesses a degradable tip layer loading glucose oxidase (GOx), as well as a dissolvable base layer encapsulating l-arginine (Arg)-loaded nanoparticles (NPs). After wound administration, the base part rapidly dissolved, resulting in prompt separation of the MN tip within the wound tissue, which subsequently responded to the overexpressed matrix metalloproteinase-9 (MMP-9) in diabetic lesions, leading to the responsive release of GOx. The released enzyme catalyzed glucose into gluconic acid and hydrogen peroxide (H2O2), which not only reduced glucose level within the diabetic wound, but also initiated the cascade reaction between H2O2 with the Arg that was released from NPs, thereby achieving continuous production of NO for 7 days. Our findings demonstrate that a single administration of the MN patch could effectively heal non-infected or biofilm-infected diabetic wounds with the multifunctional properties.

Malva sylvestris L. (commonly known as mallow) has been widely used in traditional Tibetan formulations to treat allergic rhinitis (AR), and malvidin is a key anti-inflammation constituent of this plant.

The present study aimed to evaluate the potential therapeutic effect and mechanism of malvidin in an AR mouse model.

Malvidin's efficacy was evaluated in an AR mouse model induced by ovalbumin (OVA) sensitization and challenge. The factors, such as nasal symptoms, serum OVA-specific immunoglobulin E (IgE) levels, histological changes in the nasal mucosa, and expressions of Th1, Th2, Th17, and Tregs and their cytokines, were assessed. Western blotting was used to analyze the effect of malvidin on signal transducer and activator of transcription 6 (STAT6) and GATA3 expression levels.

Malvidin reduced the allergic symptoms and serum levels of OVA-specific IgE in the AR model. Histological analysis indicated that malvidin alleviates nasal mucosal edema, eosinophil infiltration, and goblet cell proliferation. In addition, it altered the expression of Th1/Th2/Th17-related cytokines, enhanced the Treg population, and reduced Th2-mediated immunity by suppressing the phosphorylation of STAT6 and expression of the GATA3 protein.

Malvidin significantly improved allergic symptoms in an OVA-induced AR mouse model by modulating Th1/Th2 immune responses and suppressing the STAT6/GATA3 pathway, indicating its potential as a naturally sourced agent for AR management.

Long noncoding RNAs (lncRNAs) have been implicated in a diverse array of human immune diseases; however, a comprehensive understanding of the expression and function of lncRNAs in the peripheral blood leukocytes of individuals suffering from house dust mite (HDM)-induced allergic rhinitis (AR) remains elusive.

To explore the potential roles and functions of long noncoding RNAs (lncRNAs) in the pathogenesis of AR.

Sequencing analysis was performed on peripheral blood leukocytes collected from patients with HDM-induced AR and healthy controls (HCs) to elucidate the expression patterns of lncRNAs. Differentially expressed (DE) lncRNAs were identified and validated, and further correlation analyses were conducted to explore their associations with visual analog scale (VAS) scores and cytokine levels in the serum and nasal secretions. Additionally, bioinformatics analyses were performed to predict the potential pathways influenced by DE lncRNAs. Finally, the diagnostic potential of these lncRNAs in AR was assessed via receiver operating characteristic (ROC) curve analysis.

Significant differences in the expression profiles of lncRNAs and mRNAs were detected between AR patients and HCs. Four lncRNAs were markedly upregulated in AR patients. AC011524.2 was positively correlated with nasal pruritus (r = 0.4492, P = 0.0411). AL133371.3 was positively correlated with runny nose (r = 0.4889, P = 0.0245). AC011524.2 was positively correlated with CXCL8 (r = 0.4504, P = 0.0035). AL133371.3 was significantly positively correlated with only IL-17 (r = 0.4028, P = 0.0100). IL-4 in the serum was positively related to IL-17 in the serum (r = 0.4163, P = 0.0002). CXCL5 in the serum was positively correlated with IFN-γ (r = 0.3336, P = 0.0354) in nasal secretions. The area under the curve (AUC) of the ROC curve resulting from the integration of the 4 lncRNAs exhibited a remarkable value of 0.940 for AR diagnosis.

Our results identified several lncRNAs associated with AR symptoms and inflammatory cytokines. Specifically, AC011524.2 and AL133371.3 exhibited strong correlations with diverse AR manifestations and serum cytokines, suggesting their pivotal role in the pathogenesis of AR, likely via neutrophil- and Th17-related pathways. However, the precise underlying mechanisms are still elusive, necessitating further exploration.

The tumour microenvironment represents a novel frontier in oncological research. Over the past decade, accumulating evidence has underscored the importance of the tumour microenvironment (TME), including tumour cells, stromal cells, immune cells, and various secreted factors, which collectively influence tumour growth, invasion, and responses to therapeutic agents. Immune cells within the TME are now widely acknowledged to play pivotal roles in tumour development and treatment. While some perspectives have posited that immune cells within the TME facilitate tumour progression and confer resistance to therapeutic interventions, contrasting conclusions also exist. Affirmative and negative conclusions appear to be context dependent, and a unified consensus has yet to be reached. The burgeoning body of research on the relationship between the gut microbiota and tumours in recent years has led to a growing understanding. Most studies have indicated that specific components of the gut microbiota, such as unique bacterial communities or specific secretory factors, play diverse roles in regulating immune cells within the TME, thereby influencing the prognosis and outcomes of cancer treatments. A detailed understanding of these factors could provide novel insights into the TME and cancer therapy. In this study, we aimed to synthesise information on the interactions between the gut microbiota and immune cells within the TME, providing an in-depth exploration of the potential guiding implications for future cancer therapies.

Dendritic cells (DCs) are uniquely capable of transporting tumor antigens to tumor-draining lymph nodes (tdLNs) and interact with effector T cells in the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)-based single-cell transcriptomics, we identified individual DCs capable of presenting antigen to CD4+ T cells in both the tdLN and TME. Our findings revealed that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both in tumors and in the tdLN and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation in the tdLN and TME to both CD4+ and CD8+ tumor-specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.

Metabolic dysfunction-associated steatohepatitis (MASH) is a common but frequently unrecognized complication of obesity and type 2 diabetes. The association between these conditions is multifaceted and involves complex interactions between metabolic, inflammatory, and genetic factors. Here we assess the underlying structural and molecular processes focusing on the immunological phase of MASH in the nonobese inflammation and fibrosis (NIF) mouse model and compare it to the human disease as well as other murine models. Histopathology together with synchrotron-radiation-based x-ray micro-computed tomography (SRµCT) was used to investigate structural changes within the hepatic sinusoids network in the NIF mouse in comparison to patients with different severities of MASH. A time-course, bulk RNA-sequencing analysis of liver tissue from NIF mice was performed to identify the dynamics of key processes associated with the pathogenesis. Transcriptomics profiling of the NIF mouse revealed a gradual transition from an initially reactive inflammatory response to a regenerative, pro-fibrotic inflammatory response suggesting new avenues for treatment strategies that focus on immunological targets. Despite the lack of metabolic stress induced liver phenotype, a large similarity between the NIF mouse and the immunological phase of human MASH was detected. The translational value was further supported by the comparative analyses with MASH patients and additional animal models. Finally, the impact of diets known to induce metabolic stress, was explored in the NIF mouse. An obesogenic diet was found to induce key physiological, metabolic, and histologic changes akin to those observed in human MASH.

Schistosomiasis is the second most debilitating neglected tropical disease in the world. Liver egg granuloma and fibrosis are the main damage of schistosomiasis. In this study, the role of allograft inflammatory factor-1 (AIF-1) in liver pathology and its regulation in immune responses were investigated in a transgenic mouse infected with Schistosoma japonicum. We found that AIF-1 overexpression reduced worm burden and decreased egg granuloma sizes and serum alanine aminotransferase levels, along with inhibited hepatic collagen deposition and serum hydroxyproline levels during S. japonicum infection. Moreover, AIF-1 overexpression resulted in an increased ratio of Th1/Th2, increased levels of IFN-γ and T-bet, and lower levels of GATA-3 in the spleen, accompanied by increased M1 percentages, decreased M2 percentages, and thus a higher ratio of M1/M2 in the peritoneal cavity and liver. AIF-1 induced CD68 and iNOS mRNA expression and protein levels of cytoplasmic p-P38 and nuclear NF-κB, along with enhanced levels of TNF-α and TGF-β in macrophages in vitro. Moreover, the hepatic pathology had a negative correlation with Th1/Th2 and M1/M2 ratios in the infected mice. The findings reveal that the beneficial role of AIF-1 in alleviating hepatic damage is related to restoring type I/II immune balance in S. japonicum infection.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by unexplained irreversible pulmonary fibrosis. Although the etiology of IPF is unclear, studies have shown that it is related to telomere length shortening. However, the prognostic value of telomere-related genes in IPF has not been investigated.

We utilized the GSE10667 and GSE110147 datasets as the training set, employing differential expression analysis and weighted gene co-expression network analysis (WGCNA) to screen for disease candidate genes. Then, we used consensus clustering analysis to identify different telomere patterns. Next, we used summary data-based mendelian randomization (SMR) analysis to screen core genes. We further evaluated the relationship between core genes and overall survival and lung function in IPF patients. Finally, we performed immune infiltration analysis to reveal the changes in the immune microenvironment of IPF.

Through differential expression analysis and WGCNA, we identified 35 significant telomere regulatory factors. Consensus clustering analysis revealed two distinct telomere patterns, consisting of cluster A (n = 26) and cluster B (n = 19). Immune infiltration analysis revealed that cluster B had a more active immune microenvironment, suggesting its potential association with IPF. Using GTEx eQTL data, our SMR analysis identified two genes with potential causal associations with IPF, including GPA33 (PSMR = 0.0013; PHEIDI = 0.0741) and MICA (PSMR = 0.0112; PHEIDI = 0.9712). We further revealed that the expression of core genes is associated with survival time and lung function in IPF patients. Finally, immune infiltration analysis revealed that NK cells were downregulated and plasma cells and memory B cells were upregulated in IPF. Further correlation analysis showed that GPA33 expression was positively correlated with NK cells and negatively correlated with plasma cells and memory B cells.

Our study provides a new perspective for the role of telomere dysfunction and immune infiltration in IPF and identifies potential therapeutic targets. Further research may reveal how core genes affect cell function and disease progression, providing new insights into the complex mechanisms of IPF.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic comorbidities remain ill-defined. Here, analysis of circulating NK cells in a longitudinal early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D, which was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aeroallergens, a risk factor for development of asthma. Individual-level longitudinal analysis in a subset of children revealed coincident reduction of NKG2D on NK cells with acquired or persistent sensitization, and this was associated with impaired skin barrier function assessed by transepidermal water loss. Low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine tumor necrosis factor-α. These observations provide important insights into a potential mechanism underlying the development of allergic comorbidity in early life in children with AD, which involves altered NK cell functional responses, and define an endotype of severe AD.

Inflammation is implicated in cardiovascular disease (CVD) pathogenesis, but causal roles of specific circulating inflammatory cytokines remain unclear. Mendelian randomization (MR) studies are well-poised to provide etiological insights beyond constraints of conventional research.

We conducted a large-scale MR study to investigate potential causal relationships of 91 inflammatory proteins with CVD outcomes and cardiac remodeling using summary-level genetic data. Outcomes included coronary artery disease, myocardial infarction, stroke, atrial fibrillation, heart failure, abdominal aortic aneurysm, deep vein thrombosis of lower extremities, pulmonary embolism, cardiac structure and functional parameters. Inverse-variance weighted analysis was undertaken as the primary analysis, with several sensitivity analyses applied.

Hepatocyte growth factor (HGF) demonstrated a causal relationship with increased susceptibility to both any stroke (OR 1.111; 95 % CI 1.044 - 1.183; P = 9.50e-04) and ischemic stroke (OR 1.121; 95 % CI 1.047 - 1.200; P = 1.04e-03). Programmed cell death 1 ligand 1 (PD-L1) was negatively associated with atrial fibrillation risk (OR 0.936, 95 % CI 0.901 - 0.973; P = 7.69e-04). CCL20, CDCP1, Flt3L and IL-10RA were identified as causal coronary artery disease risk factors, while LIF and ST1A1 had protective effects. IL-4 and LIF-R demonstrated causal links with right heart functional changes.

Our MR study nominates specific circulating inflammatory cytokines as potential targets for CVD treatment and prevention. Further research into mechanisms and clinical translation are warranted.

CD4+ T cells are an integral component of the adaptive immune response, carrying out many functions to combat a diverse range of pathogenic challenges. These cells exhibit remarkable plasticity, differentiating into specialized subsets such as T helper type 1 (TH1), TH2, TH9, TH17, TH22, regulatory T cells (Tregs), and follicular T helper (TFH) cells. Each subset is capable of addressing a distinct immunological need ranging from pathogen eradication to regulation of immune homeostasis. As the immune response subsides, CD4+ T cells rest down into long-lived memory phenotypes-including central memory (TCM), effector memory (TEM), resident memory (TRM), and terminally differentiated effector memory cells (TEMRA) that are localized to facilitate a swift and potent response upon antigen re-encounter. This capacity for long-term immunological memory and rapid reactivation upon secondary exposure highlights the role CD4+ T cells play in sustaining both adaptive defense mechanisms and maintenance. Decades of mouse, human, and to a lesser extent, pig T cell research has provided the framework for understanding the role of CD4+ T cells in immune responses, but these model systems do not always mimic each other. Although our understanding of pig immunology is not as extensive as mouse or human research, we have gained valuable insight by studying this model. More akin to pigs, our understanding of CD4+ T cells in dogs is much less complete. This disparity exists in part because canine immunologists depend on paradigms from mouse and human studies to characterize CD4+ T cells in dogs, with a fraction of available lineage-defining antibody markers. Despite this, every major CD4+ T cell subset has been described to some extent in dogs. These subsets have been studied in various contexts, including in vitro stimulation, homeostatic conditions, and across a range of disease states. Canine CD4+ T cells have been categorized according to lineage-defining characteristics, trafficking patterns, and what cytokines they produce upon stimulation. This review addresses our current understanding of canine CD4+ T cells from a comparative perspective by highlighting both the similarities and differences from mouse, human, and pig CD4+ T cell biology. We also discuss knowledge gaps in our current understanding of CD4+ T cells in dogs that could provide direction for future studies in the field.

Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children.

We sought to determine whether nasal allergen challenge (NAC) responses to cockroach allergen would improve following 1 year of SCIT.

Urban children with asthma, who were cockroach-sensitized and reactive on NAC, participated in a year-long randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean Total Nasal Symptom Score (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test wheal size, serum allergen-specific antibody production, and T-cell responses to cockroach allergen were assessed.

Changes in mean NAC TNSS did not differ between SCIT-assigned (n = 28) versus placebo-assigned (n = 29) participants (P = .63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum-specific IgE decreased to a similar extent in both groups, while decreased cockroach skin prick test wheal size was greater among SCIT participants (P = .04). A 200-fold increase in cockroach serum-specific IgG4 was observed among subjects receiving SCIT (P < .001) but was unchanged in the placebo group. T-cell IL-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (P = .002), while no effect was observed for IL-10 or IFN-γ.

A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum-specific IgG4 serum production and down-modulation of allergen-stimulated T-cell responses.

A comprehensive understanding of the intricate cellular and molecular changes governing the complex interactions between cells within acne lesions is currently lacking. Herein, we analyzed early papules from six subjects with active acne vulgaris, utilizing single-cell and high-resolution spatial RNA sequencing. We observed significant changes in signaling pathways across seven different cell types when comparing lesional skin samples (LSS) to healthy skin samples (HSS). Using CellChat, we constructed an atlas of signaling pathways for the HSS, identifying key signal distributions and cell-specific genes within individual clusters. Further, our comparative analysis revealed changes in 49 signaling pathways across all cell clusters in the LSS- 4 exhibited decreased activity, whereas 45 were upregulated, suggesting that acne significantly alters cellular dynamics. We identified ten molecules, including GRN, IL-13RA1 and SDC1 that were consistently altered in all donors. Subsequently, we focused on the function of GRN and IL-13RA1 in TREM2 macrophages and keratinocytes as these cells participate in inflammation and hyperkeratinization in the early stages of acne development. We evaluated their function in TREM2 macrophages and the HaCaT cell line. We found that GRN increased the expression of proinflammatory cytokines and chemokines, including IL-18, CCL5, and CXCL2 in TREM2 macrophages. Additionally, the activation of IL-13RA1 by IL-13 in HaCaT cells promoted the dysregulation of genes associated with hyperkeratinization, including KRT17, KRT16, and FLG. These findings suggest that modulating the GRN-SORT1 and IL-13-IL-13RA1 signaling pathways could be a promising approach for developing new acne treatments.

In Alzheimer's Disease (AD), amyloidogenic proteins (APs), such as β-amyloid (Aβ) and tau, may act as alarmins/damage-associated molecular patterns (DAMPs) to stimulate neuroinflammation and cell death. Indeed, recent evidence suggests that brain-specific type 2 immune networks may be important in modulating amyloidogenicity and brain homeostasis. Central to this, components of innate neuroimmune signaling, particularly type 2 components, assume distinctly specialized roles in regulating immune homeostasis and brain function. Whereas balanced immune surveillance stems from normal type 2 brain immune function, appropriate microglial clearance of aggregated misfolded proteins and neurotrophic and synaptotrophic signaling, aberrant pro-inflammatory activity triggered by alarmins might disrupt this normal immune homeostasis with reduced microglial amyloid clearance, synaptic loss, and ultimately neurodegeneration. Furthermore, since increased inflammation may in turn cause neurodegeneration, it is predicted that AP aggregation and neuroinflammation could synergistically promote even more damage. The reasons for maintaining such adverse biological conditions which have not been weeded out during evolution remain unclear. Here, we discuss these issues from a viewpoint of amyloidogenic evolvability, namely, aEVO, a hypothetic view of an adaptation to environmental stress by AP aggregates. Speculatively, the interaction of AP aggregation and neuroinflammation for aEVO in reproduction, which is evolutionally beneficial, might become a co-activating relationship which promotes AD pathogenesis through antagonistic pleiotropy. If validated, simultaneously suppressing both AP aggregation and specific innate neuroinflammation could greatly increase therapeutic efficacy in AD. Overall, combining a better understanding of innate neuroimmunity in aging and disease with the aEVO hypothesis may help uncover novel mechanism of pathogenesis of AD, leading to improved diagnostics and treatments.

Adaptive immune dysfunction may play a crucial role in Parkinson's disease (PD) development. Isolated rapid eye movement sleep behavior disorder (iRBD) represents the prodromal stage of synucleinopathies, including PD. Elucidating the peripheral adaptive immune system is crucial in iRBD, but current knowledge remains limited.

This study aimed to characterize peripheral lymphocyte profiles in iRBD patients compared with healthy control subjects (HCs).

This cross-sectional study recruited polysomnography-confirmed iRBD patients and age- and sex-matched HCs. Venous blood was collected from each participant. Flow cytometry was used to evaluate surface markers and intracellular cytokine production in peripheral blood mononuclear cells.

Forty-four iRBD patients and 36 HCs were included. Compared with HCs, patients with iRBD exhibited significant decreases in absolute counts of total lymphocytes and CD3+ T cells. In terms of T cell subsets, iRBD patients showed higher frequencies and counts of proinflammatory T helper 1 cells and INF-γ+ CD8+ T cells, along with lower frequencies and counts of anti-inflammatory T helper 2 cells. A significant increase in the frequency of central memory T cells in CD8+ T cells was also observed in iRBD. Regarding B cells, iRBD patients demonstrated reduced frequencies and counts of double-negative memory B cells compared with control subjects.

This study demonstrated alterations in the peripheral adaptive immune system in iRBD, specifically in CD4+ and INF-γ+ CD8+ T cell subsets. An overall shift toward a proinflammatory state of adaptive immunity was already evident in iRBD. These observations might provide insights into the optimal timing for initiating immune interventions in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Porcine epidemic diarrhoea virus (PEDV) infects pigs of all ages by invading small intestine, causing acute diarrhoea, vomiting, and dehydration with high morbidity and mortality among newborn piglets. However, current PEDV vaccines are not effective to protect the pigs from field epidemic strains because of poor mucosal immune response and strain variation. Therefore, it is indispensable to develop a novel oral vaccine based on epidemic strains. Bacillus subtilis spores are attractive delivery vehicles for oral vaccination on account of the safety, high stability, and low cost. In this study, a chimeric gene CotC-Linker-COE (CLE), comprising of the B. subtilis spore coat gene cotC fused to the core neutralizing epitope CO-26 K equivalent (COE) of the epidemic strain PEDV-AJ1102 spike protein gene, was constructed. Then recombinant B. subtilis displaying the CLE on the spore surface was developed by homologous recombination. Mice were immunized by oral route with B. subtilis 168-CLE, B. subtilis 168, or phosphate-buffered saline (PBS) as control. Results showed that the IgG antibodies and cytokine (IL-4, IFN-γ) levels in the B. subtilis 168-CLE group were significantly higher than the control groups. This study demonstrates that B. subtilis 168-CLE can generate specific systemic immune and mucosal immune responses and is a potential vaccine candidate against PEDV infection.