Search Results (1,191)

Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by autoantibody production and multi-organ involvement. Anifrolumab, a monoclonal antibody targeting the type I interferon (IFN) receptor, has been approved for the treatment of SLE. Our aim was to investigate the long-term effects of inhibited type I IFN signaling on circulating follicular helper T subsets (T_FH), follicular regulatory T cells (T_FR), and B lymphocyte subpopulations, reflecting the ongoing germinal center reactions in SLE patients. Peripheral blood samples were obtained from ten SLE patients before the initiation of anifrolumab treatment, and at months 6 and 12 of the intervention period. Flow cytometry analysis was performed to assess the frequencies of circulating T_FH cell subsets, T_FR cells, and certain B cell subpopulations. Serological parameters, including autoantibody levels and complement components, were determined as part of the routine diagnostic evaluation. We observed a significant and sustained reduction in the percentage of activated circulating T_FH cells. Notably, the frequency of CXCR3⁻CCR6⁺ T_FH17 cells decreased, whereas the proportion of CXCR3⁺CCR6⁻ T_FH1 cells increased significantly. Furthermore, the proportion of the IgD⁻CD27⁻ double-negative B lymphocytes was also significantly reduced. These findings suggest that anifrolumab therapy attenuates T_FH cell activation, which may contribute to its clinical efficacy by modulating germinal center responses in SLE. 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: Alopecia areata (AA), an autoimmune condition causing non-scarring hair loss, often coexists with atopic dermatitis (AD) due to shared T-helper cell type 2 (Th2)-mediated pathways. Dupilumab, a monoclonal antibody inhibiting IL-4 and IL-13 signaling, is a cornerstone treatment for AD but has conflicting reports regarding its impact on AA, with some suggesting therapeutic benefits and others indicating AA induction. Methods: This retrospective study, utilizing the TriNetX Research Network’s de-identified data from over 300 million patient records, investigates the association between dupilumab use and AA risk in AD patients. Results: After propensity score matching, 23,782 dupilumab users were compared with an equal number of controls. Results revealed a statistically significant increased AA risk in dupilumab users (odds ratio: 1.436, 95% CI: 1.066–1.935, p = 0.0167) after 16 weeks. Cases occurring within 16 weeks were excluded. Conclusions: Potential mechanisms include immune rebalancing, with Th2 suppression possibly upregulating Th1/Th17 pathways or unmasking latent AA in predisposed individuals. These findings challenge dupilumab’s potential as an AA treatment and highlight the need for vigilant monitoring, including routine scalp examinations and patient education. Future research should focus on mechanistic pathways, risk stratification, and comparative studies with other biologics to optimize personalized treatment strategies for AD and AA. Full article

Fasciola gigantica (F. gigantica) is a vital parasite that causes fasciolosis. Liver fluke infections affect livestock animals, and the Fasciola species (Fasciola spp.) vaccine has been tested for many types of these diseases. Currently, computer-based vaccine design represents an attractive alternative for constructing vaccines. Thus, this study aimed to design the epitopes of linear B-cells (BCL) and helper T lymphocytes (HTL) using an immunoinformatic approach and to investigate in silico and the mice’s immune response. A non-conserved host region, overlapping F. gigantica cathepsin B proteins (FgCatB), and the highest conserved residue percentages were the criteria used to construct epitopes. The GPGPG linker was used to link epitopes in the multi-epitope Fasciola gigantica cathepsin B (MeFgCatB) peptide. The MeFgCatB peptide has high antigenicity, non-allergenicity, non-toxicity, good solubility, and a high-quality structure. The molecular docking between the MeFgCatB peptide and Toll-like receptor 2 (TLR-2) was evaluated. The IgM, IgG1, and IgG2 levels were elevated in silico. In mice, the MeFgCatB peptide was synthesized and administered as an injection. The MeFgCatB-specific IgG1 and IgG2a levels were elevated after week 2, showing a predominance of IgG1. The rFgCatB1, rFgCatB2, and rFgCatB3 were detected using the MeFgCatB peptide-immunized sera. The MeFgCatB peptide-immunized sera were detected at approximately 28–34 kDa in the whole body. In addition, the MeFgCatB immunized sera can positively signal at the caecal epithelium in the NEJ, 4WKJ, and adult stages. In summary, the MeFgCatB peptide is able to induce mixed Th1/Th2 immune responses with Th2 dominating and to detect the native protein of F. gigantica. The MeFgCatB peptide should help against F. gigantica in future experiments. Full article

The main challenge after engraftment of human tissues to mice is the development of graft-versus-host disease. It often occurs in an acute form, which reduces the time frame for observations. This is especially important to take into account when planning long-term studies of chronic diseases such as HIV infection. In addition, in mice, even with a similar genotype but different origin, the interaction between the graft and the recipient’s organism can manifest itself differently. We engrafted human immune cells in three different concentrations into immunodeficient NOD/Shi-Prkdc^scid Il2rg^em1/Cyagen mice. Then, the initial points of development of a severe graft-versus-host reaction and the maximum possible time window for humane observation were determined. The study included regular complete blood count and the monitoring of the dynamics of the concentration of human cells in the blood of mice. In addition, the effect of grafts on the activation of the recipient’s immune system was assessed. Finally, necropsy and histological and immunohistochemical examinations of the organs were performed to determine the localization of human cells. In this way, critical factors determining the success of human immune system reconstitution in mice were identified. Full article

Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment—including immunotherapy and targeted therapies—have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future. Full article

SLE is characterized by the generation of a variety of autoantibodies including anti-dsDNA autoantibodies, causing damage in various organs. If autoimmunity is defined by the generation of a variety of autoantibodies against the self, SLE is the only disease to qualify. Identification of the SLE-causing factor must fulfill the following criteria: (i) the factor induces SLE, (ii) the factor is operating in active SLE and (iii) SLE heals after removal of the factor. All candidate factors are reviewed from this viewpoint in this review. As to the cause of SLE, high levels of interferon α can induce SLE; however, interferon α in most patients did not reach this high level. BAFF (B cell activating factor of the TNF family) is increased in SLE. BAFF itself induced some manifestation of SLE, whereas removal of interferon α or BAFF by an antibody (Ab) did not heal SLE. BXSB male mice with a duplicated TLR7 gene develop SLE; however, the gene Sle1 is also required for the development of SLE. In addition, sanroque mice develop a variety of autoantibodies and SLE; the sanroque mutation, which disrupts one of the repressors of ICOS, results in increased CCR7^lo CXCR5⁺Tfh cells, IL-21 and SLE. ICOS⁺T follicular helper (Tfh) cells increase in SLE and SLE-model (NZBxNZW)F1 mice, and the blockade of Tfh development ameliorated SLE, indicating the importance of Tfh cells in the pathogenesis of SLE. Self-organized criticality theory shows that SLE is caused by repeated infection, wherein SLE-inducing pathogens can vary individually depending on one’s HLA; however, the pathogen presented on HLA stimulates the T cell receptor (TCR) strongly beyond self-organized criticality. This stimulation generates TCR-revised, autoreactive DOCK8⁺Tfh cells, which induced a variety of autoantibodies and SLE. The SARS-CoV-2 virus is an example pathogen because SLE occurs after SARS-CoV-2 infection and vaccination. DOCK8⁺Tfh cells and SLE decreased after conventional or anti-DOCK Ab therapies. Thus, DOCK8⁺Tfh cells newly generated after repeated infection fulfill the criteria (i), (ii) and (iii) as the cause of SLE. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer, with limited responsiveness to immune checkpoint inhibitors (ICIs). Cancer vaccine therapy is a promising novel immunotherapeutic approach that stimulates tumor-specific T cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is overexpressed in malignant tumors but minimally expressed in normal tissues, presents a promising target for immunotherapy. This study aimed to evaluate ROR1 as a target for helper T lymphocyte (HTL)-based peptide vaccine immunotherapy in HNSCC. Methods: ROR1 expression in HNSCC tissues was assessed by immunohistochemistry. A novel ROR1-derived epitope (ROR1_403–417) was identified and used to generate ROR1-reactive HTLs. Functional assays measuring IFN-γ and granzyme B secretion, as well as direct cytotoxicity, were performed. The effects of ICIs on HTL activity were also examined. The presence of ROR1-reactive T cells in the peripheral blood of patients with HNSCC was evaluated. Results: ROR1 positivity rates in HNSCC tissues were significantly higher (80.0%) than those in healthy controls (16.7%), and high ROR1 expression correlated with advanced clinical stages. HTL lines recognized the ROR1_403–417 peptide in a human leukocyte antigen (HLA)-DR-restricted manner, secreted effector cytokines, and exhibited direct cytotoxicity against ROR1+ tumor cells. Dual PD-L1/PD-L2 blockade further enhanced HTL responses. ROR1-reactive T cells were detected in the peripheral blood of patients with HNSCC. Conclusions: ROR1 represents a promising target for immunotherapy in HNSCC. The ROR1_403–417 peptide can elicit ROR1-reactive HTLs that exhibit antitumor responses against HNSCC cell lines, which can be enhanced by ICIs. These findings support the potential of ROR1-targeted peptide vaccine therapy for HNSCC. Full article

Cutibacterium acnes (C. acnes) is a commensal bacterium of the skin microbiota that can transform itself into a pathogen depending on the peculiar susceptibility of the host: it is the sole microorganism so far to be found in the specific organ lesions of sarcoidosis, and C. acnes-induced activation of T-helper-type-1 cell responses is generally higher in patients with sarcoidosis than in healthy subjects. This bacterium acts as an opportunistic agent in several inflammatory conditions other than sarcoidosis, such as prostate cancer and prosthetic joint infections. Both innate and adaptive immunity systems are involved in the pathogenesis of C. acnes-mediated sarcoid lesions, and a seminal role is played by host toll-like receptor (TLR)-2, TLR-4, TLR-6, NOD-like receptors, and mononuclear cell cytoplasmic receptors. This review summarizes current knowledge on the potential cause–effect relationship existing between C. acnes and sarcoidosis, addressing issues of future research directions and novel therapeutic strategies in the management of a complex disease such as sarcoidosis. Full article

Autistic traits—such as social communication deficits, cognitive rigidity, and repetitive behaviors—are increasingly recognized in individuals with schizophrenia, particularly in early-onset cases and subtypes with predominant negative symptoms. This overlap has prompted investigations into shared pathophysiological mechanisms. One emerging area of focus is the role of neuroinflammation in schizophrenia, which may contribute to the manifestation of autistic features. Immunological research indicates the presence of chronic low-grade inflammation, microglial activation, and disruption of the blood–brain barrier in schizophrenia. In particular, an imbalance in T-helper (Th) cell responses—specifically a shift toward Th2 dominance or concurrent Th1/Th2 activation—may lead to dysregulated cytokine production and disturbances in neural function. These findings highlight the importance of exploring immunological pathways as a basis for specific symptom profiles. Additionally, current efforts aim to identify reliable inflammatory biomarkers in schizophrenia that could support diagnosis, predict disease course, and guide treatment. Evaluating neuroinflammatory markers in patients with autistic features may provide novel insight into schizophrenia subtypes and help tailor immunomodulatory therapies. This review explores the expression of autistic traits in schizophrenia and examines the role of neuroinflammation and Th1/Th2 imbalance as potential mechanisms and biomarkers. Full article

Objectives: Given the emerging role of peroxisome proliferator-activated receptor gamma (PPARgamma) in immune regulation and the increasing prevalence of allergic rhinitis (AR), we sought to understand how modulation of the PPARgamma pathway impacts the balance of CD4⁺ T-cell subsets, particularly regulatory T cells (Tregs) and T helper (TH)1, TH2, and TH17 cells, which are key players in the pathogenesis of AR. This knowledge is crucial for developing novel therapeutic strategies targeting the PPARgamma-CD4⁺ T-cell axis to manage AR more effectively. Methods: We used PPARgamma^f/fLyz2-Cre mice for PPARgamma deletion. In an ovalbumin (OVA)-induced AR mouse model, PPARgamma^+/-f/fLyz2-Cre mice were assessed for allergic symptoms, splenic Tregs, and nasal eosinophils. Additionally, the effects of a PPARgamma agonist on the polarization of naïve CD4⁺ T cells were examined. Results: PPARgamma^+/-f/fLyz2-Cre mice showed worsened allergic symptoms, reduced splenic Tregs, and increased nasal mucosa eosinophilic infiltration. PPARgamma agonist treatment promoted naïve CD4⁺ T-cell polarization into Tregs and inhibited their differentiation into TH1, TH2, and TH17 subsets. Conclusions: Our findings indicate that PPARgamma plays a crucial role in regulating TH-cell subsets in AR. PPARgamma agonists could be a potential therapeutic strategy to mitigate allergic inflammation in AR by promoting Treg development and suppressing pathogenic TH-cell responses. Full article

Background: The Bacille Calmette–Guérin (BCG) vaccine is part of the Extended Programme on Immunization (EPI) and as such is generally administered at birth. The global introduction of BCG not only protected many vaccinated infants against severe complications of tuberculosis but also resulted in markedly reduced overall childhood mortality. Studies in human adults determined that BCG vaccination induces epigenetic reprogramming of innate immune cells (also known as trained immunity) and can also enhance T cell responses to both mycobacterial and non-mycobacterial antigens. Goal and Methods: The current study tested the hypothesis that BCG immunization similarly impacts the functionally distinct infant immune system. Towards this goal, we applied RNA sequencing to assess transcriptome changes in circulating CD4⁺ T cells of Malawian infants prior to and 2 to 13 weeks after BCG immunization. Results: In the first three months of life, transcriptome changes of infant CD4 T cells implied a functional shift towards T helper 1 and Th17 immunity. Vaccination with BCG resulted in additional modulation of the CD4 T cell transcriptome and differentially expressed genes could be linked to metabolomic function. Conclusions: These findings are consistent with data reported in BCG vaccinated adults and contribute to the understanding of molecular changes in infant CD4 T cells that may explain the improved capacity of the infant immune system to respond to pathogens after BCG vaccination. Full article

Background/Objectives: The administration of human monoclonal antibodies (mAb) in preclinical pharmacokinetics and toxicology studies often triggers an immune response, leading to the formation of anti-drug antibodies (ADA). To mitigate this effect, we have recently performed and reported on studies using short-term immunosuppressive regimens to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. Here, we report on the development of a semi-mechanistic modeling approach that quantitatively integrates pharmacokinetic and immunogenicity assessments from immune tolerance induction studies to provide a framework for the simulation-based evaluation of different immune induction scenarios for the maintenance of prolonged immune tolerance towards human mAbs. Methods: The integrated pharmacokinetic/pharmacodynamic (PK/PD) modeling approach combined a semi-mechanistic model of the adaptive immune system to predict ADA formation kinetics with a population pharmacokinetic model to assess the impact of the time course of the ADA magnitude on the PK of erenumab in rats. Model-derived erenumab concentration–time profiles served as input for a quantitative system pharmacology-style semi-mechanistic model of the adaptive immune system to conceptualize the ADA response as a function of the kinetics of CD4⁺ T helper cells and T regulatory cells. Results: The model adequately described the observed ADA magnitude–time profiles in all treatment groups and reasonably simulated the kinetics of selected immune cells responsible for ADA formation. It also successfully captured the impact of tacrolimus/sirolimus immunomodulation on ADA formation, demonstrating that the regimen effectively suppressed ADA formations and induced immune tolerance. Conclusions: This work demonstrates the utility of modeling approaches to integrate pharmacokinetic and immunogenicity assessment data for the prospective planning of long-term toxicology studies to support the preclinical development of mAbs. Full article

Infectious laryngotracheitis (ILT) is a severe upper respiratory disease highly contagious in chickens that causes a huge economic impact on the poultry industry all over the world. The current study aimed to design a multi-epitope-based vaccine candidate using envelope glycoprotein B and glycoprotein D of the ILT virus using an immune informatics approach. The glycoproteins B and D are crucial for attachment as well as entry of ILT virus inside the cell, which makes them a potential option for designing vaccine candidates. The prediction of epitopes, viz. helper T lymphocyte, cytotoxic T lymphocyte and interferon-gamma producing epitopes, was performed and high-scoring predicted epitopes were joined in an organized manner using suitable linkers to design the final vaccine candidate. The avian beta-defensin 1 was included as an adjuvant in the amino-terminal of the vaccine design that possesses antimicrobial activity and histidine residues at the carboxy-terminal for the purpose of purification. The final vaccine candidate was evaluated for its physicochemical characteristics, solubility, antigenicity, stability, and allergenicity and validated for its modeling. Molecular docking, binding affinity, and interacting residues between the vaccine candidate and immune receptors, viz. TLR 3, MHC Class I and Class II were assessed. Further, to assess the immune response profile generated by the final vaccine design, an insilico immune simulation study was also performed. The findings of this study revealed that the final vaccine candidate was antigenic, nonallergenic, stable, interacted with immune receptors, and able to produce antibodies as well as cellular immune responses against ILTV infection. Full article

The aim of this systematic review was to evaluate the current evidence for the involvement of epithelial-derived extracellular vesicles (EVs) in Immunoglobulin E (IgE)-mediated allergic sensitisation. Original clinical and research studies specifically examining the effect of epithelial-derived EVs in IgE-mediated allergic sensitisation were included. Non-IgE mediated allergies, abstracts and review articles were excluded. A total of 18 publications were identified from three databases (EMBASE, Web of Science and PubMed) that indicate epithelial-derived EVs have the potential to promote tolerance or allergic sensitisation. For example, epithelial-derived EVs have the potential to promote IgE-mediated allergic sensitisation by delivering mRNAs that promote T helper 2 (Th2) polarisation and cytokine secretion, or promote tolerance through the induction of T regulatory (Treg) cells. The results also indicate that the potential role of epithelial-derived EVs in IgE-mediated allergic sensitisation may be dependent on the barrier, with all publications related to intestinal epithelium driving tolerance, but publications on nasal and bronchial/alveolar epithelia gaving mixed effects. No publications were found on cutaneous epithelia. Taken together, the literature suggests that epithelial-derived EVs play a key role in influencing IgE-mediated allergic sensitisation. Further research examining all epithelial barriers, using both robust human in vitro models that give more biologically relevant information, as well as clinical studies, are required to further characterise the role of epithelial-derived EVs in IgE-mediated allergic sensitisation. Full article