Objective: Heart transplantation remains the definitive treatment for patients with advanced heart failure, but post-transplant complications such as acute cellular rejection (ACR) continue to limit long-term outcomes. The current standard for ACR surveillance is endomyocardial biopsy, which is invasive and associated with procedural risks, variability in interpretation, high healthcare utilization costs, and poor patient tolerability. For these reasons, there is increasing interest in identifying non-invasive biomarkers that can reliably detect ACR. This review details the range of non-invasive methods for detecting ACR and to provide practical guidance for clinicians considering a transition to less invasive monitoring protocols following heart transplantation. Methods: We conducted a narrative review of published literature focusing on non-invasive biomarkers for ACR in heart transplantation. We specifically focused on evaluating donor-derived cell-free DNA, gene expression profiling, plasma microRNA, metabolomics, cytokines and chemokines, and extracellular vesicle approaches, with emphasis on clinical applicability, diagnostic performance, and limitations. Results: Our review identified several promising non-invasive biomarkers for ACR detection, with donor-derived cell-free DNA and gene expression profiling showing the most advanced clinical integration. Emerging approaches such as microRNA profiling, metabolomics, cytokine or chemokine panels, and extracellular vesicle analysis demonstrate potential in early-phase studies but require further validation. Most biomarkers exhibited high negative predictive value, though sensitivity and positive predictive values remained variable across platforms along with their applications in the early perioperative and late follow-up periods. None of the biomarker platforms distinguish ACR from antibody mediated rejection. Practical challenges including cost, assay standardization, and limited availability continue to impact widespread adoption. Conclusion: Non-invasive blood-based biomarkers show promise for improving acute cellular rejection surveillance in heart transplant recipients. While markers such as dd-cfDNA, extracellular vesicles, and microRNAs have demonstrated encouraging early results, their clinical use remains limited by variable inadequate sensitivity, low positive predictive value, inability to distinguish ACR from AMR, and lack of standardization. Ongoing investigations are expected to refine their diagnostic performance and guide their integration into routine clinical care.
Current therapies for antibody-mediated autoimmune diseases largely rely on broad immunosuppression or lineage-wide B-cell depletion. These approaches are associated with increased risks of infection and other adverse effects. This commentary focuses on Chimeric Autoantibody Receptor (CAAR) T-cell technology as a precision immunotherapy that selectively eliminates pathogenic autoreactive B-cell clones while preserving protective immunity. Using Pemphigus Vulgaris (PV) as a representative model, CAAR-T cells engineered to express desmoglein 3 (Dsg3) demonstrate antigen-specific targeting of B cells expressing anti-Dsg3 B cell receptors. Notably, these cells maintain cytolytic efficacy despite high circulating autoantibody titers and show tissue selectivity, sparing keratinocytes, potentially due to biophysical constraints governing immune synapse formation. We further discuss key translational challenges, including manufacturing complexity, the presence of additional pathogenic antibody populations (e.g., anti-Dsg1), and long-term cellular persistence. Collectively, CAAR-T technology represents a mechanistically distinct and potentially scalable therapeutic paradigm for antibody-mediated autoimmune disorders, emphasizing antigen-specific immune editing over global immune suppression.
The recently published review by Baeten et al. outlines the scientific and translational evidence supporting the role of cyclin dependent kinase (CDK) 4/6 in rheumatoid arthritis (RA) pathology, and it discusses how this stromal (synovial fibroblast) target provides the basis for a drug class with a novel non-immunosuppressive mechanism of action that could change the current immunosuppressive treatment paradigm in RA. The early clinical trial (phase 1b) of the next generation CDK4/6 inhibitor, ELV001, showed the rapid clinical improvement, and ELV001 was well tolerated with no clinically meaningful safety signals. This warrants further clinical evaluation of ELV001 in a larger group of patients with active RA, and the phase 2 study with ELV001 (START SYNERGY) is currently in progress. This commentary article on the published review by Baeten et al. describes additional perspectives, in particular, what is the next step in the clinical development of CDK4/6 inhibition for RA, as well as where CDK4/6 inhibition could be positioned in the RA treatment algorithm. A novel combination strategy that pairs systemic immunosuppression (current therapeutic options) with a synovial-targeted non-immunosuppressive anti-rheumatic therapy (with ELV001) is expected to leverage orthogonal mechanisms of action, and this approach would represent a distinct therapeutic paradigm for RA.
1,1-Bis(3’-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) compounds in the presence or absence of a 4-hydroxylphenyl group bind both orphan nuclear receptor 4A1 (NR4A1) and NR4A2. In cancer cells, these compounds bind and inactivate pro-oncogenic NR4A1 and NR4A2 and downstream pathways acting as inverse agonists that inhibit cancer cell growth, survival, migration and invasion, and induce ferroptosis. Similar results are observed in endometriotic cells where the DIM-3,5 dual NR4A1/2 ligands inhibit NR4A1/NR4A2-mediated pro-endometriotic genes and pathways. The potency of these DIM-3,5 dual NR4A1/NR4A2 ligands is also observed in tumor infiltrating lymphocytes where both receptors are expressed and regulate comparable functions.
The “Generation Gold Standard” (GGS) initiative, launched by NIH and BARDA, seeks to advance pandemic preparedness through β-propiolactone (BPL)–inactivated whole-virus vaccines. While positioned as a transformative platform, GGS relies on legacy technology with known limitations, including waning immunity and limited cross-variant protection, as seen in COVID-19 vaccines such as CoronaVac. This Perspective critiques GGS’s scientific rationale and transparency, arguing that it overlooks recent advances in epitope-based vaccinology, AI-driven design, and systems biology. By prioritizing scalability over immunological precision, GGS risks delaying progress toward more effective, adaptable vaccine platforms. We propose a forward-looking approach that conserved epitope targeting, antigen sequence optimization, multi-omics integration, and transparent preclinical validation to enhance efficacy and public trust. As the window for applying lessons from COVID-19 narrows, redirecting resources toward mechanistically innovative platforms is essential for global health security.
Glioblastoma multiforme (GBM), the most aggressive primary brain malignancy, continues to pose an insurmountable therapeutic challenge due to its profound intratumoral heterogeneity, inherent drug resistance, and highly immunosuppressive tumor microenvironment [1]. The urgent need to identify actionable molecular targets to overcome these barriers has driven intensive research in GBM immunology and precision oncology. As core regulators of chromatin dynamics, inflammation, and immune modulation, the high mobility group (HMG) family is well-studied in cancer. Within it, HMGB1 and HMGB2 have been extensively investigated in GBM: HMGB1 drives GBM’s immunosuppressive TME via TLR4/Akt signaling, while HMGB2 correlates with GBM stem cell maintenance and radioresistance [2–4]. In contrast, the undercharacterized HMGB3 has only recently emerged as a potential onco-immunological target. Studies in non-small cell lung cancer (NSCLC) and breast cancer show HMGB3 overexpression links to tumor immune evasion and poor prognosis [5]. Against this backdrop, Wang et al.’s study, titled “Comprehensive bioinformatics analysis identified HMGB3 as a promising immunotherapy target for glioblastoma multiforme,” published in Discover Oncology, represents a significant step forward [6]. By leveraging multi-omics data and robust bioinformatics tools, the study systematically characterizes the role of HMGB3 in GBM pathogenesis, immunosuppression, and therapeutic responsiveness. This commentary evaluates the study’s core strengths, critically examines its limitations, and proposes targeted future directions to fully realize the translational potential of HMGB3 in GBM treatment. All analyses are strictly based on the content of the referenced manuscript throughout the study.
The article "USP50 regulates NLRP3 inflammasome activation in duodenogastric reflux-induced gastric tumorigenesis" published in Frontiers in Immunology, has greatly piqued our curiosity. Zhao et al. describe how bile acids elevate ubiquitin-specific protease 50 (USP50) in macrophages, facilitating NLRP3 inflammasome assembly, HMGB1 release, and activation of PI3K/AKT and MAPK/ERK pathways that may promote gastric cancer progression. In their study, the authors used multiple cell lines for in vitro analyses, including the murine macrophage line RAW264.7, human monocytic U937 cells, and human embryonic kidney 293T cells. They reported detectable ASC protein in RAW264.7 cells and utilized U937 and 293T cells for key ASC-focused mechanistic assays (e.g., ASC-USP50 interaction, ASC specks formation, ASC oligomerization, and ASC ubiquitination); additionally, canonical readouts of inflammasome activation (including cleaved caspase-1 and mature IL-1β) were reported in RAW264.7 cells. However, ample evidence confirms that RAW264.7 cells lack ASC expression due to epigenetic silencing and are widely recommended as a negative control for ASC detection. Thus, the detection of ASC signals and downstream inflammasome activation in RAW264.7 cells is inconsistent with established characteristics of this cell line, and this discrepancy may stem from antibody cross-reactivity, cell contamination, or inaccurate cell line characterization. Notably, this limitation is specific to the RAW264.7-based ASC-dependent inflammasome experiments and does not affect the validity of other key findings in Zhao et al.’s study, including in vivo mouse data, clinical sample analyses, and investigations into the PI3K/AKT and ERK tumor-related pathways. Thus, verification of RAW264.7 cell line identity and ASC expression status is essential solely for consolidating the ASC-related inflammasome conclusions.
Introduction: Inflammation is a natural defense response of higher organisms to various external aggressors, such as physicochemical factors or microbial infections. The objective of this work is to enhance a medicinal formula derived from a mixture of Gossypium hirsutum L. and Terminalia catappa L. by evaluating and improving its anti-inflammatory activity. Methods: The two plant species selected for this study are Gossypium hirsutum L. and Terminalia catappa L. The aqueous extract of the medicinal formulation was obtained by mixing 42 g of Gossypium hirsutum L. powder with 24 g of Terminalia catappa L. pericarp powder, then 4.5 L of distilled water was added to this mixture and boiled for 30 min. The anti-inflammatory activity in rats was evaluated using the 1% carrageenan edema induction method, which triggers an inflammatory response. Calipers were used to assess the size of the edema in rats. The C-reactive protein (CRP) assay was performed using a COBAS 311 (Roche Hitachi) analyzer. Results: The percentage of inhibition of AEGhTc 300 mg/kg of pw was 42.50 ± 05.70 % after 3 hours compared to 26.73± 10.00% for diclofenac at 10 mg/kg (P<0.05). It is important to note that the 300 mg/kg dose of AEGhTc (0.03 ± 0.02 mg/l) induced the lowest CRP concentration compared to the highest doses of AEGhTc 1000 and AEGhTc 2000 (0.28 ± 0.15 mg/l and 0.07 ± 0.04 mg/l). Conclusion: The aqueous extract of the mixture of Gossypium hirsutum L. and Terminalia catappa L. exhibited significant anti-inflammatory activity at a dose of 300 mg/kg of AEGhTc.
Background: Sepsis arises when an uncontrolled systemic immune response to infection leads to life-threatening organ dysfunction. Despite available therapies, sepsis remains a major global health challenge with high mortality. Further research into molecular mechanisms, diagnostic and prognostic biomarkers, and novel treatments is critical to improve outcomes. Main Text: This review explores recent advances in preclinical sepsis research, which provides pivotal insights to guide clinical practice. Studies have revealed intricate molecular pathways underlying dysregulated inflammation, coagulation, mitochondrial dysfunction, and cell death signaling that drive sepsis progression. This has enabled identification of potential therapeutic targets like toll-like receptors, inflammasomes, and endothelial dysfunction. Innovative pharmacological agents, immunomodulatory therapies, and cell-based treatments have shown promise in preclinical evaluations. Precision medicine approaches leveraging genomics, biomarkers, and AI may further enable personalized care. To study sepsis, researchers utilize animal models and in vitro systems, which continue to improve in replicating human pathophysiology. However, enhanced translation of preclinical findings to patients remains a barrier. Short conclusions: Preclinical research has uncovered novel strategies to combat sepsis, but ongoing efforts are vital to translate these scientific innovations into clinical impact. A multifaceted approach can help overcome current management limitations and save lives. Further unraveling molecular mechanisms, developing new therapies, and bridging preclinical-clinical gaps
The skin inflammasome is a critical component of the immune system, pivotal not only in responding to acute threats but also in contributing to the chronic inflammation associated with aging. This review provides an in-depth examination of the molecular mechanisms of the skin inflammasome, detailing its role in dermatological conditions like acne, atopic dermatitis, psoriasis, and hyperpigmentation, as well as its impact on systemic aging. We explore how longevity science is now focusing on these pathways to enhance skin resilience and potentially extend human health span. This involves innovative approaches such as drug repurposing, understanding the modulation of skin inflammation, and recognizing the systemic health reflections through the gut-skin axis.
Coenurosis is a socioeconomically significant zoonotic disease. The neuroimmunopathology of this disease is complex, involving a dynamic interplay between the parasite and immune system dynamics of several hosts. Although current diagnostic and treatment approaches remain inadequate, there is some solace in the recent investigations leading to proper prevention and control mechanisms of coenurosis with the One Health philosophy, integrating veterinary medicine, parasitology, immunology, community medicine, and public health—while also addressing other neglected trematode pathogens. Comprehensive research into the molecular mechanisms of coenurosis pathogenesis is still required to develop accurate diagnostic tools and effective therapeutic approaches, ultimately enabling adequate public health intervention strategies to limit the effect of this disease.
Innate immunity is the oldest form in evolution and is present in all multicellular organisms, including vertebrates and invertebrates. Although humans are the most recent evolutionary phylum, there is abundant evidence of a genetic inheritance shared between invertebrates and humans. There is correspondence between molecular pathways associated with the recognition systems of pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs) and Peptidoglycan recognition proteins (PGRPs). From a molecular point of view, intimate associations occur in key components of the molecular signaling process such as signal transducer and activator of transcription (STAT), Janus kinase (JAK), c-Jun N-terminal kinase (JNK), Toll-like receptor (TLR). Using these parallels is essential for a better understanding and conservation of living organisms, establishing essential biotechnological strategies for the progress of the understanding of the immune system.
Background: Chronic Spontaneous Urticaria (CSU) is a multifactorial disease with an incompletely understood etiology. COVID-19 vaccines can influence the immune system. This study evaluates the risk factors and comorbidities associated with CSU in patients who developed CSU following COVID-19 vaccination or infection. Methods: This cross-sectional study was conducted in Shiraz, Iran, and enrolled thirty-six adult patients with new-onset CSU developing within two months of COVID-19 vaccination or infection, persisting for at least six weeks. Diagnosis of CSU was confirmed by allergy and clinical immunology subspecialists based on EAACI guidelines. Clinical history, physical examination, laboratory findings, and skin prick test (SPT) results were collected. Associated diseases, allergy history, and inflammatory markers were also assessed. Results: The mean age of participants was 38.17 ± 15.50 years. The median onset of CSU symptoms was 7.0 days (5.25, 12.25) for the AstraZeneca group and 7.0 days (2.50, 10.50) for the COVID-19 infection group, earlier than in other vaccine groups. CSU occurred more frequently after the first vaccine dose (P≤0.001) and more commonly at night. Most patients (66.7%) had a pruritus score of 3; 47.2% had a wheal score of 2. A history of allergy, atopy, or comorbidities was present in most patients. Positive SPT to aeroallergens was found in 63.9%. Laboratory data for autoinflammatory markers (e.g., ESR, CRP) were collected but did not show significant elevation. Daily use of second-generation H1 antihistamines controlled symptoms in 75% of patients. Conclusion: CSU was most likely to develop within 6.5 days following the first dose of COVID-19 vaccination, especially AstraZeneca and Sinopharm. The high rate of positive SPT and allergy history suggests a predisposing allergic background. Most cases were not severe and responded well to antihistamine therapy.
Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment by harnessing the host immune system to target malignancies. Melanoma, head and neck squamous cell carcinoma (HNSCC), and triple-negative breast cancer (TNBC) were among the first solid tumors to gain regulatory approval for ICIs due to their immunogenicity and unmet clinical needs. Melanoma exemplifies the success of ICI therapy, with durable responses driven by its high mutation burden and neoantigen landscape, yet both primary and acquired resistance remain major challenges. In contrast, HNSCC demonstrates clinically meaningful but modest responses in the context of a highly immunosuppressive tumor microenvironment, while TNBC derives limited benefit from ICI, often requiring combination strategies to achieve efficacy. Resistance to ICIs arises from complex tumor-intrinsic, microenvironmental, and systemic mechanisms that collectively undermine effective anti-tumor immunity. This review highlights both shared and cancer-specific mechanisms of ICI resistance across melanoma, TNBC and HNSCC. We also discuss emerging strategies, including combination therapies, neoantigen-based vaccines, adoptive T cell therapies, and precision oncology approaches, to overcome resistance and improve clinical outcomes. Together, these insights provide a framework for optimizing immunotherapy and advance durable benefit in these challenging malignancies.
Influenza and other seasonal respiratory viruses affect millions annually. While age is generally known to be correlated with risk and outcome, the mechanisms underlying these differences, especially in the infected, have been poorly defined. Previous studies have focused primarily on cell-subset shifts in older adults, leaving a gap in understanding of how cytokine responses vary across the full age spectrum. Cytokine data from Luminex assays were compiled from Stanford clinical studies and after batch control filtering, the dataset included 181 healthy individuals (ages 4-97) and 27 symptomatic individuals (mostly confirmed influenza, ages 14-77). Ordinary least squares regression was applied to assess cytokine differences due to infection status, age, and their interaction, with statistical significance defined as p<0.05. The results illustrated that pro-inflammatory cytokines were found to be significantly elevated in infected individuals, with a trend of stronger effects in the young supported by comparison of intercepts between the regressions for the healthy and infected cohorts. The concept of inflammaging was also seen through several biomarkers with significant non-zero slopes in healthy cohorts that were not well-established in prior research. Our findings reveal both expected and novel cytokine behavior in influenza infection across a wide range of ages. By incorporating younger individuals and including age as a continuous variable, the study makes progress towards a deeper understanding of the changes in the immune system and its response to influenza across the lifespan.
