TH17 cytokines are implicated in systemic lupus erythematosus (SLE) pathogenesis. Mercury is an environmental factor associated with the exacerbation of SLE pathology, potentially by regulating the ThH17 pathway. Humans are primarily exposed to mercury from dental amalgams and fish consumption. Fish are also a rich source of the n-3 long chain polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and have been shown to reduce SLE disease symptoms. This pilot in-vitro investigation isolated peripheral blood mononuclear cells (PBMC) from SLE patients (N = 15) and healthy controls (HC, N = 15). The cells were stimulated with lipopolysaccharide (LPS) and exposed to 200 nM of mercury (II) chloride (HgCl) for 24 hr, with or without pre-exposure (24 hr) to either EPA or DHA at 100 μM each. The TH17-associated cytokines were quantified in the PBMC supernatants. Pre-exposure to EPA resulted in significantly lower concentrations of IL-27 in supernatants of LPS-HgCl treated PBMC from SLE patients (29.58 [± 22.62] pg/mL) compared to HCs (51.63 [± 42.96] pg/mL) (p = 0.04). While DHA-LPS-HgCl had significantly lower IL-27 concentrations compared in LPS-HgCl in PBMC from SLE patients and HCs, there was no significant difference between groups. IL-27 exhibits pro/anti-inflammatory effects on the immune system. We suggest that the observed reductions in IL-27 concentrations following EPA-LPS-HgCl treatment support the protective role of n-3 PUFA in autoimmune responses.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants associated with immunotoxicity; however, their effect on innate immune function in fish at ambient concentrations remains unclear. Perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS) are legacy PFAS prevalent in aquatic ecosystems and have been well studied in zebrafish at high concentrations.  The present study evaluated the effects of embryonic exposure (morula through 2 days post hatch) to environmentally relevant concentrations of PFOS or PFHxS (∼0.8-800 ng/L) on the innate immune response of zebrafish (Danio rerio) and fathead minnow (Pimephales promelas). Impacts on the innate immune response were assessed by quantifying neutrophil recruitment and an in vivo respiratory burst. Neutrophil migration was impacted more in fathead minnows, while zebrafish had greater alterations in the respiratory burst. Fathead minnows were more sensitive than zebrafish with respect to the overall response, and PFHxS was slightly more immunotoxic than PFOS. In silico comparison of the peroxisome proliferator-activated receptor (PPARΥ) predicts that the fathead minnow receptor could have a stronger ligand-binding affinity. These findings demonstrate that environmentally- relevant PFHxS or PFOS exposures can suppress innate immune function in a species specific and non-monotonic dose response, potentially increasing susceptibility to pathogen-induced mortality in fish.

Exposure to World Trade Center (WTC) dust following the September 11, 2001 attacks has been linked to numerous negative health outcomes in First Responders, including cognitive impairment disproportionately impacting First Responders with aging. However, the mechanisms underlying neurocognitive decline remain poorly characterized. This investigation examined the effects of WTC dust exposure on myelin integrity and neuroinflammatory signaling in twelve-week old male spontaneously hypertensive rats. To model Ground Zero exposure in First Responders, WTC dust was intratracheally administered for two consecutive days (2.43 [± 0.78] mg/day). It was hypothesized that WTC dust exposure would enhance neuroinflammatory signaling and promote an earlier, progressive decline of myelin abundance. Rats were euthanized at 3 and 12 mo post-exposure. Changes in myelin abundance (Black-Gold II), myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), and microglial responses (ionized calcium-binding protein; Iba1) were assessed through immunohistochemical staining, and cytokines were measured in brain homogenates. WTC dust exposure resulted in increased Black-Gold II staining at 3 mo despite no changes in MBP or CNPase. In contrast, microglial activation and IL-1β concentrations were elevated in dust-exposed rats at 12 mo. Collectively, these data suggest WTC dust exposure induces sustained neuroinflammatory signaling and may elicit a compensatory myelin response indicative of early neurodegeneration.

Atopic dermatitis (AD) is primarily a TH2-driven pathology, yet seasonal factors may activate additional immune pathways. This study examined seasonal variation in plasma cytokines in adults with AD treated with dupilumab (N = 20), AD patients without systemic therapy (N = 15), and healthy controls (N = 34). Cytokines (interleukin [IL]-17A, thymic stromal lymphopoietin (TSLP), interferon (IFN)γ, tumor necrosis factor (TNFα), IL-2, IL-6, IL-12p70, IL-23, and IL-31) were measured during summer and winter under unstimulated and phorbol 12-myristate 13-acetate (PMA)/ionomycin-stimulated conditions. Dupilumab-treated patients showed significant winter increases in stimulated IFNγ, TNFα, IL-2, IL-6, and TSLP, indicating preserved inducible TH1/innate and alarmin activity. Untreated AD patients displayed winter elevation of stimulated IL-6 and unstimulated IFNγ, while healthy controls showed broad winter up-regulation of stimulated TH1/innate cytokines. Higher winter cytokine levels tended to occur in dupilumab-treated patients with scoring atopic dermatitis (SCORAD) > 10 (evaluation of severity AD - scoring of atopic dermatitis). The findings obtained here suggest that seasonal environmental factors modulate immune responses even under biologic therapy, supporting season-aware, individualized AD management.

Bispecific CD3 T-cell engagers (TCE) redirect endogenous T-cells to tumor cells and have demonstrated substantial clinical activity, but their mechanism of action also drives immune-mediated toxicities that are often underpredicted in nonhuman primate (NHP) studies. To investigate the biological basis of this translational gap, we performed a comparative evaluation of human and cynomolgus macaque T-cells using immunophenotyping, functional characterization with TCE, and single-cell transcriptomic profiling. Human and NHP donors showed broadly similar T-cell frequencies, subset distributions, and robust responses to polyclonal stimulation, confirming preserved intrinsic effector capacity in both species. However, across multiple CD20-, BCMA-, and GPRC5D-targeted TCE, human PBMC consistently exhibited greater cytotoxic potency and markedly elevated IFNγ production relative to NHP. Transcriptomic analyses revealed that although global TCR signaling architecture is conserved, human T-cells exhibit increased expression of some proximal signaling mediators, including LAT, PAG1, SKP1, and PI3K-family genes. These functional and molecular differences provide a mechanistic explanation for reduced pharmacologic responsiveness observed in NHP toxicology studies. While NHP studies can provide valuable insight for identifying antigen-dependent cytotoxic hazards, their limitations underscore the increasing importance of incorporating human-relevant models in nonclinical safety assessment.

The fire ant Solenopsis invicta is an aggressive invasive species whose venom frequently triggers hypersensitivity reactions, including severe anaphylaxis. In endemic regions, its stings represent a significant cause of Hymenoptera-related allergy. Four venom allergens have been identified - phospholipase A1 (Sol i 1), antigen 2 (Sol i 2), antigen 3 (Sol i 3), and antigen 4 (Sol i 4) - with Sol i 3 recognized as the predominant sensitizer. However, the molecular determinants that drive Sol i 3 allergenicity and its potential cross-reactivity with other Hymenoptera venoms remain insufficiently understood. This study identified the linear immunoglobulin E (IgE) epitopes of Sol i 3 and examined their recognition by sera from yellow jacket venom (YJV) - and Polistes wasp-allergic patients. Two linear epitopes were mapped: Sol i 3_e1 (ELRQRVASGKEMRG) and Sol i 3_e2 (WAKTTKIGCGRIMF). Although Sol i 3 exhibits limited sequence and structural similarity to other antigen 5 proteins, it contains a conserved immunoreactive core (WAKTTK), analogous to the WAKTKE motif described for the allergen Poly p 5 from Polybia paulista. This conserved region may represent a shared epitope contributing to cross-reactivity among Hymenoptera venoms. Consistently, sera from P. dominula-sensitized patients and YJV-sensitized patients recognized Sol i 3_e2. These findings define key B-cell epitopes of Sol i 3 and reveal a conserved motif that may underlie cross-reactivity, offering implications for improved diagnosis and immunotherapy.

Neutrophil functions are tightly regulated by numerous membrane receptors, the activation of which determines the appropriate response to various endogenous and exogenous factors. Accumulating evidence indicates that environmental endocrine-disrupting chemicals (EDC) can modulate immune system function, inter alia, by influencing neutrophil activity. Imazalil (IMZ), an EDC known to exhibit antagonistic activity against the androgen receptor expressed on neutrophils, exemplifies a compound that may potentially affect these processes. The aim of this study was to evaluate the effect of imazalil and testosterone on the expression of CD molecules associated with fundamental neutrophil functions. Whole blood collected from healthy men served as the study material. Plasma imazalil concentrations were determined using GC-MS. Isolated neutrophils were incubated in the presence of IMZ (at a concentration established in the present study: 28 ng/ml) or testosterone (at a physiological concentration). Cytometric analysis revealed that exposing cells to imazalil resulted in an elevated percentage of neutrophils expressing CD14, CD66b, CD62L, and CD284, accompanied by a decrease in the percentage of cells expressing CD10, CD11c, CD15, CD49d HLA-DR, as well as a reduction in MPO[+] neutrophils. No changes in the percentage of neutrophils expressing the analyzed molecules were observed in the presence of testosterone. In conclusion, imazalil modulates the neutrophil immunophenotype, which may inhibit functions such as adhesion, migration, chemotaxis, and phagocytosis. Consequently, this may predispose individuals exposed to this compound to innate immunity disorders.

Micro- and nanoplastics (MNP) are ubiquitous environmental stressors increasingly detected in human tissues and directly linked to clinical cardiovascular events. This review proposes immunometabolic reprogramming as the central nexus through which MNP drive systemic immune dysregulation and chronic inflammation. Upon entering via multiple routes, MNP selectively sequester in immune organs, disrupting mitochondrial quality control via Drp1-mediated fission and activating the cGAS-STING pathway. Furthermore, MNP induce a pseudohypoxic state that stabilizes HIF-1a, driving a glycolytic "Warburg-like" shift that promotes pro-inflammatory macrophage polarization. These intracellular perturbations are further amplified by "lipid corona" formation and gut microbiota dysbiosis, which depletes anti-inflammatory short-chain fatty acids. Collectively, this systemic immunometabolic remodeling provides a mechanistic framework for understanding MNP-related risks for cardiovascular, metabolic, and neurodegenerative disorders.  This review emphasizes the necessity of integrating immunometabolic parameters into future environmental health risk assessment frameworks.

Fine particulate matter (PM2.5) exposure contributes to over 4 million premature deaths annually, yet the mechanistic role of lung microbiota in PM2.5-induced pulmonary inflammation remains poorly understood. In collaboration of 16S rRNA and single-cell RNA multi-omics analysis and in vivo/in vitro experimental validation with antibiotic intervention strategies, the study here examined PM2.5-microbiota interactions in murine PM2.5 exposure models and cellular systems. It was found that PM2.5 exposure induced lung microbiota dysbiosis characterized by Gram-negative bacterial expansion, particularly Proteobacteria dominance, accompanied by reduced microbial diversity. scRNA analysis revealed coordinated activation of TLR4/MyD88/NLRP3 inflammatory signaling pathways and p53/p21/p16-mediated cell cycle arrest. Moreover, PM2.5 exposure activated NLRP3 inflammosome-dependent macrophage pyroptosis as evidenced by increased interleukin (IL)-1β, IL-18, caspase-1, and GSDMD expression. In vitro studies demonstrated that the inflammatory changes induced by PM2.5 exposure were statistically indistinguishable from those of LPS-positive controls, confirming endotoxin-like mechanisms. Critically, antibiotic pretreatment effectively attenuated PM2.5-induced inflammatory responses, cell cycle arrest, and tissue pathology, which established causality between microbiota disruption and pulmonary dysfunction. In conclusion, this study revealed lung microbiota dysbiosis as a critical mediator of PM2.5-induced pulmonary inflammation through Gram-negative bacterial expansion and subsequent endotoxin-like activation of inflammatory cascades, thereby providing novel mechanistic insights and potential microbiome-targeted therapeutic strategies for air pollution-associated respiratory diseases.

Drug-induced autoimmune (DIA) toxicity represents a significant challenge in drug safety evaluation, and traditional autoantibody biomarker antinuclear antibodies (ANA) exhibits limitations in DIA assessment, highlighting the urgent need for more reliable biomarkers. This study employed d-penicillamine to induce an autoimmune disease model in Brown Norway (BN) rats and systematically investigated the expression changes of autoimmunity-related microRNAs (miRNAs) in spleen, exploring their potential value as novel biomarkers for predicting DIA toxicity. A total of 30 male BN rats were randomly divided into control group (0 mg/kg), low-dose d-penicillamine group (150 mg/kg), and high-dose group (450 mg/kg), with necropsy performed at days 7 and 14 post-administration. ANA detection, histopathological examination of spleen, surface immune-related proteins CD11a and CD278 on splenic CD3[+]CD4[+] T-cells, and miRNA expression profiling in spleen tissue were conducted. Receiver operating characteristic (ROC) curves were plotted to evaluate the correlation of ANA and miRNAs with the degree of splenic pathological damage, and the relationships between miRNAs and both ANA and CD11a/CD278 were analyzed. The results demonstrated that 16 miRNAs were significantly up-regulated in spleen tissue, among which 13 miRNAs showed superior predictive performance (AUC = 0.828-0.898) compared to the traditional biomarker ANA (AUC = 0.783), with most of these miRNAs exhibiting correlation with CD11a/CD278 expression. These findings indicate that aberrant miRNA expression in the d-penicillamine-induced autoimmune disease preclinical model in BN rats holds potential for early prediction of DIA toxicity, with some miRNAs demonstrating higher diagnostic value than ANA, thereby providing novel molecular biomarker candidates for early diagnosis of DIA toxicity.

Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality, particularly in older adults and patients with chronic co-morbidities. Cytokine patterns and simple hematological indices may improve risk stratification beyond conventional clinical scores. In this prospective single-center study, 41 adults with CAP treated at Kaunas Hospital of Lithuanian University of Health Sciences between November 2024 and March 2025 were enrolled. Clinical data, pneumonia severity index (PSI), complete blood count-derived indices (neutrophil-lymphocyte ratio [NLR], platelet-lymphocyte ratio [PLR], systemic immune-inflammation index [SII]), and serum concentrations of interleukin (IL)-6, IL-8, interferon (IFN)-γ, and G-CSF were obtained on admission (Visit 1) and after 7 days of treatment (Visit 2). Patients were stratified by age (≤65 vs >65 years), co-morbidities, and PSI class. Non-parametric tests and Spearman correlations were applied. The results indicate that patients with co-morbidities and those > 65 years had significantly higher IL-6 levels than younger and non-comorbid patients. IL-6, IFNγ, and G-CSF concentrations were highest at admission and declined by day 7, particularly in PSI Class II patients. Higher PSI classes were associated with increased IL-8, IL-6, and IFNγ. NLR and SII were significantly higher in older patients and in PSI III-IV compared with PSI I-II. IL-6 and G-CSF showed strong positive correlations with NLR and SII, especially in elderly and comorbid patients, whereas PLR displayed weaker and less consistent associations. From these data, it is concluded that in CAP, serum IL-6, IFNγ, and G-CSF reflect age, co-morbidity burden, and disease severity, while NLR and SII closely mirror cytokine-driven systemic inflammation. These readily available indices may serve as cost-effective prognostic markers and, combined with cytokine profiling, could enhance early risk stratification and guide individualized management in CAP.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by impaired skin barrier function, persistent inflammation, and increased vulnerability to environmental irritants. Chronic inflammation in AD can also contribute to premature skin aging by promoting collagen degradation, wrinkle formation, and reduced skin elasticity. Conventional treatments, including topical corticosteroids, may lead to adverse effects with long-term use, underscoring the need for safer, sustainable alternatives. Glycomacropeptide (GMP), a bioactive peptide derived from κ-casein during cheese production, has attracted interest for its anti-inflammatory, antioxidant, and skin barrier-supporting properties. Evidence from in vitro, in vivo, and limited clinical studies suggests that GMP may modulate inflammatory responses, attenuate oxidative stress, support collagen integrity, and promote wound healing. Its amphiphilic nature also enables its use as a natural emulsifier in topical formulations. In addition, the utilization of GMP contributes to sustainable development by valorizing dairy byproducts. This narrative review synthesizes current literature on GMP's dermatological potential, with a focus on its applicability in AD management and skin aging mitigation, while identifying research gaps and directions for future clinical evaluation.

This review was undertaken because it is known that high doses of atrazine activate the HPA axis, leading to increased corticosterone secretion, which could result in immunosuppression. The mammalian immunotoxicity of atrazine was evaluated based on in vitro and in vivo studies and the association between chlorotriazine use and the risk of cancer in humans based on epidemiological studies. In vitro studies reported that μM concentrations of atrazine may adversely affect cytokine production, lymphocytes, and dendritic cell function. However, there were no consistent patterns of effects of the chlorotriazines on the developing or mature immune system in sub-chronic, chronic, and lifetime animal studies. In a detailed immunotoxicity study on atrazine in rats, there were no effects of atrazine treatment on T-cell-dependent, IgM antibody production or natural killer cell activity. Based on the compendium of toxicology data reviewed, it was concluded that atrazine is unlikely to be immunotoxic at any dose to which humans might realistically be exposed. This conclusion was supported by epidemiological studies indicating that there was no consistent association between occupational exposure to atrazine and cancers of the immune system.