Search Results (73)

In acute lymphoblastic leukemia (ALL), neutropenia and fever of unknown origin may occur, indicating the use of antimicrobials to control a probable infection. However, in 60–70% of cases there is no obvious infectious focus so treatment is empirical, increasing the risk of developing systemic inflammatory response syndrome (SIRS). The construction of a prognostic model of fever and development of SIRS based on the identification of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs) and inflammatory cytokines, can help identify children with ALL and fever or SIRS and who do not have an infection. A cohort of 30 children with recently diagnosed ALL and absence of infectious microorganisms before starting the remission induction phase was studied. Two groups were identified: (1) a group with SIRS (fever, tachycardia, tachypnea, and leukopenia, without focus of infection) and (2) a group without SIRS. The DAMPs, namely HMGB1 and S100A8 proteins, were quantified by ELISA and inflammatory mediators were determined by multiple protein analysis. The medians of DAMPs and inflammatory mediators in children with SIRS were higher than in children who did not have SIRS, and the delta values of the biomarkers studied in patients with and without SIRS showed important differences, with statistically higher medians in patients with SIRS compared to those without SIRS. HMGB1 together with IL-1β, IL-8, IL-10, and MCP-1 can serve as biomarkers to identify children with ALL and fever or SIRS who should not receive antimicrobial treatment because the origin of their fever is not due to an infectious agent. Full article

Asthma is defined as a chronic respiratory disease, the processes of which are mainly related to the hyperreactivity of the immune system. Airway hyperresponsiveness and remodeling are other hallmarks of asthma that are strongly involved in the progression of the disease. Moreover, asthma is associated with the occurrence of atopic dermatitis, chronic sinusitis, allergic rhinitis, and a high profile of T2-type cytokines, such as IL-4, IL-5 and IL-13. The hyperresponsiveness of the immune system is a consequence of aberrant levels of alarmins, endogenous molecules that induce pro-inflammatory responses. They are released as a result of a defect or cell death, leading to the initiation of an inflammatory reaction. High-mobility group box 1 (HMGB1), S100 proteins, interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and IL-25 bind to various receptors, influencing the behavior of immune cells, resulting in stimulated migration and activation of these cells. In this review, we will discuss the potential role of alarmins in the pathogenesis of asthma. Full article

Ostertagia ostertagi, also known as the brown stomach worm, causes significant pathology in the abomasum, resulting in production and nutritional losses in cattle. Alternative control measures, such as vaccination, are urgently needed because of rapidly growing anthelmintic drug resistance. There is a need to understand host responses to the infection, especially immune responses, to advance vaccine discovery and design. Therefore, the present study investigated comprehensive changes in gene transcription in the abomasal mucosa of cattle infected with O. ostertagi at 0, 3–5, 7–9, 10, and 21 days post-infection (dpi) using RNA sequencing (RNA-seq). Compared to uninfected controls, infected animals exhibited significant increases in differentially expressed genes (DEGs) throughout the infection period. Infection induced more upregulated than downregulated genes in the abomasal fundic mucosa (FUN) when compared to the abomasal pyloric mucosa (PYL). The largest transcriptional changes occurred between 7–9 and 10 dpi during the final development of the L4 and their emergence from the gastric glands. Most DEGs are associated with host immunity, cellular reorganization, cell migration, and proliferation. Tuft/epithelial cell response to the infection was atypical, lacking an anticipated increase in key alarmin cytokine genes. Numerous genes associated with T helper (Th) 1, Th2, and Th17 responses and T cell exhaustion were upregulated, suggesting altered immune regulation. The data collectively indicate that O. ostertagi infection elicits massive host responses, particularly immune responses, which are intertwined with the parasite’s disruption of abomasal function, which likely impairs the nutrient utilization of the host. The infection is characterized by the absence of a dominant Th response and displaying a mixed activation of Th1, Th2, and Th17 pathways. Elevated expression of T cell exhaustion genes and lack of increase in epithelial alarmin cytokine genes suggest a downregulation of, or a deficiency in initiating, effective host immunity to the infection. Understanding mechanisms of parasite-mediated immune evasion and their nutritional consequences will facilitate the rational design of protective vaccines against infections of complex nematode parasites. Full article

Biologic therapies have revolutionized the treatment of severe allergic diseases, including asthma, atopic dermatitis (AD), chronic spontaneous urticaria (CSU), chronic rhinosinusitis with nasal polyps (CRSwNP), eosinophilic gastrointestinal diseases (EGIDs), and allergic rhinitis (AR). These molecularly targeted agents provide significant benefits for patients unresponsive to conventional treatments by addressing underlying immune mechanisms, particularly type 2 inflammation driven by cytokines such as IL-4, IL-5, and IL-13. Recent advancements include biologics targeting alarmins like thymic stromal lymphopoietin (TSLP) and IL-33, which may address both type 2 and non-type 2 inflammation, broadening their therapeutic scope. Despite their effectiveness, biologics remain expensive, posing socioeconomic challenges, and there are concerns regarding long-term safety and inter-individual variability in responses. Promising innovations such as bispecific antibodies and ultra-long-acting agents are under investigation, alongside digital health tools like remote biomarker monitoring and AI-driven decision support systems, which aim to enhance personalized care. However, disparities in access, particularly for underserved populations, underscore the need for policy reforms and affordable biosimilars. This review synthesizes recent findings and emerging trends, highlighting the evolving role of biologics in transforming allergic disease management and offering insights into future research directions. Full article

TSLP is an alarmin released upon activation of epithelia in response to various external stimuli and is involved in type 2 cytokine-mediated pathological disorders. The formation of a high-affinity heterodimeric receptor complex, comprising the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα, is required for signaling. This study investigated whether TSLP and TSLPR expression in peripheral blood or nasal polyps could provide a valuable approach for the molecular phenotyping of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). The study population comprised 156 unrelated Caucasian individuals, including 45 controls and 111 patients with CRSwNP. Quantitative PCR analysis of TSLP and TSLPR was performed on the population study’s peripheral blood and nasal biopsy. The data were analyzed for potential associations, and possible use as a biomarker was studied. Significant differences were observed in TSLP and TSLPR blood expression between the control group and patients. Similarly, the expression of TSLP observed in biopsy samples was statistically significantly elevated in the polyp tissue of the patient compared with healthy controls. The combination of TSLP and TSLPR expression testing with peripheral blood eosinophils represents a more specific biomarker in patients exhibiting low eosinophil values. Further investigation of TSLP/TSLPR mRNA levels in peripheral blood may yield new minimally invasive biomarkers. Full article

Evaluation of skin inflammation biomarkers in canine atopic dermatitis (AD) currently requires skin biopsies. Tape stripping has been shown to be a reliable technique to study biomarkers in the stratum corneum (SC) in humans. The aim of this study was to assess the immune response and identify biomarkers in the SC of dogs with canine AD using D-squame^® as a minimally invasive technique. Eight beagle dogs were epicutaneously sensitized to Dermatophagoides farinae extract after tape stripping on sensitized site (S); twice a week for 49 days. Two sites were determined: lesional site (L) and non-lesional site (NL) on eight dogs affected spontaneously with AD. Adhesive tape strips D-Squame^® were applied on each site. Skin concentrations of 10 cytokines were analyzed with an ELISA kit. Our results revealed a significant increase of IL-13, IL-4, and TNF-α concentrations in S and L sites. Regarding IFN-γ, its concentration was significantly increased in L skin and increased but not significantly in S sites. All the alarmins were not differentially expressed except IL-33 in the S site. IL-31, IL-1β, and IL-10 were not detectable. D-squame^® seems to be a suitable technique to extract inflammatory cytokines from the SC of dogs, and IL-13, IL-4, TNF-α, and IFN-γ could be interesting biomarkers of canine AD. Full article

Major Depressive Disorder (MDD) is a prevalent mental health condition with a complex pathophysiology involving neuroinflammation, neurodegeneration, and disruptions in neuronal and glial cell function. Microglia, the innate immune cells of the central nervous system, release inflammatory cytokines in response to pathological changes associated with MDD. Damage-associated molecular patterns (DAMPs) act as alarms, triggering microglial activation and subsequent inflammatory cytokine release. This review examines the cellular mechanisms underlying MDD pathophysiology, focusing on the lipid-mediated modulation of neuroinflammation. We explore the intricate roles of microglia and astrocytes in propagating inflammatory cascades and discuss how these processes affect neuronal integrity at the cellular level. Central to our analysis are three key molecules: High Mobility Group Box 1 (HMGB1) and S100 Calcium Binding Protein β (S100β) as alarmins, and Neuron-Specific Enolase (NSE) as an indicator of neuronal stress. We present evidence from in vitro and ex vivo studies demonstrating how these molecules reflect and contribute to the neuroinflammatory milieu characteristic of MDD. The review then explores the potential of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) as neuroinflammation modulators, examining their effects on microglial activation, cytokine production, and neuronal resilience in cellular models of depression. We critically analyze experimental data on how ω-3 PUFA supplementation influences the expression and release of HMGB1, S100β, and NSE in neuronal and glial cultures. By integrating findings from lipidomic and cellular neurobiology, this review aims to elucidate the mechanisms by which ω-3 PUFAs may exert their antidepressant effects through modulation of neuroinflammatory markers. These insights contribute to our understanding of lipid-mediated neuroprotection in MDD and may inform the development of targeted, lipid-based therapies for both depression and neurodegenerative disorders. Full article

Studies have shown that eosinophilic COPD (eCOPD) is a distinct phenotype of the disease. It is well established that innate lymphoid cells are involved in the development of eosinophilic inflammation. Interleukin(IL)-25, thymic stromal lymphopoietin (TSLP) and IL-33 are a group of cytokines produced by epithelium in response to danger signals, e.g., cigarette smoke, and potent activators of ILC2s. In the present study, we examined circulating and sputum ILC2 numbers and expression of intracellular IL-5 as well as receptors for TSLP, IL-33 and IL-25 by ILC2s in non-atopic COPD patients with and without (neCOPD) airway eosinophilic inflammation and healthy smokers. In addition, we examined the association between ILC2s and clinical indicators of COPD burden (i.e., symptom intensity and risk of exacerbations). ILC2s were enumerated in peripheral blood and induced sputum by means of flow cytometry. We noted significantly greater numbers of airway IL-5⁺ILC2s and TSLPR⁺ILC2s in eCOPD compared with neCOPD (p < 0.05 and p < 0.01, respectively) and HSs (p < 0.001 for both). In addition, we showed that IL-5⁺ILC2s, IL-17RB⁺ILC2s and ST2⁺ILC2s are significantly increased in the sputum of eCOPD patients compared with HSs. In all COPD patients, sputum ILC2s positively correlated with sputum eosinophil percentage (r = 0.48, p = 0.002). We did not find any significant correlations between sputum ILC2s and dyspnea intensity as measured by the modified Medical Research Council scale (mMRC) and symptom intensity measured by the COPD Assessment Test (CAT). These results suggest the involvement of epithelial alarmin-activated ILC2s in the pathobiology of eosinophilic COPD. Full article

Asthma is a chronic respiratory condition predominantly driven by a type 2 immune response. Epithelial-derived alarmins such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 orchestrate the activation of downstream Th2 cells and group 2 innate lymphoid cells (ILC2s), along with other immune effector cells. While these alarmins are produced in response to inhaled triggers, such as allergens, respiratory pathogens or particulate matter, disproportionate alarmin production by airway epithelial cells can lead to asthma exacerbations. With alarmins produced upstream of the type 2 inflammatory cascade, understanding the pathways by which these alarmins are regulated and expressed is critical to further explore new therapeutics for the treatment of asthmatic patients. This review emphasizes the critical role of airway epithelium and epithelial-derived alarmins in asthma pathogenesis and highlights the potential of targeting alarmins as a promising therapeutic to improve outcomes for asthma patients. Full article

Asthma is a chronic inflammatory lung disease. Refractory asthma poses a significant challenge in management due to its resistance to standard therapies. Key molecular pathways of refractory asthma include T2 inflammation mediated by Th2 and ILC2 cells, eosinophils, and cytokines including IL-4, IL-5, and IL-13. Additionally, non-T2 mechanisms involving neutrophils, macrophages, IL-1, IL-6, and IL-17 mediate a corticosteroid resistant phenotype. Mediators including alarmins (IL-25, IL-33, TSLP) and OX40L have overlap between T2 and non-T2 inflammation and may signify unique pathways of asthma inflammation. Therapies that target these pathways and mediators have proven to be effective in reducing exacerbations and improving lung function in subsets of severe asthma patients. However, there are patients with severe asthma who do not respond to approved therapies. Small molecule inhibitors, such as JAK-inhibitors, and monoclonal antibodies targeting mast cells, IL-1, IL-6, IL-33, TNFα, and OX40L are under investigation for their potential to modulate inflammation involved in refractory asthma. Understanding refractory asthma heterogeneity and identifying mediators involved are essential in developing therapeutic interventions for patients unresponsive to currently approved biologics. Further investigation is needed to develop personalized treatments based on these molecular insights to potentially offer more effective treatments for this complex disease. Full article

Background: The secretion of alarmin cytokines by epithelial cells, including thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33, initiates inflammatory cascades in asthma. However, alarmin cytokine expression in the upper airways in asthma remains largely unknown. Methods: We recruited 40 participants with asthma into four groups as per the Global Initiative for Asthma (GINA) steps (10 in each group of GINA 1/2, 3, 4, and 5). Cells were derived from nasal, buccal, and throat brushings. Intracellular cytokine expression (TSLP, IL-25, and IL-33) was assessed by flow cytometry in cytokeratin 8⁺ (Ck8⁺) epithelial cells immediately following collection. Results: TSLP was significantly increased (p < 0.001) in GINA 5 patients across nasal, buccal, and throat Ck8⁺ epithelial cells, while IL-25 was elevated in nasal and throat samples (p < 0.003), and IL-33 levels were variable, compared with GINA 1–4 patients. Individual GINA subgroup comparison showed that TSLP levels in nasal samples from GINA 5 patients were significantly (p = 0.03) elevated but did not differ between patients with and without nasal comorbidities. IL-25 and IL-33 (obtained from nasal, buccal, and throat samples) were not significantly different in individual groups. Conclusions: Our study demonstrates for the first time that Ck8⁺ nasal epithelial cells from GINA 5 asthma patients express elevated levels of TSLP. Full article

Background: The immune response dynamics in COVID-19 patients remain a subject of intense investigation due to their implications for disease severity and treatment outcomes. We examined changes in leukocyte levels, eosinophil activity, and cytokine profiles in patients hospitalized with COVID-19. Methods: Serum samples were collected within the first 10 days of hospitalization/confirmed infection and analyzed for eosinophil granule proteins (EGP) and cytokines. Information from medical records including comorbidities, clinical symptoms, medications, and complete blood counts were collected at the time of admission, during hospitalization and at follow up approximately 3 months later. Results: Serum levels of eotaxin, type 1 and type 2 cytokines, and alarmin cytokines were elevated in COVID-19 patients, highlighting the heightened immune response (p < 0.05). However, COVID-19 patients exhibited lower levels of eosinophils and eosinophil degranulation products compared to hospitalized controls (p < 0.05). Leukocyte counts increased consistently from admission to follow-up, indicative of recovery. Conclusion: Attenuated eosinophil activity alongside elevated chemokine and cytokine levels during active infection, highlights the complex interplay of immune mediators in the pathogenesis COVID-19 and underscores the need for further investigation into immune biomarkers and treatment strategies. Full article

Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33. Functionally, TSLP is a key player in the immune response to environmental insults, initiating a number of downstream inflammatory pathways. TSLP performs its role by binding to a high-affinity heteromeric complex composed of the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα. In recent years, the important role of proinflammatory cytokines in the etiopathogenesis of various chronic diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), chronic obstructive pulmonary diseases (COPDs), and chronic spontaneous urticaria has been studied. Although alarmins have been found to be mainly implicated in the mechanisms of type 2 inflammation, studies on monoclonal antibodies against TSLP demonstrate partial efficacy even in patients whose inflammation is not definable as T2 and the so-called low T2. Tezepelumab is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. Several clinical trials are evaluating the safety and efficacy of Tezepelumab in various inflammatory disorders. In this review, we will highlight major recent advances in understanding the functional role of TSLP, its involvement in Th2-related diseases, and its suitability as a target for biological therapies. Full article

The Pulsatilla decoction is a well-known herbal remedy used in clinical settings for treating vulvovaginal candidiasis (VVC). However, the specific mechanism that makes it effective is still unclear. Recent studies have shown that in cases of VVC, neutrophils recruited to the vagina, influenced by heparan sulfate (HS), do not successfully engulf Candida albicans (C. albicans). Instead, they release many inflammatory factors that cause damage to the vaginal mucosa. This study aims to understand the molecular mechanism by which the n-butanol extract of Pulsatilla decoction (BEPD) treats VVC through transcriptomics. High-performance liquid chromatography was used to identify the primary active components of BEPD. A VVC mouse model was induced using an estrogen-dependent method and the mice were treated daily with BEPD (20 mg/kg, 40 mg/kg, and 80 mg/kg) for seven days. The vaginal lavage fluid of the mice was analyzed for various experimental indices, including fungal morphology, fungal burden, degree of neutrophil infiltration, and cytokines. Various assessments were then performed on mouse vaginal tissues, including pathological assessment, immunohistochemistry, immunofluorescence, Western blot (WB), quantitative real-time PCR, and transcriptome assays. Our results showed that BEPD reduced vaginal redness and swelling, decreased white discharge, inhibited C. albicans hyphae formation, reduced neutrophil infiltration and fungal burden, and attenuated vaginal tissue damage compared with the VVC model group. The high-dose BEPD group even restored the damaged vaginal tissue to normal levels. The medium- and high-dose groups of BEPD also significantly reduced the levels of IL-1β, IL-6, TNF-α, and LDH. Additionally, transcriptomic results showed that BEPD regulated several chemokine (CXCL1, CXCL3, and CXCL5) and S100 alarmin (S100A8 and S100A9) genes, suggesting that BEPD may treat VVC by affecting chemokine- and alarmin-mediated neutrophil chemotaxis. Finally, we verified that BEPD protects the vaginal mucosa of VVC mice by inhibiting neutrophil recruitment and chemotaxis in an animal model of VVC via the TLR4/MyD88/NF-κB pathway. This study provides further evidence to elucidate the mechanism of BEPD treatment of VVC. Full article

Background: Tropomyosins (TM) from vertebrates are generally non-allergenic, while invertebrate homologs are potent pan-allergens. This study aims to compare the risk of sensitization between chicken TM and shrimp TM through affecting the intestinal epithelial barrier integrity and type 2 mucosal immune activation. Methods: Epithelial activation and/or barrier effects upon exposure to 2–50 μg/mL chicken TM, shrimp TM or ovalbumin (OVA) as a control allergen, were studied using Caco-2, HT-29MTX, or HT-29 intestinal epithelial cells. Monocyte-derived dendritic cells (moDC), cocultured with HT-29 cells or moDC alone, were exposed to 50 μg/mL chicken TM or shrimp TM. Primed moDC were cocultured with naïve Th cells. Intestinal barrier integrity (TEER), gene expression, cytokine secretion and immune cell phenotypes were determined in these human in vitro models. Results: Shrimp TM, but not chicken TM or OVA exposure, profoundly disrupted intestinal barrier integrity and increased alarmin genes expression in Caco-2 cells. Proinflammatory cytokine secretion in HT-29 cells was only enhanced upon shrimp TM or OVA, but not chicken TM, exposure. Shrimp TM enhanced the maturation of moDC and chemokine secretion in the presence or absence of HT-29 cells, while only in the absence of epithelial cells chicken TM activated moDC. Direct exposure of moDC to shrimp TM increased IL13 and TNFα secretion by Th cells cocultured with these primed moDC, while shrimp TM exposure via HT-29 cells cocultured with moDC sequentially increased IL13 expression and IL4 secretion in Th cells. Conclusions: Shrimp TM, but not chicken TM, disrupted the epithelial barrier while triggering type 2 mucosal immune activation, both of which are key events in allergic sensitization. Full article