Previous
Aim:
This study aims to analyze the impact of sucrose consumption on inflammatory and immunological parameters of newborn offspring of females with gestational diabetes mellitus (GDM).
Methods:
4 groups of pregnant female CD1 mice were created (n = 6): A, without GDM, without sucrose supplementation; B, without GDM, with sucrose supplementation; C, with GDM, without sucrose supplementation; and D, with GDM, with sucrose supplementation. GDM was induced by subcutaneous injection of streptozotocin, with a dose of 230 mg/kg. Sucrose supplementation was administered at a concentration of 41.66 mg/mL per oral stool (500 μL volume) to each female daily at 8:00 am from confirmation of gestational diabetes until the end of pregnancy. Immediately after birth, the pups were sacrificed in the first 2 h of life. The following were quantified in each group of 8 newborns: body weight, glycaemia, leptin, adiponectin, insulin, HOMA-IR index, percentage of lymphocytes: CD3, CD4, and CD8, immunoglobulins (IgA and IgG), cytokines (IL-1β, IL-6, TNF-α, and IFN-γ), and redox activity: (carbonylated proteins, malondialdehyde, superoxide dismutase, catalase, reduced glutathione, total antioxidant capacity).
Results:
Sucrose consumption increased the levels of adiponectin, IL-1β, IL-6 and decreased the concentration of IgA in the offspring. Group C and D caused lower body weight and higher concentration of carbonylated proteins. The combination of sucrose and GDM favored an increase in blood glucose, the HOMA-IR index, the percentage of T lymphocytes, the concentration of proinflammatory cytokines, and reduced glutathione, with reduction of catalase.
Conclusions:
Sucrose consumption by mothers during pregnancy and the presence of GDM generate alterations at the cellular, immunological, metabolic, hormonal, and redox levels in newborns. This results in an inflammatory state, with an imbalance in the redox state, which predisposes the newborn to short and medium-term metabolic problems from birth.
Aim:
This study aims to analyze the impact of sucrose consumption on inflammatory and immunological parameters of newborn offspring of females with gestational diabetes mellitus (GDM).
Methods:
4 groups of pregnant female CD1 mice were created (n = 6): A, without GDM, without sucrose supplementation; B, without GDM, with sucrose supplementation; C, with GDM, without sucrose supplementation; and D, with GDM, with sucrose supplementation. GDM was induced by subcutaneous injection of streptozotocin, with a dose of 230 mg/kg. Sucrose supplementation was administered at a concentration of 41.66 mg/mL per oral stool (500 μL volume) to each female daily at 8:00 am from confirmation of gestational diabetes until the end of pregnancy. Immediately after birth, the pups were sacrificed in the first 2 h of life. The following were quantified in each group of 8 newborns: body weight, glycaemia, leptin, adiponectin, insulin, HOMA-IR index, percentage of lymphocytes: CD3, CD4, and CD8, immunoglobulins (IgA and IgG), cytokines (IL-1β, IL-6, TNF-α, and IFN-γ), and redox activity: (carbonylated proteins, malondialdehyde, superoxide dismutase, catalase, reduced glutathione, total antioxidant capacity).
Results:
Sucrose consumption increased the levels of adiponectin, IL-1β, IL-6 and decreased the concentration of IgA in the offspring. Group C and D caused lower body weight and higher concentration of carbonylated proteins. The combination of sucrose and GDM favored an increase in blood glucose, the HOMA-IR index, the percentage of T lymphocytes, the concentration of proinflammatory cytokines, and reduced glutathione, with reduction of catalase.
Conclusions:
Sucrose consumption by mothers during pregnancy and the presence of GDM generate alterations at the cellular, immunological, metabolic, hormonal, and redox levels in newborns. This results in an inflammatory state, with an imbalance in the redox state, which predisposes the newborn to short and medium-term metabolic problems from birth.
DOI: https://doi.org/10.37349/ei.2025.1003195
This article belongs to the special issue The Nutritional Influence on Immune Functionality
Aim:
Mutations in key regulators of apoptosis have necessitated exploring the alternative cell death pathways like necroptosis in breast cancer (BC). Necroptosis is immunogenic due to the release of damage-associated molecular patterns (DAMPs) into extracellular environment, which can trigger pro- or anti-tumor immune responses. Inducing necroptosis in estrogen receptor-positive (ER+) BC cells leads to the release of DAMPs, which can influence macrophages polarisation within the tumor microenvironment. The study aims to identify and characterize the DAMPs released from ER+ BC cells after necroptosis induction and to investigate their effects on macrophage properties.
Methods:
Necroptosis was induced by treating T-47D cells with Z-VAD-FMK and TNF-α (24 hours). The culture medium was collected as induction medium (IM). Necrostatin-1 alongside Z-VAD-FMK and TNF-α was added to inhibit necroptosis, the culture medium was collected as inhibition medium (InM) and used as a negative control for necroptosis. IM also referred as conditioned medium (CM), was analyzed using LC-MS/MS for the identification of DAMPs. THP-1 macrophages were incubated with the CM (24 hours), and their differentiation into M1 or M2 subtypes was assessed using qPCR, by evaluating the expression of specific M1 and M2 markers.
Results:
A total of 35 unique proteins with potential DAMP activity were identified in the IM. Functional and pathway analyses using PANTHER and DAVID revealed their involvement in immune regulation, metabolism, stress responses, and key pathways such as glycolysis, signaling, and inflammation. These proteins were primarily intracellular or secretory and included cytoskeletal components, chaperones, and binding modulators. Furthermore, IM treatment promoted THP-1 monocyte differentiation into both M1 and M2 macrophage subtypes.
Conclusions:
These findings highlight the role of necroptosis in generating DAMPs, which can modulate macrophage differentiation within the BC microenvironment. The identified DAMPs hold potential for further investigation as prognostic or predictive biomarkers and therapeutic targets in future studies.
Aim:
Mutations in key regulators of apoptosis have necessitated exploring the alternative cell death pathways like necroptosis in breast cancer (BC). Necroptosis is immunogenic due to the release of damage-associated molecular patterns (DAMPs) into extracellular environment, which can trigger pro- or anti-tumor immune responses. Inducing necroptosis in estrogen receptor-positive (ER+) BC cells leads to the release of DAMPs, which can influence macrophages polarisation within the tumor microenvironment. The study aims to identify and characterize the DAMPs released from ER+ BC cells after necroptosis induction and to investigate their effects on macrophage properties.
Methods:
Necroptosis was induced by treating T-47D cells with Z-VAD-FMK and TNF-α (24 hours). The culture medium was collected as induction medium (IM). Necrostatin-1 alongside Z-VAD-FMK and TNF-α was added to inhibit necroptosis, the culture medium was collected as inhibition medium (InM) and used as a negative control for necroptosis. IM also referred as conditioned medium (CM), was analyzed using LC-MS/MS for the identification of DAMPs. THP-1 macrophages were incubated with the CM (24 hours), and their differentiation into M1 or M2 subtypes was assessed using qPCR, by evaluating the expression of specific M1 and M2 markers.
Results:
A total of 35 unique proteins with potential DAMP activity were identified in the IM. Functional and pathway analyses using PANTHER and DAVID revealed their involvement in immune regulation, metabolism, stress responses, and key pathways such as glycolysis, signaling, and inflammation. These proteins were primarily intracellular or secretory and included cytoskeletal components, chaperones, and binding modulators. Furthermore, IM treatment promoted THP-1 monocyte differentiation into both M1 and M2 macrophage subtypes.
Conclusions:
These findings highlight the role of necroptosis in generating DAMPs, which can modulate macrophage differentiation within the BC microenvironment. The identified DAMPs hold potential for further investigation as prognostic or predictive biomarkers and therapeutic targets in future studies.
DOI: https://doi.org/10.37349/ei.2025.1003194
Primary immunodeficiency disease (PID) now known as inborn errors of immunity (IEI) is genetic disorder(s) that impair the immune system. IEI is a heterogeneous group of diseases of more than 485 lifelong genetic disorders mainly due to intrinsic defect(s) in human immune system. Adults, children, and neonates can be affected by IEI diseases. The first IEI defects were reported in the 1950s, but Bruton’s use of immunoglobulin in 1952 to treat an 8-year-old boy suffering from pneumonia and other bacterial sino-pulmonary infections brought the PID or IEI and associated diseases into limelight. This review will focus on a general description of IEI (history, epidemiology, pathophysiology, and diagnosis), inborn errors of metabolism, and the management (cure or therapy) of IEI diseases.
Primary immunodeficiency disease (PID) now known as inborn errors of immunity (IEI) is genetic disorder(s) that impair the immune system. IEI is a heterogeneous group of diseases of more than 485 lifelong genetic disorders mainly due to intrinsic defect(s) in human immune system. Adults, children, and neonates can be affected by IEI diseases. The first IEI defects were reported in the 1950s, but Bruton’s use of immunoglobulin in 1952 to treat an 8-year-old boy suffering from pneumonia and other bacterial sino-pulmonary infections brought the PID or IEI and associated diseases into limelight. This review will focus on a general description of IEI (history, epidemiology, pathophysiology, and diagnosis), inborn errors of metabolism, and the management (cure or therapy) of IEI diseases.
DOI: https://doi.org/10.37349/ei.2025.1003193
Monogenic muscular dystrophies (MDs), such as Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy (LGMD), are characterized by chronic inflammation, progressive fibrosis, and impaired muscle regeneration. Central to these pathological processes are macrophages, which exhibit dynamic polarization states that influence the dystrophic microenvironment. In early disease stages, macrophages support tissue repair and regeneration, but chronic inflammation skews their activity toward pro-fibrotic phenotypes, driving excessive extracellular matrix (ECM) deposition and muscle dysfunction. Macrophages also interact with other immune cells, such as T cells and neutrophils, and non-immune cells, including fibroblasts and satellite cells, to regulate inflammatory and fibrotic responses. These interactions establish a dysregulated immune environment that exacerbates muscle damage and impairs effective regeneration. Preclinical studies using the mdx mouse model of DMD highlight the critical role of macrophages in sustaining inflammation and fibrosis, particularly through transforming growth factor-beta (TGF-β) signaling and fibro-adipogenic progenitor (FAP) activation. Therapeutically, targeting macrophages offers significant potential to mitigate disease progression. Strategies include modulating macrophage polarization toward a pro-regenerative M2 phenotype, inhibiting macrophage recruitment via chemokine signaling, and reprogramming macrophage metabolism to support oxidative phosphorylation and mitochondrial function. Additionally, anti-fibrotic interventions targeting TGF-β signaling or macrophage-FAP crosstalk have shown promise in reducing ECM deposition and preserving muscle architecture. In this review, we curate relevant studies and provide insights into the molecular mechanisms governing macrophage behavior in dystrophic muscle. Herein, we discuss how emerging therapeutic strategies targeting macrophage-mediated pathways can be leveraged to mitigate inflammation and fibrosis, enhance muscle regeneration, and improve clinical outcomes.
Monogenic muscular dystrophies (MDs), such as Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy (LGMD), are characterized by chronic inflammation, progressive fibrosis, and impaired muscle regeneration. Central to these pathological processes are macrophages, which exhibit dynamic polarization states that influence the dystrophic microenvironment. In early disease stages, macrophages support tissue repair and regeneration, but chronic inflammation skews their activity toward pro-fibrotic phenotypes, driving excessive extracellular matrix (ECM) deposition and muscle dysfunction. Macrophages also interact with other immune cells, such as T cells and neutrophils, and non-immune cells, including fibroblasts and satellite cells, to regulate inflammatory and fibrotic responses. These interactions establish a dysregulated immune environment that exacerbates muscle damage and impairs effective regeneration. Preclinical studies using the mdx mouse model of DMD highlight the critical role of macrophages in sustaining inflammation and fibrosis, particularly through transforming growth factor-beta (TGF-β) signaling and fibro-adipogenic progenitor (FAP) activation. Therapeutically, targeting macrophages offers significant potential to mitigate disease progression. Strategies include modulating macrophage polarization toward a pro-regenerative M2 phenotype, inhibiting macrophage recruitment via chemokine signaling, and reprogramming macrophage metabolism to support oxidative phosphorylation and mitochondrial function. Additionally, anti-fibrotic interventions targeting TGF-β signaling or macrophage-FAP crosstalk have shown promise in reducing ECM deposition and preserving muscle architecture. In this review, we curate relevant studies and provide insights into the molecular mechanisms governing macrophage behavior in dystrophic muscle. Herein, we discuss how emerging therapeutic strategies targeting macrophage-mediated pathways can be leveraged to mitigate inflammation and fibrosis, enhance muscle regeneration, and improve clinical outcomes.
DOI: https://doi.org/10.37349/ei.2025.1003192
Aim:
To assess circulating levels of tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) in mid-gestation pregnant women from South India, with (RPL) and without history of recurrent pregnancy loss (non-RPL) and its correlation with neutrophil to lymphocyte ratio (NLR).
Methods:
Blood samples were collected from 400 pregnant women attending government maternity hospital, Hyderabad, and subjected to enzyme linked immunosorbent assay (ELISA) for cytokines. NLR was calculated from absolute cell counts obtained from hospital records. Mann-Whitney U and Spearman r correlation was conducted as data followed non-normal distribution.
Results:
We found significantly decreased level of TGF-β and elevated TNF-α, TNF-α/TGF-β (P < 0.0001), and NLR (P = 0.0007) in patients over controls. Receiver operating curve characteristics of TNF-α/TGF-β (area under curve: 0.96) were superior to individual cytokines and NLR for patients when compared to the control group. A negative correlation was noted between NLR and TGF-β in the RPL group (P = 0.0041).
Conclusions:
Our results are indicative of predominant pro-inflammatory environment during mid-gestation in patients contrary to the anti-inflammatory milieu in controls. This is first study that attempted to connect cytokines with cellular ratio in RPL. The affordability of NLR to track inflammation is promised by its inverse correlation with TGF-β. However, further longitudinal studies are warranted spanning all stages of gestation in normal pregnant and RPL women to establish our observations. The limitations of the study include other factors that drive pro-inflammatory status like emotional dysregulation in women associated with chronic pro-inflammatory status is unexplored.
Aim:
To assess circulating levels of tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) in mid-gestation pregnant women from South India, with (RPL) and without history of recurrent pregnancy loss (non-RPL) and its correlation with neutrophil to lymphocyte ratio (NLR).
Methods:
Blood samples were collected from 400 pregnant women attending government maternity hospital, Hyderabad, and subjected to enzyme linked immunosorbent assay (ELISA) for cytokines. NLR was calculated from absolute cell counts obtained from hospital records. Mann-Whitney U and Spearman r correlation was conducted as data followed non-normal distribution.
Results:
We found significantly decreased level of TGF-β and elevated TNF-α, TNF-α/TGF-β (P < 0.0001), and NLR (P = 0.0007) in patients over controls. Receiver operating curve characteristics of TNF-α/TGF-β (area under curve: 0.96) were superior to individual cytokines and NLR for patients when compared to the control group. A negative correlation was noted between NLR and TGF-β in the RPL group (P = 0.0041).
Conclusions:
Our results are indicative of predominant pro-inflammatory environment during mid-gestation in patients contrary to the anti-inflammatory milieu in controls. This is first study that attempted to connect cytokines with cellular ratio in RPL. The affordability of NLR to track inflammation is promised by its inverse correlation with TGF-β. However, further longitudinal studies are warranted spanning all stages of gestation in normal pregnant and RPL women to establish our observations. The limitations of the study include other factors that drive pro-inflammatory status like emotional dysregulation in women associated with chronic pro-inflammatory status is unexplored.
DOI: https://doi.org/10.37349/ei.2025.1003189
Neoantigen vaccines are a promising strategy in cancer immunotherapy that leverage tumor-specific mutations to elicit targeted immune responses. Although they have considerable potential, development challenges related to antigen prediction accuracy, manufacturing complexity, and scalability remain key obstacles to their widespread clinical use. This literature review was conducted using PubMed, Scopus, Web of Science, and Google Scholar databases to identify relevant studies. Keywords included “neoantigen vaccines,” “personalized cancer immunotherapy,” “tumor heterogeneity,” “bioinformatics pipelines,” and “prediction algorithms”. Clinical trial data were sourced from ClinicalTrials.gov, Trialtrove, and other publicly available registries. Eligible studies included peer-reviewed research articles, systematic reviews, and clinical trials focusing on neoantigen vaccine development, bioinformatic strategies, and immunotherapy. Tumor heterogeneity and clonal evolution significantly impact vaccine efficacy, necessitating multi-epitope targeting and adaptive vaccine design. Current neoantigen prediction algorithms suffer from high false-positive and false-negative rates, requiring further integration with multi-omics data and machine learning to enhance accuracy. Manufacturing remains complex, time-intensive, and costly, necessitating advancements in standardization and automation. Combination therapies, such as immune checkpoint inhibitors and adoptive cell therapies, counteract the immunosuppressive tumor microenvironment, improving treatment outcomes. Neoantigen vaccines hold great potential for personalized cancer therapy but require advancements in bioinformatics, manufacturing scalability, and immunomodulatory strategies to enhance clinical efficacy. Continued research and interdisciplinary collaboration are essential for refining clinical applications.
Neoantigen vaccines are a promising strategy in cancer immunotherapy that leverage tumor-specific mutations to elicit targeted immune responses. Although they have considerable potential, development challenges related to antigen prediction accuracy, manufacturing complexity, and scalability remain key obstacles to their widespread clinical use. This literature review was conducted using PubMed, Scopus, Web of Science, and Google Scholar databases to identify relevant studies. Keywords included “neoantigen vaccines,” “personalized cancer immunotherapy,” “tumor heterogeneity,” “bioinformatics pipelines,” and “prediction algorithms”. Clinical trial data were sourced from ClinicalTrials.gov, Trialtrove, and other publicly available registries. Eligible studies included peer-reviewed research articles, systematic reviews, and clinical trials focusing on neoantigen vaccine development, bioinformatic strategies, and immunotherapy. Tumor heterogeneity and clonal evolution significantly impact vaccine efficacy, necessitating multi-epitope targeting and adaptive vaccine design. Current neoantigen prediction algorithms suffer from high false-positive and false-negative rates, requiring further integration with multi-omics data and machine learning to enhance accuracy. Manufacturing remains complex, time-intensive, and costly, necessitating advancements in standardization and automation. Combination therapies, such as immune checkpoint inhibitors and adoptive cell therapies, counteract the immunosuppressive tumor microenvironment, improving treatment outcomes. Neoantigen vaccines hold great potential for personalized cancer therapy but require advancements in bioinformatics, manufacturing scalability, and immunomodulatory strategies to enhance clinical efficacy. Continued research and interdisciplinary collaboration are essential for refining clinical applications.
DOI: https://doi.org/10.37349/ei.2025.1003190
Diet plays a complex role in the management of inflammatory bowel disease (IBD), significantly influencing the microbiome and metabolome. Three key metabolites implicated in IBD are short chain fatty acids, bile acids and tryptophan, all of which can be modulated through diet. This study analyses the impact of various diets on these metabolites. Despite the anti-inflammatory effects of short chain fatty acids, their levels do not increase during successful remission with exclusive enteral nutrition. Additionally, changes in tryptophan and bile acids are non-specific across different diets, suggesting these metabolic shifts are secondary to dietary efficacy in IBD. Dietary therapies vary in efficacy across individuals, as the established microbiome may not produce the desired metabolites. This variability is further compounded by differences in immune responses influenced by genetic factors and disease duration. Furthermore, inflammation and symptom resolution do not always coincide, revealing a discrepancy in dietary impacts on IBD. These limitations highlight the need for a deeper understanding of the interconnectedness of disease heterogeneity, dietary effects, the microbiome, and their influence on the mucosal immune system to develop more personalised dietary therapies. While no single diet is universally effective for all IBD patients, future research should focus on establishing a more rigid definition of dietary interventions for IBD and their long-term effects on clinical outcomes.
Diet plays a complex role in the management of inflammatory bowel disease (IBD), significantly influencing the microbiome and metabolome. Three key metabolites implicated in IBD are short chain fatty acids, bile acids and tryptophan, all of which can be modulated through diet. This study analyses the impact of various diets on these metabolites. Despite the anti-inflammatory effects of short chain fatty acids, their levels do not increase during successful remission with exclusive enteral nutrition. Additionally, changes in tryptophan and bile acids are non-specific across different diets, suggesting these metabolic shifts are secondary to dietary efficacy in IBD. Dietary therapies vary in efficacy across individuals, as the established microbiome may not produce the desired metabolites. This variability is further compounded by differences in immune responses influenced by genetic factors and disease duration. Furthermore, inflammation and symptom resolution do not always coincide, revealing a discrepancy in dietary impacts on IBD. These limitations highlight the need for a deeper understanding of the interconnectedness of disease heterogeneity, dietary effects, the microbiome, and their influence on the mucosal immune system to develop more personalised dietary therapies. While no single diet is universally effective for all IBD patients, future research should focus on establishing a more rigid definition of dietary interventions for IBD and their long-term effects on clinical outcomes.
DOI: https://doi.org/10.37349/ei.2025.1003191
This article belongs to the special issue The Nutritional Influence on Immune Functionality
Immune response, inflammation, and lipid metabolism have important effects on cancer development and progression. Several proteins in tumoral cells and/or tumor microenvironment are involved in any of these processes, whereas some of them participate in all three, such as the zinc finger E-box-binding homeobox 1 (ZEB1) protein. This protein has been proposed to have an important role in invasion and metastasis of cancer cells, as well as to be involved in malignant transformation and resistance to cancer treatments. So, in this study, we present the participation of ZEB1 in immune, inflammatory, and membrane remodeling (lipid metabolism) processes, as well as its interaction with proteins that participate in them. Due to the importance of ZEB1 in cancer progression, it may be a potential biomarker of cancer prognosis and a target for the development of new cancer therapies.
Immune response, inflammation, and lipid metabolism have important effects on cancer development and progression. Several proteins in tumoral cells and/or tumor microenvironment are involved in any of these processes, whereas some of them participate in all three, such as the zinc finger E-box-binding homeobox 1 (ZEB1) protein. This protein has been proposed to have an important role in invasion and metastasis of cancer cells, as well as to be involved in malignant transformation and resistance to cancer treatments. So, in this study, we present the participation of ZEB1 in immune, inflammatory, and membrane remodeling (lipid metabolism) processes, as well as its interaction with proteins that participate in them. Due to the importance of ZEB1 in cancer progression, it may be a potential biomarker of cancer prognosis and a target for the development of new cancer therapies.
DOI: https://doi.org/10.37349/ei.2025.1003187
Cutaneous reactions present a diagnostic challenge, mainly when multiple factors, such as infections, medications, and environmental triggers, contribute to the clinical picture. Erythema multiforme (EM) is an acute, self-limiting mucocutaneous disorder that is most commonly triggered by herpes simplex virus (HSV) but can also be associated with drug-induced hypersensitivity reactions. Diagnosing EM becomes even more complex in patients taking photosensitizing medications, such as doxycycline, which can cause phototoxic or photoallergic reactions. Differentiating between drug-induced and infection-associated EM, as well as distinguishing it from more severe conditions like Stevens-Johnson syndrome (SJS), is crucial for appropriate management. This case report presents a case of a 57-year-old Caucasian female with a history of penicillin allergy who developed a phototoxic reaction to doxycycline following sun exposure. She was treated with silver sulfadiazine for her skin lesions but subsequently developed EM, with target-like lesions predominantly on the legs and a concurrent herpes simplex labialis infection. Laboratory findings were unremarkable, and there was no mucosal involvement. Given the suspected drug-induced nature of the reaction and the presence of HSV, a cautious approach was taken. Treatment with oral prednisone led to the resolution of symptoms without recurrence. Patch testing for doxycycline and silver sulfadiazine was omitted due to the risk of severe cutaneous adverse drug reactions (SCARs) and their non-essential status. Instead, penicillin testing was prioritized due to its clinical importance, and the patient successfully passed the oral amoxicillin challenge. This case highlights the diagnostic challenges of differentiating between drug-induced, infection-triggered, and photosensitivity-related cutaneous reactions. A careful evaluation of medication history, infection status, and clinical presentation is essential to guide the management of this condition.
Cutaneous reactions present a diagnostic challenge, mainly when multiple factors, such as infections, medications, and environmental triggers, contribute to the clinical picture. Erythema multiforme (EM) is an acute, self-limiting mucocutaneous disorder that is most commonly triggered by herpes simplex virus (HSV) but can also be associated with drug-induced hypersensitivity reactions. Diagnosing EM becomes even more complex in patients taking photosensitizing medications, such as doxycycline, which can cause phototoxic or photoallergic reactions. Differentiating between drug-induced and infection-associated EM, as well as distinguishing it from more severe conditions like Stevens-Johnson syndrome (SJS), is crucial for appropriate management. This case report presents a case of a 57-year-old Caucasian female with a history of penicillin allergy who developed a phototoxic reaction to doxycycline following sun exposure. She was treated with silver sulfadiazine for her skin lesions but subsequently developed EM, with target-like lesions predominantly on the legs and a concurrent herpes simplex labialis infection. Laboratory findings were unremarkable, and there was no mucosal involvement. Given the suspected drug-induced nature of the reaction and the presence of HSV, a cautious approach was taken. Treatment with oral prednisone led to the resolution of symptoms without recurrence. Patch testing for doxycycline and silver sulfadiazine was omitted due to the risk of severe cutaneous adverse drug reactions (SCARs) and their non-essential status. Instead, penicillin testing was prioritized due to its clinical importance, and the patient successfully passed the oral amoxicillin challenge. This case highlights the diagnostic challenges of differentiating between drug-induced, infection-triggered, and photosensitivity-related cutaneous reactions. A careful evaluation of medication history, infection status, and clinical presentation is essential to guide the management of this condition.
DOI: https://doi.org/10.37349/ei.2025.1003188
This article belongs to the special issue Hypersensitivity Syndrome Reactions versus Allergy and Drug
Aim:
Plasma cell disorders (PCD), a group of B-cell neoplasms, have undefined etiology. Mast cells (MC) have been found to promote the proliferation and differentiation of B cells in several B cell lymphoproliferative disorders; however, their role in PCD is unclear. The study therefore aims to evaluate bone marrow MC (BM-MC) in the context of PCD.
Methods:
Thirty patients with PCD and 20 control subjects were selected. The BM sample was collected and mononuclear cells were isolated to identify the MC percentage among mononuclear cells using flow cytometry. A 24-hour BM culture was also performed and tryptase levels in the culture supernatant were measured by an enzyme immunoassay.
Results:
In the patient group, the median of MC was 0.04% compared to 0.002% in the control group (p = 0.00001). Median BM-MC tryptase levels were also high in patients (10.1 ng/mL) against the control levels of 7.0 ng/mL (p = 0.011). While 50% of patients were found to have raised tryptase levels, only 10% of controls had tryptase levels beyond the cutoff levels of (p = 0.003).
Conclusions:
BM-MC number and tryptase levels are increased in PCD, suggesting their role in disease pathogenesis.
Aim:
Plasma cell disorders (PCD), a group of B-cell neoplasms, have undefined etiology. Mast cells (MC) have been found to promote the proliferation and differentiation of B cells in several B cell lymphoproliferative disorders; however, their role in PCD is unclear. The study therefore aims to evaluate bone marrow MC (BM-MC) in the context of PCD.
Methods:
Thirty patients with PCD and 20 control subjects were selected. The BM sample was collected and mononuclear cells were isolated to identify the MC percentage among mononuclear cells using flow cytometry. A 24-hour BM culture was also performed and tryptase levels in the culture supernatant were measured by an enzyme immunoassay.
Results:
In the patient group, the median of MC was 0.04% compared to 0.002% in the control group (p = 0.00001). Median BM-MC tryptase levels were also high in patients (10.1 ng/mL) against the control levels of 7.0 ng/mL (p = 0.011). While 50% of patients were found to have raised tryptase levels, only 10% of controls had tryptase levels beyond the cutoff levels of (p = 0.003).
Conclusions:
BM-MC number and tryptase levels are increased in PCD, suggesting their role in disease pathogenesis.
DOI: https://doi.org/10.37349/ei.2025.1003186
In hematological malignancies, autologous immunotherapy with T lymphocytes expressing a chimeric antigen receptor (CAR-T) has been successfully applied. CAR enhances the immuno-cellular effector system directly against cells expressing target antigens. The objective here was to discuss the prospects of applying CAR-T and its variants in autoimmune diseases (AIDs) to deplete pathogenic autoantibodies by eliminating B lymphocytes and plasma cells. B cells play a crucial role in the pathogenesis of AID through the production of autoantibodies, cytokine dysregulation, antigen presentation, and regulatory dysfunction. In AID with numerous autoreactive clones against various autoantigens, such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, myositis, and systemic sclerosis, CAR-T targeting CD19/CD20 and B-cell maturation antigen (BCMA) have shown success in preclinical and clinical studies, representing an innovative option for refractory patients when standard treatments fail. The suppression of B lymphocytes reactive against specific antigens using cytolytic T cells carrying a chimeric autoantibody receptor (CAAR-T) offers a promising approach for managing various AIDs, especially those with characterized pathogenic autoantibodies, such as pemphigus vulgaris, myasthenia gravis, and anti-NMDAR autoimmune encephalitis. CAAR-T allows the elimination of autoreactive B lymphocytes without compromising the general functionality of the immune system, minimizing common side effects in general immunosuppressive therapies, including immunobiologicals and CAR-T. In vitro, preclinical, and clinical (phase 1) studies have demonstrated the efficacy and specificity of CAR-T and CAAR-T in several AIDs; however, extensive clinical trials (phase 3) are required to assess their safety and clinical applicability. These advances promise to enhance precision medicine in the management of AIDs, offering personalized treatments for individual patients.
In hematological malignancies, autologous immunotherapy with T lymphocytes expressing a chimeric antigen receptor (CAR-T) has been successfully applied. CAR enhances the immuno-cellular effector system directly against cells expressing target antigens. The objective here was to discuss the prospects of applying CAR-T and its variants in autoimmune diseases (AIDs) to deplete pathogenic autoantibodies by eliminating B lymphocytes and plasma cells. B cells play a crucial role in the pathogenesis of AID through the production of autoantibodies, cytokine dysregulation, antigen presentation, and regulatory dysfunction. In AID with numerous autoreactive clones against various autoantigens, such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, myositis, and systemic sclerosis, CAR-T targeting CD19/CD20 and B-cell maturation antigen (BCMA) have shown success in preclinical and clinical studies, representing an innovative option for refractory patients when standard treatments fail. The suppression of B lymphocytes reactive against specific antigens using cytolytic T cells carrying a chimeric autoantibody receptor (CAAR-T) offers a promising approach for managing various AIDs, especially those with characterized pathogenic autoantibodies, such as pemphigus vulgaris, myasthenia gravis, and anti-NMDAR autoimmune encephalitis. CAAR-T allows the elimination of autoreactive B lymphocytes without compromising the general functionality of the immune system, minimizing common side effects in general immunosuppressive therapies, including immunobiologicals and CAR-T. In vitro, preclinical, and clinical (phase 1) studies have demonstrated the efficacy and specificity of CAR-T and CAAR-T in several AIDs; however, extensive clinical trials (phase 3) are required to assess their safety and clinical applicability. These advances promise to enhance precision medicine in the management of AIDs, offering personalized treatments for individual patients.
DOI: https://doi.org/10.37349/ei.2025.1003185
This article belongs to the special issue Advances in Cellular and Molecular Treatment of Autoimmune Diseases
Aim:
The objectives of our study were to evaluate a range of circulating biomarkers in COVID-19-related long-term neurological dysfunction.
Methods:
The study involved 30 patients with post-COVID syndrome (PCS) and 28 patients after COVID-19 without PCS. The third cohort consisted of 29 patients with acute COVID-19 of varying severity. The severity of COVID-19 was classified as mild and moderate to severe. The Montreal Cognitive Assessment (MOCA) and the SAGE test were used to study cognitive functions. The Hospital Anxiety and Depression Scale (HADS), the Sheehan Anxiety Scale, and the Beck Depression Inventory were used to study affective functions. The levels of serum cytokines and IgM, IgG, IgA to the SARS-CoV-2 coronavirus were determined using the Vector-Best test systems (Novosibirsk, Russia). We also studied the IgG subclasses to the spike protein of the SARS-CoV-2.
Results:
А mild to moderate COVID-19 infection primarily increases the risk of affective disorders and asthenia and, to a lesser extent, the development of cognitive impairment. The levels of IFN-α, IL-6, as well as serum antibodies to the SARS-CoV-2 among patients with PCS were significantly higher compared to convalescents without PCS. IgM to the SARS-CoV-2 was detected in the blood of patients with PCS during 2–7 months after the disease. After moderate and severe COVID-19, IgG2 and IgG4 were predominant in the blood of patients with PCS and neurological symptoms. The levels of IL-1, IL-4, IL-6, IL-8 in the blood serum of patients with PCS were higher after moderate and severe COVID-19 compared to patients who had mild COVID-19.
Conclusions:
The obtained data on an elevated level of cytokines and IFN-α in the blood of PCS patients can suggest the hypothesis about the participation of chronic inflammation in neurological disorders. The main limitation of the study is the relatively small sample size, which limits the statistical analyses.
Aim:
The objectives of our study were to evaluate a range of circulating biomarkers in COVID-19-related long-term neurological dysfunction.
Methods:
The study involved 30 patients with post-COVID syndrome (PCS) and 28 patients after COVID-19 without PCS. The third cohort consisted of 29 patients with acute COVID-19 of varying severity. The severity of COVID-19 was classified as mild and moderate to severe. The Montreal Cognitive Assessment (MOCA) and the SAGE test were used to study cognitive functions. The Hospital Anxiety and Depression Scale (HADS), the Sheehan Anxiety Scale, and the Beck Depression Inventory were used to study affective functions. The levels of serum cytokines and IgM, IgG, IgA to the SARS-CoV-2 coronavirus were determined using the Vector-Best test systems (Novosibirsk, Russia). We also studied the IgG subclasses to the spike protein of the SARS-CoV-2.
Results:
А mild to moderate COVID-19 infection primarily increases the risk of affective disorders and asthenia and, to a lesser extent, the development of cognitive impairment. The levels of IFN-α, IL-6, as well as serum antibodies to the SARS-CoV-2 among patients with PCS were significantly higher compared to convalescents without PCS. IgM to the SARS-CoV-2 was detected in the blood of patients with PCS during 2–7 months after the disease. After moderate and severe COVID-19, IgG2 and IgG4 were predominant in the blood of patients with PCS and neurological symptoms. The levels of IL-1, IL-4, IL-6, IL-8 in the blood serum of patients with PCS were higher after moderate and severe COVID-19 compared to patients who had mild COVID-19.
Conclusions:
The obtained data on an elevated level of cytokines and IFN-α in the blood of PCS patients can suggest the hypothesis about the participation of chronic inflammation in neurological disorders. The main limitation of the study is the relatively small sample size, which limits the statistical analyses.
DOI: https://doi.org/10.37349/ei.2025.1003184
Coronavirus disease 2019 (COVID-19) infected individuals showed either mild symptoms or were paucisymptomatic, with severe impact on human health, revealing heightened risk and direct effects on health. Among various factors contributing to complications, bacterial and fungal co-infection remains very common and is highly lethal. This narrative review aims to focus on the collective role of gut microbiota and mycobiota in COVID-19. Fungal infection has been identified as a key risk factor for the spread of COVID-19 and mortality. Gut mycobiomes diversity and abundance also vary due to the different types of SARS-CoV-2 variant infection. Their cross-talk plays a vital role in immune regulation and disease severity, with an emphasis on understanding the altered condition as a predictive marker. On the other hand, the gut microbiome is well known for shaping metabolic functions, generating immune responses, and deciphering the signal to decide the healthy state and disease condition of an individual. Immune response during COVID-19 infection was also linked with metabolites produced by the gut microflora, specifically amino acids, sugar metabolites, and neurotransmitters. The cross-talk between gut microbiota and gut mycobiota for clinical implications in terms of early detection, identification of the disease severity, and even therapeutic alternatives will open newer avenues. A deep dive understanding of the cross-talk between the microbiome and mycobiome, and their role in immune response will take scientific discovery knowledge to develop gut-targeted safe therapeutic approaches in the form of FMT (fecal microbiota transplantation) probiotics, peptides, antibacterial, and antifungal metabolites. Overall cross-talk and immune interplay are critical determinants of host immunity, providing insights into their role and key take home lessons for better management of crisis in the future.
Coronavirus disease 2019 (COVID-19) infected individuals showed either mild symptoms or were paucisymptomatic, with severe impact on human health, revealing heightened risk and direct effects on health. Among various factors contributing to complications, bacterial and fungal co-infection remains very common and is highly lethal. This narrative review aims to focus on the collective role of gut microbiota and mycobiota in COVID-19. Fungal infection has been identified as a key risk factor for the spread of COVID-19 and mortality. Gut mycobiomes diversity and abundance also vary due to the different types of SARS-CoV-2 variant infection. Their cross-talk plays a vital role in immune regulation and disease severity, with an emphasis on understanding the altered condition as a predictive marker. On the other hand, the gut microbiome is well known for shaping metabolic functions, generating immune responses, and deciphering the signal to decide the healthy state and disease condition of an individual. Immune response during COVID-19 infection was also linked with metabolites produced by the gut microflora, specifically amino acids, sugar metabolites, and neurotransmitters. The cross-talk between gut microbiota and gut mycobiota for clinical implications in terms of early detection, identification of the disease severity, and even therapeutic alternatives will open newer avenues. A deep dive understanding of the cross-talk between the microbiome and mycobiome, and their role in immune response will take scientific discovery knowledge to develop gut-targeted safe therapeutic approaches in the form of FMT (fecal microbiota transplantation) probiotics, peptides, antibacterial, and antifungal metabolites. Overall cross-talk and immune interplay are critical determinants of host immunity, providing insights into their role and key take home lessons for better management of crisis in the future.
DOI: https://doi.org/10.37349/ei.2025.1003182
Wound healing is an area of growing importance in the healthcare field, especially chronic wounds associated with comorbidities like diabetes mellitus (DM), hypoxic stress, obesity, and malnutrition. Chronic wounds significantly increase healthcare costs and reduce patients’ quality of life. Cytokines are a promising therapeutic target, as they regulate all stages of wound healing, and dysfunction in cytokine production can cause inflammatory non-healing wounds. Interleukin-1 (IL-1), IL-2, IL-6, IL-8, and tumour necrosis factor-α (TNF-α) facilitate leukocyte recruitment and clear dead cells during the initial inflammation stage while transforming growth factor-β (TGF-β), IL-4, and IL-13 inhibit inflammation and stimulate proliferation of fibroblasts to begin extracellular matrix (ECM) deposition. Given the complexity of cytokine interactions and their diverse cellular targets, a comprehensive understanding of these signaling pathways is crucial. This review examines the multifaceted roles of cytokines in wound healing and discusses recent advancements in the therapeutic application of cytokine modulation for improved wound care outcomes. Despite significant advancements in improving the specificity of cytokine therapies, further research is needed to focus on targeting downstream signaling pathways or specific receptors to minimize the adverse effects associated with these treatments.
Wound healing is an area of growing importance in the healthcare field, especially chronic wounds associated with comorbidities like diabetes mellitus (DM), hypoxic stress, obesity, and malnutrition. Chronic wounds significantly increase healthcare costs and reduce patients’ quality of life. Cytokines are a promising therapeutic target, as they regulate all stages of wound healing, and dysfunction in cytokine production can cause inflammatory non-healing wounds. Interleukin-1 (IL-1), IL-2, IL-6, IL-8, and tumour necrosis factor-α (TNF-α) facilitate leukocyte recruitment and clear dead cells during the initial inflammation stage while transforming growth factor-β (TGF-β), IL-4, and IL-13 inhibit inflammation and stimulate proliferation of fibroblasts to begin extracellular matrix (ECM) deposition. Given the complexity of cytokine interactions and their diverse cellular targets, a comprehensive understanding of these signaling pathways is crucial. This review examines the multifaceted roles of cytokines in wound healing and discusses recent advancements in the therapeutic application of cytokine modulation for improved wound care outcomes. Despite significant advancements in improving the specificity of cytokine therapies, further research is needed to focus on targeting downstream signaling pathways or specific receptors to minimize the adverse effects associated with these treatments.
DOI: https://doi.org/10.37349/ei.2025.1003183
Aim:
Immunization with meningococcal vaccine (MV) is the most effective measure to control and prevent the transmission of meningococcal infections. In this study, in order to support the appropriate use of various MVs in the prevention of meningococcal meningitis (MM), the effects of MVs, especially single-dose and inter-booster administered, on inflammatory parameters in < 5-year-old children were investigated.
Methods:
A total of 464 healthy children were included in this study. The data of those who received the first 2 doses at 2-month intervals and the next dose between 8–12 months were included. Nimenrix® (Pfizer) administered as a single dose to children from 12 months of age. Bexsero® (GSK) was administered as 2 + 1 doses under 2 years of age and 2 doses 2 months apart over 2 years of age. Neutrophil, lymphocyte, monocyte, platelet counts, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation response index (SIR-I), and systemic immune inflammation index (SII) were evaluated.
Results:
Of the 464 participants, 58.2% were male, with a mean age of 3.81 years, and both sex ratios and ages were similar across the Nimenrix and Bexsero groups. The laboratory and inflammatory parameters of the two vaccine groups were similar. In both vaccine groups, changes in laboratory parameters before and 3-months after vaccination were similar. The changes in laboratory parameters over time between vaccine groups and their interactions were not significant.
Conclusions:
The NLR, dNLR, PLR, SIR-I, and SII are useful biomarkers indicating the inflammatory response of Nimenrix and Bexsero vaccines. Inflammatory markers can be used as both a safety endpoint and a protection endpoint for MVs (Nimenrix and Bexsero). However, further studies involving larger patient cohorts as well as detailed laboratory data on specific markers of inflammation are needed to draw comprehensive conclusions regarding the inflammatory response following vaccination.
Aim:
Immunization with meningococcal vaccine (MV) is the most effective measure to control and prevent the transmission of meningococcal infections. In this study, in order to support the appropriate use of various MVs in the prevention of meningococcal meningitis (MM), the effects of MVs, especially single-dose and inter-booster administered, on inflammatory parameters in < 5-year-old children were investigated.
Methods:
A total of 464 healthy children were included in this study. The data of those who received the first 2 doses at 2-month intervals and the next dose between 8–12 months were included. Nimenrix® (Pfizer) administered as a single dose to children from 12 months of age. Bexsero® (GSK) was administered as 2 + 1 doses under 2 years of age and 2 doses 2 months apart over 2 years of age. Neutrophil, lymphocyte, monocyte, platelet counts, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation response index (SIR-I), and systemic immune inflammation index (SII) were evaluated.
Results:
Of the 464 participants, 58.2% were male, with a mean age of 3.81 years, and both sex ratios and ages were similar across the Nimenrix and Bexsero groups. The laboratory and inflammatory parameters of the two vaccine groups were similar. In both vaccine groups, changes in laboratory parameters before and 3-months after vaccination were similar. The changes in laboratory parameters over time between vaccine groups and their interactions were not significant.
Conclusions:
The NLR, dNLR, PLR, SIR-I, and SII are useful biomarkers indicating the inflammatory response of Nimenrix and Bexsero vaccines. Inflammatory markers can be used as both a safety endpoint and a protection endpoint for MVs (Nimenrix and Bexsero). However, further studies involving larger patient cohorts as well as detailed laboratory data on specific markers of inflammation are needed to draw comprehensive conclusions regarding the inflammatory response following vaccination.
DOI: https://doi.org/10.37349/ei.2025.1003181
This article belongs to the special issue Chronic Inflammation and Autoimmunity
Aim:
This study aims to identify the factors affecting the formation of neutralizing antibodies (NAbs) in healthy adults four weeks post-COVID-19 vaccination.
Methods:
A cross-sectional study was conducted among mass vaccination attendees using inactivated CoronaVac. Collected the peripheral blood serum four weeks following the second vaccine dose. Forty-four adults aged 26–85 were split into two groups based on age (≤ 60 years and > 60 years) and BMI (non-obese ≤ 25 kg/m2 and obese > 25 kg/m2). Variables like age, gender, BMI, and the presence of comorbidities were recorded. CD4/CD8 ratio and vitamin D levels were examined for their influence on NAbs formation. NAbs were measured using ELISA, T-cells via flow cytometry, and vitamin D through radioimmunoassay. Descriptive data analysis was performed as mean ± standard deviation to show the characteristics of the sample. Students’ t-tests and multivariate and univariate regression analyses were used to evaluate the data.
Results:
Significant variations in NAbs levels were observed with age (P = 0.013), BMI (P = 0.004), and comorbidities (P = 0.034). The elderly demonstrated higher NAb levels, potentially due to the high vitamin D levels compared to the adult group. The vitamin D levels strongly correlated with NAb titer (P < 0.001; R = 0.843). A collective correlation was found between NAb levels and the factors of age, BMI, and CD4/CD8 ratio (P = 0.033). A negative correlation existed between BMI and NAb levels (P = 0.018; R = –0.356) and between age and the CD4/CD8 ratio (P = 0.440; R = –0.119), but age alone did not correlate with NAb titer.
Conclusions:
Age, BMI, CD4/CD8 ratio, and comorbidities influence the production of post-vaccination NAbs. Sufficient vitamin D levels in the elderly significantly boost post-vaccination NAb levels. Maintaining a healthy body weight is also vital, as studies have revealed a significant and negative correlation between BMI and the level of NAbs, suggesting a possible need for adjusted vaccine doses in obese individuals.
Aim:
This study aims to identify the factors affecting the formation of neutralizing antibodies (NAbs) in healthy adults four weeks post-COVID-19 vaccination.
Methods:
A cross-sectional study was conducted among mass vaccination attendees using inactivated CoronaVac. Collected the peripheral blood serum four weeks following the second vaccine dose. Forty-four adults aged 26–85 were split into two groups based on age (≤ 60 years and > 60 years) and BMI (non-obese ≤ 25 kg/m2 and obese > 25 kg/m2). Variables like age, gender, BMI, and the presence of comorbidities were recorded. CD4/CD8 ratio and vitamin D levels were examined for their influence on NAbs formation. NAbs were measured using ELISA, T-cells via flow cytometry, and vitamin D through radioimmunoassay. Descriptive data analysis was performed as mean ± standard deviation to show the characteristics of the sample. Students’ t-tests and multivariate and univariate regression analyses were used to evaluate the data.
Results:
Significant variations in NAbs levels were observed with age (P = 0.013), BMI (P = 0.004), and comorbidities (P = 0.034). The elderly demonstrated higher NAb levels, potentially due to the high vitamin D levels compared to the adult group. The vitamin D levels strongly correlated with NAb titer (P < 0.001; R = 0.843). A collective correlation was found between NAb levels and the factors of age, BMI, and CD4/CD8 ratio (P = 0.033). A negative correlation existed between BMI and NAb levels (P = 0.018; R = –0.356) and between age and the CD4/CD8 ratio (P = 0.440; R = –0.119), but age alone did not correlate with NAb titer.
Conclusions:
Age, BMI, CD4/CD8 ratio, and comorbidities influence the production of post-vaccination NAbs. Sufficient vitamin D levels in the elderly significantly boost post-vaccination NAb levels. Maintaining a healthy body weight is also vital, as studies have revealed a significant and negative correlation between BMI and the level of NAbs, suggesting a possible need for adjusted vaccine doses in obese individuals.
DOI: https://doi.org/10.37349/ei.2025.1003180
This article belongs to the special issue Immunology, Immunopathology and Genomics of SARS-COV-2
Aim:
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality and is characterized by T-cell exhaustion, particularly in effector CD8+ T-cells. This exhaustion, driven by persistent immunosuppressive signals in the tumor microenvironment, impairs immune function and hinders effective immunotherapy. This study aimed to identify key exhaustion-related marker genes in CD8+ T-cells linked to PDAC and assess the potential of repurposing anti-inflammatory drugs to counteract T-cell exhaustion and enhance immune responses against PDAC.
Methods:
We employed a multi-omics approach, integrating single-cell RNA sequencing data with whole genome sequencing to identify dysregulated exhaustion-related immune markers in CD8+ T-cells in PDAC. We examined gene expression profiles and conducted functional enrichment analysis to evaluate their roles in immune exhaustion. We analyzed mutations in the shortlisted biomarkers from The Cancer Genome Atlas (TCGA) and performed in silico mutational analysis using Maestro to evaluate the impact of an IL7R mutation (K110N) on protein function. Virtual screening using a deep learning framework, GNINA, explored the inhibitory features of the anti-inflammatory drugs oxaprozin and celecoxib on IL7R.
Results:
Key dysregulated exhaustion-related immune markers were identified including PRF1, GZMA, CD8A, CD3D, NKG7, IL7R, and IL2RG. Pathway enrichment analysis indicated significant involvement in T-cell receptor signaling, Th1 and Th2 differentiation, and Th17 differentiation pathways, correlating with reported poor survival outcomes in PDAC patients. Mutational analysis of IL7R revealed a likely pathogenic mutation (K110N) located in the IL-7Ralpha fibronectin type III domain. Drug repurposing of oxaprozin and celecoxib showed favorable binding interactions with both wild and mutant IL7R proteins.
Conclusions:
The K110N mutation, despite not causing significant structural changes, may impact T-cell and B-cell homeostasis and development. Our findings suggest that oxaprozin and celecoxib could effectively inhibit T-cell exhaustion through favorable interactions with IL7R. Further clinical studies are necessary to validate the therapeutic potential of these anti-inflammatory drugs in enhancing immune responses in pancreatic cancer.
Aim:
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality and is characterized by T-cell exhaustion, particularly in effector CD8+ T-cells. This exhaustion, driven by persistent immunosuppressive signals in the tumor microenvironment, impairs immune function and hinders effective immunotherapy. This study aimed to identify key exhaustion-related marker genes in CD8+ T-cells linked to PDAC and assess the potential of repurposing anti-inflammatory drugs to counteract T-cell exhaustion and enhance immune responses against PDAC.
Methods:
We employed a multi-omics approach, integrating single-cell RNA sequencing data with whole genome sequencing to identify dysregulated exhaustion-related immune markers in CD8+ T-cells in PDAC. We examined gene expression profiles and conducted functional enrichment analysis to evaluate their roles in immune exhaustion. We analyzed mutations in the shortlisted biomarkers from The Cancer Genome Atlas (TCGA) and performed in silico mutational analysis using Maestro to evaluate the impact of an IL7R mutation (K110N) on protein function. Virtual screening using a deep learning framework, GNINA, explored the inhibitory features of the anti-inflammatory drugs oxaprozin and celecoxib on IL7R.
Results:
Key dysregulated exhaustion-related immune markers were identified including PRF1, GZMA, CD8A, CD3D, NKG7, IL7R, and IL2RG. Pathway enrichment analysis indicated significant involvement in T-cell receptor signaling, Th1 and Th2 differentiation, and Th17 differentiation pathways, correlating with reported poor survival outcomes in PDAC patients. Mutational analysis of IL7R revealed a likely pathogenic mutation (K110N) located in the IL-7Ralpha fibronectin type III domain. Drug repurposing of oxaprozin and celecoxib showed favorable binding interactions with both wild and mutant IL7R proteins.
Conclusions:
The K110N mutation, despite not causing significant structural changes, may impact T-cell and B-cell homeostasis and development. Our findings suggest that oxaprozin and celecoxib could effectively inhibit T-cell exhaustion through favorable interactions with IL7R. Further clinical studies are necessary to validate the therapeutic potential of these anti-inflammatory drugs in enhancing immune responses in pancreatic cancer.
DOI: https://doi.org/10.37349/ei.2025.1003179
This article belongs to the special issue The Role of Immune Checkpoint Molecules in Cancer and Hematological Malignancies
Nociplastic pain is the fourth category of pain defined in recent years. It is a pain arising from altered nociception, despite the lack of clear evidence of actual or threatened tissue damage that causes activation of peripheral nociceptors nor evidence for disease or lesion of the somatosensory system causing the pain. This type of pain is usually multifocal, more diffuse or intense than expected and it is usually associated with other central nervous system-derived symptoms, such as fatigue, sleep, memory, and mood problems. It can occur in isolation or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain. It is associated with increased social and sanitary costs due to the difficulty of adequately treating it. Its pathogenesis is still poorly understood, even if a mounting body of evidence suggests a pivotal role in inflammation and immunity, which may be triggered by an infection and/or a trauma. This narrative review aims to summarise the current knowledge about the interplay of the immune system and nociplastic pathways activation and amplification. The challenge for the future will be to identify the exact role of inflammation and immunity, the cause of this activation, and its link to other pathogenetic factors of nociplastic pain, such as diet or microbiota alteration, social and phycological factors, together with a genetic and epigenetic predisposition.
Nociplastic pain is the fourth category of pain defined in recent years. It is a pain arising from altered nociception, despite the lack of clear evidence of actual or threatened tissue damage that causes activation of peripheral nociceptors nor evidence for disease or lesion of the somatosensory system causing the pain. This type of pain is usually multifocal, more diffuse or intense than expected and it is usually associated with other central nervous system-derived symptoms, such as fatigue, sleep, memory, and mood problems. It can occur in isolation or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain. It is associated with increased social and sanitary costs due to the difficulty of adequately treating it. Its pathogenesis is still poorly understood, even if a mounting body of evidence suggests a pivotal role in inflammation and immunity, which may be triggered by an infection and/or a trauma. This narrative review aims to summarise the current knowledge about the interplay of the immune system and nociplastic pathways activation and amplification. The challenge for the future will be to identify the exact role of inflammation and immunity, the cause of this activation, and its link to other pathogenetic factors of nociplastic pain, such as diet or microbiota alteration, social and phycological factors, together with a genetic and epigenetic predisposition.
DOI: https://doi.org/10.37349/ei.2025.1003178
This article belongs to the special issue Immunology and Pain
Ovarian cancer is the deadliest malignant tumor in the female reproductive system. Despite advancements in standard treatments such as tumor debulking surgery and platinum-based chemotherapy, the overall survival rate remains low. The emergence of targeted therapies, including Poly(ADP-ribose) polymerase (PARP) inhibitors and anti-angiogenic agents, has provided new avenues for treatment. However, drug resistance and disease heterogeneity continue to pose significant challenges. Immune checkpoint inhibitors (ICIs), as an emerging therapeutic approach, primarily target the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways to restore anti-tumor immune responses. Although ICIs have shown significant efficacy in other malignancies, their effectiveness in ovarian cancer is limited, with a response rate of only 10–15% for monotherapy. Recent studies have focused on combining ICIs with chemotherapy, anti-angiogenic agents, or PARP inhibitors to enhance therapeutic outcomes. This article reviews the progress of ICIs in ovarian cancer, including monotherapy and combination treatment strategies, and explores emerging therapeutic targets and strategies aimed at improving patient prognosis and achieving personalized treatment. By gaining a deeper understanding of the tumor microenvironment and its immune evasion mechanisms, there is hope for developing more effective treatment options in the future, ultimately improving the survival rates and quality of life for ovarian cancer patients.
Ovarian cancer is the deadliest malignant tumor in the female reproductive system. Despite advancements in standard treatments such as tumor debulking surgery and platinum-based chemotherapy, the overall survival rate remains low. The emergence of targeted therapies, including Poly(ADP-ribose) polymerase (PARP) inhibitors and anti-angiogenic agents, has provided new avenues for treatment. However, drug resistance and disease heterogeneity continue to pose significant challenges. Immune checkpoint inhibitors (ICIs), as an emerging therapeutic approach, primarily target the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways to restore anti-tumor immune responses. Although ICIs have shown significant efficacy in other malignancies, their effectiveness in ovarian cancer is limited, with a response rate of only 10–15% for monotherapy. Recent studies have focused on combining ICIs with chemotherapy, anti-angiogenic agents, or PARP inhibitors to enhance therapeutic outcomes. This article reviews the progress of ICIs in ovarian cancer, including monotherapy and combination treatment strategies, and explores emerging therapeutic targets and strategies aimed at improving patient prognosis and achieving personalized treatment. By gaining a deeper understanding of the tumor microenvironment and its immune evasion mechanisms, there is hope for developing more effective treatment options in the future, ultimately improving the survival rates and quality of life for ovarian cancer patients.
DOI: https://doi.org/10.37349/ei.2024.00177
This article belongs to the special issue The Role of Immune Checkpoint Molecules in Cancer and Hematological Malignancies
The efficacy of chimeric antigen receptor (CAR)-T therapy may not match initial expectations due to the influence of multiple circumstances, some of which cannot be predicted. CAR-T treatment groups include high-risk patients, particularly those with TP53 mutations. A significant body of research has demonstrated that mutations in the TP53 gene play a pivotal role in cancer development and progression. Any aberration in the TP53 gene in cancer is invariably associated with complications and a poor prognosis. Moreover, mutations in the TP53 gene have been observed to correlate with resistance to conventional chemotherapy, prompting the use of alternative therapeutic approaches, including CAR-T therapy. However, there is a possibility that abnormalities in the TP53 gene may affect patients after CAR-T cell administration reducing the efficacy of therapy. This review examines the link between TP53 mutations in cancer and the efficacy of CAR-T therapy, as well as the potential implications of this aspect in therapeutic planning.
The efficacy of chimeric antigen receptor (CAR)-T therapy may not match initial expectations due to the influence of multiple circumstances, some of which cannot be predicted. CAR-T treatment groups include high-risk patients, particularly those with TP53 mutations. A significant body of research has demonstrated that mutations in the TP53 gene play a pivotal role in cancer development and progression. Any aberration in the TP53 gene in cancer is invariably associated with complications and a poor prognosis. Moreover, mutations in the TP53 gene have been observed to correlate with resistance to conventional chemotherapy, prompting the use of alternative therapeutic approaches, including CAR-T therapy. However, there is a possibility that abnormalities in the TP53 gene may affect patients after CAR-T cell administration reducing the efficacy of therapy. This review examines the link between TP53 mutations in cancer and the efficacy of CAR-T therapy, as well as the potential implications of this aspect in therapeutic planning.
DOI: https://doi.org/10.37349/ei.2024.00176
