Search

We present a 44-year-old man with metastatic clear cell renal cell cancer undergoing treatment with nivolumab immunotherapy. Three months post-initiation, he developed symmetric recurrent nodules and boils in intertriginous areas, diagnosed as stage II hidradenitis suppurativa of the groin and gluteal cleft. The progressive course, lesion symmetry and location, worsening with nivolumab infusions, and biopsy findings supported the diagnosis. Hidradenitis suppurativa pathogenesis involves immune dysregulation marked by elevated IL17 and neutrophil-dominated inflammation [1]. Immune checkpoint inhibitors, including anti-PD1 agents like nivolumab, are linked to immune-related adverse events related to widespread T cell activation, potentially increasing IL17 signaling associated with HS [2,3]. Clinicians should be aware of, and observant for anti-PD1-induced HS, a rare immune-related adverse event, in patients undergoing immune checkpoint inhibitor therapy.

BackgroundMaternal inflammation can result from immune dysregulation and metabolic perturbations during pregnancy. Whether conditions associated with inflammation during pregnancy increase the likelihood of autism spectrum disorder (ASD) or other neurodevelopmental disorders (DDs) is not well understood.MethodsWe conducted a case-control study among children born in California from 2011 to 2016 to investigate maternal immune-mediated and cardiometabolic conditions during pregnancy and risk of ASD (n = 311) and DDs (n = 1291) compared with children from the general population (n = 967). Data on maternal conditions and covariates were retrieved from electronic health records. Maternal genetic data were used to assess a causal relationship.ResultsUsing multivariable logistic regression, we found that mothers with asthma were more likely to deliver infants later diagnosed with ASD (odds ratio [OR] = 1.62, 95% CI: 1.15-2.29) or DDs (OR = 1.30, 95% CI: 1.02-1.64). Maternal obesity was also associated with child ASD (OR = 1.51, 95% CI: 1.07-2.13). Mothers with both asthma and extreme obesity had the greatest odds of delivering an infant later diagnosed with ASD (OR = 16.9, 95% CI: 5.13-55.71). These increased ASD odds were observed among female children only. Polygenic risk scores for obesity, asthma, and their combination showed no association with ASD risk. Mendelian randomization did not support a causal relationship between maternal conditions and ASD.ConclusionsInflammatory conditions during pregnancy are associated with risk for neurodevelopmental disorders in children. These risks do not seem to be due to shared genetic risk; rather, inflammatory conditions may share nongenetic risk factors with neurodevelopmental disorders. Children whose mothers have both asthma and obesity during pregnancy may benefit from earlier screening and intervention.

ABSTRACT The COVID‐19 pandemic caused by the SARS‐CoV‐2 virus was arguably one of the worst public health disasters of the last 100 years. As many infectious disease experts were focused on influenza, MERS, ZIKA, or Ebola as potential pandemic‐causing agents, SARS‐CoV‐2 appeared to come from nowhere and spread rapidly. As with any zoonotic agent, the initial pathogen was able to transmit to a new host (humans), but it was poorly adapted to the immune environment of the new host and resulted in a maladapted immune response. As the host‐pathogen interaction evolved, subsequent variants of SARS‐CoV‐2 became less pathogenic and acquired immunity in the host provided protection, at least partial protection, to new variants. As the host‐pathogen interaction has changed since the beginning of the pandemic, it is possible the clinical results discussed here may not be applicable today as they were at the start of the pandemic. With this caveat in mind, we present an overview of the immune response of severe COVID‐19 from a clinical research perspective and examine clinical trials utilizing immunomodulating agents to further elucidate the importance of hyperinflammation as a factor contributing to severe COVID‐19 disease. [ABSTRACT FROM AUTHOR]

Background: Immune dysregulation has been identified as a contributing factor in the pathophysiology of schizophrenia. This study aimed to investigate variations in specific immune regulators and their correlation with psychopathology and cognitive functions in male patients with chronic schizophrenia. Methods: Employing a cross-sectional design, this study included 72 male patients with chronic schizophrenia. The Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status were utilized to assess psychopathology and cognitive functions, respectively. Results: Serum levels of interleukin (IL)-4, IL-10, IL-12p40, IL-13, and monocyte chemoattractant protein-1 (MCP-1) were measured. There were significantly increased levels of IL-4, IL-13, and MCP-1, alongside decreased levels of IL-10 in patients compared to controls (all P < 0.05). IL-4 levels showed a significant negative association with PANSS positive symptoms (beta=-0.222, P = 0.042). After controlling for antipsychotic medication, BMI, and smoking, this correlation was no longer significant (r=-0.232, P = 0.055). Additionally, positive correlations of IL-4 (beta = 0.297, P = 0.008), IL-13 (beta = 0.371, P = 0.001), and MCP-1 (beta = 0.280, P = 0.013) with language scores were observed. Increased levels of IL-4 (P = 0.044, OR = 1.994), IL-13 (P = 0.019, OR = 2.245), as well as IL-4 and MCP-1 interactions (P = 0.043, OR = 2.000) were positively associated with the risk of chronic schizophrenia, while lower levels of IL-10 (P = 0.003, OR = 0.2.867) were also linked to an increased risk. Conclusion: The identified associations between specific immune markers and the clinical and cognitive features of chronic schizophrenia in males underscored the potential immune-mediated mechanisms underlying schizophrenia. [ABSTRACT FROM AUTHOR]

Peri-implantitis, a complex condition that can lead to dental implant failure, is characterized by inflammatory destruction resulting from immune dysregulation. Oral microbial dysbiosis and foreign body stimulation are the main factors contributing to such dysregulation, impairing immune cell function and triggering an inflammatory response. Immune dysregulation plays a critical role in the pathophysiology of peri-implantitis, impacting the balance of T cell subsets, the production of inflammatory factors, and immune-related molecular signaling pathways. Understanding the relationship between immune dysregulation and peri-implantitis is crucial for developing targeted strategies for clinical diagnosis and individualized treatment planning. This review explores the similarities and differences in the immune microenvironment of oral bacterial infections and foreign body rejection, analyzes the relevant molecular signaling pathways, and identifies new key targets for developing innovative immunotherapeutic drugs and effective and personalized treatment modalities for peri-implantitis. Additionally, it addresses the challenges and potential directions for translating immunotherapy into clinical practice for peri-implantitis, offering insights that bridge the gaps in current literature and pave the way for future research. [ABSTRACT FROM AUTHOR]

Introduction: Inborn errors of immunity (IEIs) are rare genetic disorders primarily identified in children due to their significant effects on immune system functionality. However, an increasing number of IEI cases are being diagnosed in adults, attributed to delayed presentation or advancements in diagnostic capabilities. This study explores the clinical and immunologic distinctions between IEIs diagnosed in adulthood versus childhood, shedding light on their differential presentations, the impact of diagnostic delays, and treatment outcomes. Methods: This study focused on 122 adult patients with IEI above 17 years old, diagnosed in adulthood or childhood. We collected comprehensive data on demographics, clinical presentations, genetic mutations, and therapeutic interventions. Results: The study revealed that 72.9% of participants were diagnosed in adulthood, facing a median diagnostic delay of 96 months. Diagnostic delays were longer in adults (132 months vs. 24 months) than in children. The most common clinical manifestations at onset were recurrent infections (46.7%) and autoimmunity (18%). Predominantly antibody deficiency was the most frequently diagnosed immunodeficiency (54.9%), followed by immunodysregulation at a rate of 26.2%. A higher incidence of immune thrombocytopenia or other complications, such as hepatomegaly and enteropathy, was observed in adult-diagnosed patients with IEI. Malignancies were more prevalent in patients with adult-onset IEI compared to those with childhood-onset (18.1% vs. 5.2%). Overall, 15 different malignancies were recorded in 13 patients (10.6%), including lymphomas and cancers of the stomach, thymus, skin, breast, and colon. Conclusions: The findings highlight a considerable diagnostic delay in recognizing IEI, especially in adults, and illustrate distinct differences in disease manifestation and progression between adult-onset and delayed-diagnosis groups. [ABSTRACT FROM AUTHOR]

A growing body of clinical and experimental evidence indicates that immune checkpoint blockade enhances patient susceptibility to hypersensitivity reactions to co-administered medications. In this study, we utilized an in vitro T-cell priming assay to demonstrate one of the mechanistic hypotheses on how this occurs; through lowering of the threshold in patients to elicit aberrant T-cell responses. We outline the dependency of de novo T-cell priming responses to drug-associated antigens on dose at initial exposure. Findings support the aforementioned hypothesis and offer an experimental representation of fundamental parameters at play in hypersensitivity reactions to low molecular weight compounds. [ABSTRACT FROM AUTHOR]

Infantile refractory diarrhea presents after first few days of life leading to intestinal insufficiency. It is a diagnostic challenge due to varied etiologies like food senstive enteropathy, anatomical defects and dysmotility disorders, transport and enzymatic defects, pancreatic malabsorption - cystic fibrosis (CF), primary epithelial causes like microvillus inclusion disease (MVID), tufting enteropathy and heparan sulfate deficiency, immunodeficiencies, metabolic diseases and autoimmune enteropathy. It is refractory to treatment making the patient dependent on total parenteral nutrition. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), is one of the rarest causes of intractable diarrhea. It occurs due to mutations in the FOXP3 gene, leading to dysfunction of T-regulatory cells and is characterised by diarrhoea, diabetes, and dermatitis. We aim to evaluate various causes of infantile refractory chronic diarrhea, and to present one such case of IPEX syndrome from this part of the world due to mutation not been reported in literature so far. [ABSTRACT FROM AUTHOR]

Background: Common Variable Immunodeficiency (CVID) represents a heterogenic group of primary immunodeficiencies (PID) characterized by impaired antibody production and susceptibility to infections. Non-infectious complications, such as autoimmune diseases, lymphoproliferative disorders, and malignancies, now significantly impact prognosis. Moreover, both hematologic and solid organ malignancies are more frequently observed in CVID patients compared to other PIDs. The risk factors for carcinogenesis in CVID remain largely unknown. Objective: This multicenter study aims to characterize the clinical profile of cancer in CVID patients in Spain and to identify independent risk factors associated with malignancy development, focusing on the role of immune dysregulation. Methods: A nationwide, cross-sectional study was conducted from November 2019 to May 2022, involving 17 hospitals treating PID patients in Spain. Data were collected systematically on demographics, infectious and non-infectious comorbidities, immunological parameters, and treatment. Statistical analysis, including multivariate logistic regression, was performed to identify risk factors associated to malignancy. Results: Of 250 CVID patients, 38 (15.26%) were diagnosed with cancer, predominantly non-Hodgkin lymphoma, gastric cancer, and lung adenocarcinoma. Cancer patients were significantly older (mean age 60.70 vs. 49.36 years, p<0.001) and had higher rates of immune dysregulation (81.58% vs. 59.7%, p=0.01). Immune dysregulation was an independent risk factor for cancer (OR 2.19, p=0.04), alongside previous immunosuppressant therapy (OR 2, p=0.031), higher IgM levels (OR 1.008 per SD, p=0.012), older age (OR 1.04, p<0.001), and lower CD4 cell counts at diagnosis (OR 0.997, p<0.001). Conclusions: This study highlights the increased cancer risk in CVID patients, with immune dysregulation, prior immunosuppressant use, elevated IgM levels, and lower CD4 cell counts as conjointly associated. These findings underscore the need for vigilant cancer screening and tailored management strategies in CVID patients to improve outcomes. Future research should focus on elucidating the molecular mechanisms linking immune dysregulation and malignancy in CVID. [ABSTRACT FROM AUTHOR]

Inflammation plays a crucial role in atherosclerosis and nonalcoholic fatty liver disease (NAFLD). We previously engineered a recombinant Lactococcus lactis strain expressing the Ling-Zhi immunomodulatory protein (L. lactis-LZ8). This study investigated the anti-atherosclerotic effects of L. lactis-LZ8 in rabbits fed a high-fat diet (HFD). Changes in body weight, serum lipid profiles, and liver function were monitored. The aorta and liver tissues were analyzed for gross pathology and histopathology. Eight-week administration of L. lactis-LZ8 with HFD ameliorated atherosclerosis by downregulating protein and gene expression associated with lipid metabolism and inflammation in the aortas. The rabbits receiving L. lactis-LZ8 exhibited a significant dose-dependent reduction in hepatic fat accumulation. RNA sequencing of the livers revealed that inflammatory genes in the L. lactis-LZ8 groups were downregulated compared to the HFD group. Disease ontology enrichment analysis indicated that these genes were involved in atherosclerosis. Gene set enrichment analysis plots revealed significant enrichment in the gene sets related to cholesterol homeostasis. CIBERSORT immune cell fraction analysis indicated significant infiltration by regulatory T cells, CD8+ T cells, activated dendritic cells, and natural killer cells in the L. lactis-LZ8 group. Our studies underscore LZ8's role in precision nutrition, providing a potential solution to the current challenges in modifying atherosclerosis and NAFLD. [ABSTRACT FROM AUTHOR]

The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls. We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular. Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms. The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only. These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and weight loss. The pathogenesis and treatment of UC remain key areas of research interest. Various factors, including genetic predisposition, immune dysregulation, and alterations in the gut microbiota, are believed to contribute to the pathogenesis of UC. Current treatments for UC include 5-aminosalicylic acids, corticosteroids, immunosuppressants, and biologics. However, study reported that the one-year clinical remission rate is only around 40%. It is necessary to prompt the exploration of new treatment modalities. Biologic therapies, such as anti-TNF-α monoclonal antibody and JAK inhibitor, primarily consist of small molecules targeting specific pathways, effectively inducing and maintaining remission. Given the significant role of the gut microbiota, research into intestinal microecologics, such as probiotics and prebiotics, and fecal microbiota transplantation (FMT) shows promising potential in UC treatment. Additionally, medicinal herbs, such as chili pepper and turmeric, used in complementary therapy have shown promising results in UC management. This article reviews recent findings on the mechanisms of UC, including genetic susceptibility, immune cell dynamics and cytokine regulation, and gut microbiota alterations. It also discusses current applications of biologic therapy, herbal therapy, microecologics, and FMT, along with their prospects and challenges. [ABSTRACT FROM AUTHOR]

Magnesium transporter 1 (MAGT1) gene loss-of-function variants lead to X-linked MAGT1 deficiency with increased susceptibility to EBV infection and N-glycosylation defect (XMEN), a condition with a variety of clinical and immunological effects. In addition, MAGT1 deficiency has been classified as a congenital disorder of glycosylation (CDG) due to its unique role in glycosylation of multiple substrates including NKG2D, necessary for viral protection. Due to the predisposition for EBV, this etiology has been linked with hemophagocytic lymphohistiocytosis (HLH), however only limited literature exists. Here we present a complex case with HLH and EBV-driven classic Hodgkin lymphoma (cHL) as the presenting manifestation of underlying immune defect. However, the patient’s underlying immunodeficiency was not identified until his second recurrence of Hodgkin disease, recurrent episodes of Herpes Zoster, and after he had undergone autologous hematopoietic stem cell transplant (HSCT) for refractory Hodgkin lymphoma. This rare presentation of HLH and recurrent lymphomas without some of the classical immune deficiency manifestations of MAGT1 deficiency led us to review the literature for similar presentations and to report the evolving spectrum of disease in published literature. Our systematic review showcased that MAGT1 predisposes to multiple viruses (including EBV) and adds risk of viral-driven neoplasia. The roles of MAGT1 in the immune system and glycosylation were highlighted through the multiple organ dysfunction showcased by the previously validated Immune Deficiency and Dysregulation Activity (IDDA2.1) score and CDG-specific Nijmegen Pediatric CDG Rating Scale (NPCRS) score for the patient cohort in the systematic review. [ABSTRACT FROM AUTHOR]

Background and objectives: Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by decreased immunoglobulins and recurrent infections, with non-infectious complications such as granulomatous–lymphocytic interstitial lung disease (GLILD) affecting up to 30% of patients. Methods: Using high-throughput 16S rRNA gene sequencing, salivary, sputum, and fecal microbiome from CVID patients with GLILD, comparing them to CVID patients without GLILD—with immune dysregulation (dCVID) and only infections (iCVID)—and healthy controls was analyzed. Results: A total of 41 CVID patients, 7 with GLILD, and 15 healthy donors were included. Global fecal biodiversity was significantly lower in GLILD patients compared to CVID subgroups and controls. GLILD patients harbored different specific bacterial communities in all niches, with some keystone species common to dCVID. Conchiformibius, Micrococcales, and Capnocytophaga are more frequent in the sputum of GLILD patients. Saliva in GLILD shows higher frequencies of Conchiformibius and Haemophilusparainfluenzae. Fecal samples from GLILD patients have higher levels of Gemella morbilorum, Lacticaseibacillus, and Cellulosimicrobium. A non-assigned Conchiformibius spp. is consistently associated with GLILD across different niches and could be a potential pathobiont or relevant microbiological marker for GLILD. Cluster network and correlation analyses show profound dysbiosis in the sputum, saliva, and feces of GLILD patients. Conclusions: These findings highlight significant microbiome alterations in CVID patients with GLILD, particularly in the respiratory tract, suggesting a possible link to both local and systemic immune dysregulation. [ABSTRACT FROM AUTHOR]

Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management. [ABSTRACT FROM AUTHOR]

Background: The multisystemic features of Down syndrome (DS) in children are accompanied by immunodeficiency, making them susceptible to infections and immune dysregulation with autoimmune, allergic, inflammatory, and hematological complications. This study was aimed at a better understanding of the abnormalities within the B and T cell compartments and their correlations with clinical immunophenotypes. Methods: Medical records of 35 DS children were retrospectively reviewed, referring to clinical symptomatology including history of infections, immune dysregulation disorders, and humoral and cellular immune response. Results: While the etiology of respiratory tract infections included typical viral and bacterial pathogens, SARS-CoV2-induced inflammatory disease and syndromic immunodeficiency contributed significantly to the deterioration of the clinical course. Allergic diseases in the form of asthma, allergic rhinitis, and alimentary allergy were the most frequent manifestations of immune dysregulation and were followed by autoimmune disorders, such as Crohn's disease, celiac disease, autoimmune thyroiditis, and alopecia, as well as inflammatory disorders, balanitis xerotica obliterans and lymphadenopathy, and a hematological disorder of myelopoiesis. Deficiency of serum immunoglobulin levels, reduced numbers of naïve B cells, and non-switched memory B cells along with low naïve T helper cells and significantly reduced regulatory T helper cells were the most prominent immune abnormalities. Conclusions: The loss of naïveté in B and T lymphocyte compartments with a deficiency of regulatory T cells may be underpinning pathomechanisms for the skewed immune response. The clinical immunophenotype in DS is complex and represents syndromic primary immunodeficiency with immune dysregulation. [ABSTRACT FROM AUTHOR]

The current literature has identified many abnormalities in the immune expression of cows infected with the bovine leukemia virus (BLV). These studies have focused on individual cell, gene, or protein expression, failing to provide a comprehensive understanding of the changes in immune expression in animals with BLV. To identify the overall alterations in immune expression during BLV infection, the transcriptomes of the peripheral blood mononuclear cells (PBMCs) of cows seropositive or seronegative for BLV antibodies were sequenced. Whole blood samples were collected from 20 dairy cows and screened for BLV antibodies and PCR was used to quantify the proviral load of the samples. PBMCs were separated from whole blood using density gradient centrifugation from which RNA was isolated and sequenced. Three seropositive samples (BLV+; n = 3), including one of each PVL category, low (n = 1), moderate (n = 1), and high (n = 1), and three seronegative samples (BLV−; n = 3) were sequenced for differential gene expression analysis. The results showed major differences in the transcriptome profiles of the BLV+ and BLV− PBMCs and revealed a wide variety of immunological pathways affected by BLV infection. Our results suggest that disease state and PBMC gene expression vary depending on BLV proviral load levels and that BLV causes the suppression of normal immune responses and influences B and T cell gene expression, resulting in immune dysfunction. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a prevalent autoimmune disease primarily characterized by the involvement of multiple systems and organs. Cardiovascular disease is the primary cause of mortality in patients with SLE, though the mechanisms underlying the increased cardiovascular risk in SLE patients remain unclear. Recent studies indicate that abnormal activation of programmed cell death (PCD) signaling and the crosstalk among various forms of cell death are critical in the immunopathogenesis of SLE. Furthermore, apoptosis, necroptosis, pyroptosis, NETosis, and ferroptosis are recognized as key cellular processes in the pathogenesis of SLE and are closely linked to cardiac involvement. This review uniquely explores the intricate crosstalk between apoptosis, necroptosis, and other cell death pathways, discussing their roles and interactions in the pathogenesis of cardiac involvement in SLE. Investigating the interplay between PCD signaling and cardiac involvement in SLE in understanding the disease's underlying mechanisms and offers opportunities for new therapeutic interventions. The integration of precision medicine and innovative strategies targeting these complex pathways holds promise for enhancing the treatment prospects of SLE with cardiac involvement. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, characterized by heterogeneous genetic, immunological, and clinical phenotypes. It is no longer conceived as a sole disease but as an umbrella diagnosis comprising a spectrum of clinical conditions, with defects in antibody biosynthesis as their common denominator and complex pathways determining B and T cell developmental impairments due to genetic defects of many receptors and ligands, activating and co-stimulatory molecules, and intracellular signaling molecules. Consequently, these genetic variants may affect crucial immunological processes of antigen presentation, antibody class switch recombination, antibody affinity maturation, and somatic hypermutation. While infections are the most common features of pediatric CVID, variants in genes linked to antibody production defects play a role in pathomechanisms of immune dysregulation with autoimmunity, allergy, and lymphoproliferation reflecting the diversity of the immunogenetic underpinnings of CVID. Herein, we have reviewed the aspects of genetics in CVID, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology. We have also briefly discussed the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes as background for CVID development. [ABSTRACT FROM AUTHOR]

Background: Phosphoinositide 3 kinases (PI3K) are lipid kinases expressed in lymphocytes/myeloid cells. PI3K/AKT/mTOR signaling defects present with recurrent infections, autoimmunity, lymphoproliferation, and agammaglobulinemia. Objective: To characterize the PI3K/AKT/mTOR pathway defects and perform pathway analyses to assess novel variant pathogenicity. Methods: We included 12 patients (heterozygous PIK3CD (n = 9) and PIK3R1 (n = 1) (activated PI3K delta syndrome (APDS) with gain‐of‐function mutations) and homozygous PIK3R1 variant (n = 2)), performed clinical/laboratory/genetic evaluation, and flow cytometric PI3K/AKT/mTOR pathway analyses. Results: Median age at onset of complaints was 17.5 months (3 months to 12 years) and at diagnosis was 15.7 years (2.5–37) in APDS. Median diagnostic delay was 12.9 years (1.6–27). Recurrent respiratory tract infections (90%), lymphoproliferation (70%), autoimmune/inflammatory findings (60%), and allergy (40%) were common in APDS. Recurrent viral infections were present in 4/10 and malignancy (non‐Hodgkin lymphoma and testicular yolk sac tumor) was present in 2/10 in APDS. Low CD4+ T cells(5/8) with increased CD4+ effector memory (8/8) and CD4+ TEMRA cells (6/8) were present in the given number of APDS patients. We diagnosed tubulointerstitial nephritis, Langerhans cell histiocytosis, and late‐onset congenital adrenal hyperplasia in APDS. Allergic findings, lymphoproliferation/malignancy, and high IgM were present in the APDS but not in PIK3R1 deficiency. Low IgM/IgG/CD19+ B cell counts were characteristic in patients with PIK3R1 homozygous loss‐of function mutations. Conclusion: Differential diagnosis with combined immunodeficiency and diseases of immune dysregulation make molecular genetic analysis crucial for diagnosing mTOR pathway defects. It is easy to differentiate APDS and homozygous PIK3R1 defects with specific laboratory features. Additionally, mTOR pathway functional analysis is a definitive diagnostic and pathogenicity assessment tool for novel APDS mutations. [ABSTRACT FROM AUTHOR]

• Cystic fibrosis patients have a specific systemic immune profile similar to other immune diseases. • Lung function heterogeneity is linked to impaired B-cell function and tregs homeostasis. • Specific microbes contribute to disrupting the balance of the immune response. Excessive inflammation and recurrent airway infections characterize people with cystic fibrosis (pwCF), a disease with highly heterogeneous clinical outcomes. How the overall immune response is affected in pwCF, its relationships with the lung microbiome, and the source of clinical heterogeneity have not been fully elucidated. Peripheral blood and sputum samples were collected from 28 pwCF and an age-matched control group. Systemic immune cell subsets and surface markers were quantified using multiparameter flow cytometry. Lung microbiome composition was reconstructed using metatranscriptomics on sputum samples, and microbial taxa were correlated to circulating immune cells and surface markers expression. In pwCF, we found a specific systemic immune profile characterized by widespread hyperactivation and altered frequencies of several subsets. These included substantial changes in B-cell subsets, enrichment of CD35+/CD49d+ neutrophils, and reduction in dendritic cells. Activation markers and checkpoint molecule expression levels differed from healthy subjects. CTLA-4 expression was increased in Tregs and, together with impaired B-cell subsets, correlated with patients' lung function. Concentrations and frequencies of key immune cells and marker expression correlated with the relative abundance of commensal and pathogenic bacteria in the lungs. The CF-specific immune signature, involving hyperactivation, immune dysregulation with alteration in Treg homeostasis, and impaired B-cell function, is a potential source of lung function heterogeneity. The activity of specific microbes contributes to disrupting the balance of the immune response. Our data provide a unique foundation for identifying novel markers and immunomodulatory targets to develop the future of cystic fibrosis treatment and management. [ABSTRACT FROM AUTHOR]

TRPM4 is a broadly expressed, calcium-activated, monovalent cation channel that regulates immune cell function in mice and cell lines. Clinically, however, partial loss- or gain-of-function mutations in TRPM4 lead to arrhythmia and heart disease, with no documentation of immunologic disorders. To characterize functional cellular mechanisms underlying the immune dysregulation phenotype in a proband with a mutated TRPM4 gene. We employed a combination of biochemical, cell biological, imaging, omics analyses, flow cytometry, and gene editing approaches. We report the first human cases to our knowledge with complete loss of the TRPM4 channel, leading to immune dysregulation with frequent bacterial and fungal infections. Single-cell and bulk RNA sequencing point to altered expression of genes affecting cell migration, specifically in monocytes. Inhibition of TRPM4 in T cells and the THP-1 monocyte cell line reduces migration. More importantly, primary T cells and monocytes from TRPM4 patients migrate poorly. Finally, CRISPR knockout of TRPM4 in THP-1 cells greatly reduces their migration potential. Our results demonstrate that TRPM4 plays a critical role in regulating immune cell migration, leading to increased susceptibility to infections. [ABSTRACT FROM AUTHOR]

Simple Summary: There are many instances in which behavioral management refinements have impacted veterinary practices (e.g., positive reinforcement training and cooperative blood collection). There are fewer examples of veterinary information impacting behavioral management practices. We propose that the neutrophil to lymphocyte ratio (NLR), a cheap, simple, and easy marker of stress and inflammation often used in human clinical practice, has welfare utility in nonhuman primates (NHPs). However, there are only 7 published studies that have specifically examined NLR in NHPs, finding associations with longevity, certain medical conditions, and stressful circumstances. Therefore, we examined NLR as a function of stress resulting from clinical and research practices (i.e., sedation order within a group and sedation rate over time). We found that baboons sedated later within a group showed significantly higher NLR than those sedated earlier in the process, perhaps indicating an acute stress response. However, baboons with higher sedation rates per month showed lower NLRs, perhaps a reflection of more chronic stress. This points to the potential utility of NLR as a veterinary measure indicating possible dysregulation as a function of stress, and the opportunity for veterinarians and behavioral managers to work together to minimize stress through refinements to the environment, clinical care, and research practices. Neutrophil to lymphocyte ratio (NLR) is a simple marker of stress and inflammation, but there is limited research regarding NLR in nonhuman primates (NHPs), with studies showing associations with longevity, certain medical conditions, and stressful circumstances. Here, we examined baboon NLR longitudinally, and as a function of health parameters. We also examined whether NLR was affected by sedation rate, as well as the order of sedation within a group, given that sedation events during clinical and research practices can induce stress in NHPs. While older adult and geriatric baboon NLR did not differ longitudinally, juvenile and young adult NLR tended to increase, primarily driven by increases in females. Additionally, baboons sedated later within a group showed significantly higher NLRs than those sedated earlier in the process. However, baboons with higher sedation rates per month showed lower NLRs. These data indicate that NLR may be dysregulated in different ways as a function of different types of stress, with sedation order (i.e., acute stress) causing pathological increases in NLR, and sedation rate over time (i.e., chronic stress) causing decreases. Importantly, we propose that NLR, a routinely obtained veterinary measure, has potential utility as a welfare indicator of stress resulting from clinical and research practices, as well as a measure that can inform behavioral management practices and interventions. [ABSTRACT FROM AUTHOR]

Potentially, patients with COVID-19 can experience long-term disturbances after the acute infection period, even people with no symptoms or mild illness. Our current understanding of brain-associated post COVID-19 condition and why some people are more affected is limited. Post COVID syndrome or long COVID, with continuing symptoms of impaired brain functioning, in particular, 'brain fog', chronic fatigue, cognitive decline, mood disturbances, anxiety, and depression, is due to multiple molecular mechanisms. This narrative review updates most important cellular and molecular brain mechanisms as well as system mechanisms underlying post COVID syndrome. [ABSTRACT FROM AUTHOR]

Abstract Background Immune dysregulation has been identified as a contributing factor in the pathophysiology of schizophrenia. This study aimed to investigate variations in specific immune regulators and their correlation with psychopathology and cognitive functions in male patients with chronic schizophrenia. Methods Employing a cross-sectional design, this study included 72 male patients with chronic schizophrenia. The Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status were utilized to assess psychopathology and cognitive functions, respectively. Results Serum levels of interleukin (IL)-4, IL-10, IL-12p40, IL-13, and monocyte chemoattractant protein-1 (MCP-1) were measured. There were significantly increased levels of IL-4, IL-13, and MCP-1, alongside decreased levels of IL-10 in patients compared to controls (all P

Anti-N-methyl-ᴅ-aspartate receptor (NMDAR) encephalitis is a rare disease with a range of neurological and psychiatric presentations. Antibodies against NMDAR receptor are purported to be pathologic, and the two known potential immunological triggers are tumors and viral infection. In half of the cases, the trigger is not known. We present two cases where stress seemed to have triggered encephalitis. These cases illustrate the possible role of stress in leading to immune dysregulation, which can lead to encephalitis. We review the role of stress in anti-NMDAR encephalitis and possible mechanisms by which stress can trigger an immune dysregulation.

Abstract Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and weight loss. The pathogenesis and treatment of UC remain key areas of research interest. Various factors, including genetic predisposition, immune dysregulation, and alterations in the gut microbiota, are believed to contribute to the pathogenesis of UC. Current treatments for UC include 5-aminosalicylic acids, corticosteroids, immunosuppressants, and biologics. However, study reported that the one-year clinical remission rate is only around 40%. It is necessary to prompt the exploration of new treatment modalities. Biologic therapies, such as anti-TNF-α monoclonal antibody and JAK inhibitor, primarily consist of small molecules targeting specific pathways, effectively inducing and maintaining remission. Given the significant role of the gut microbiota, research into intestinal microecologics, such as probiotics and prebiotics, and fecal microbiota transplantation (FMT) shows promising potential in UC treatment. Additionally, medicinal herbs, such as chili pepper and turmeric, used in complementary therapy have shown promising results in UC management. This article reviews recent findings on the mechanisms of UC, including genetic susceptibility, immune cell dynamics and cytokine regulation, and gut microbiota alterations. It also discusses current applications of biologic therapy, herbal therapy, microecologics, and FMT, along with their prospects and challenges.

Abstract The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls. We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular. Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms. The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only. These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.

Li Chen,1,2 Xi-Le Peng,1,2 Zhi-Xuan Chen,1,2 Lu-Ming Qi,1,2 Ting-Ting Deng,2,3 Li-Na Xia1,2 1School of Health Preservation and Rehabilitation, Chengdu University of TCM, Chengdu, Sichuan, People’s Republic of China; 2Key Laboratory of Traditional Chinese Medicine Regimen and Health Industry Development, State Administration of TCM, Chengdu, Sichuan, People’s Republic of China; 3School of Nursing, Chengdu University of TCM, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Li-Na Xia, School of Health Preservation and Rehabilitation, Chengdu University of TCM, Chengdu, Sichuan, People’s Republic of China, Email xialina@cdutcm.edu.cnBackground: Excessive salt consumption has been associated with detrimental health consequences, including hypertension, colitis, and autoimmune disorders. However, recent studies have proposed that high salt diet (HSD) can both stimulate the immune system, affecting the differentiation of immune cells, promoting or inhibiting cytokine secretion to fight cancer or elicit a more potent autoimmune response, and exerting an immunosuppressive effect to influence disease development, providing mechanistic insights into the direction of immune regulation in which HSD affects disease.Objective: This paper reviews the immunomodulatory effects of HSD on various innate immune and adaptive cells, especially macrophages, dendritic cells, and T cells, in relation to disease development.Methods: We identified papers by electronically searching the Web of Science (WOS) database from inception through March 2023.Results: A growing number of animal experiments and in vitro cell culture studies have shown that HSD can regulate the differentiation and activation of a variety of immune cells, and promote or inhibit different cytokines to mediate the development of a variety of diseases, including nephropathy, hypertension, cancer, inflammatory bowel disease, and a number of autoimmune diseases. These findings provide a new mechanism for pathological changes in the direction of immune regulation and suggest that HSD is a predisposing factor for a variety of diseases, providing new mechanistic insights into dietary health modification.Conclusion: HSD mediates the development of multiple diseases by regulating the differentiation and activation of a variety of immune cells, and the underlying mechanisms may be related to gut microbes and their metabolites.Keywords: HSD, immune dysregulation, disease pathogenesis, mechanistic insights, review

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by immune system dysfunction that can lead to serious health issues and mortality. Recent investigations highlight the role of gut microbiota alterations in modulating inflammation and disease severity in SLE. This review specifically summaries the variations in gut microbiota composition across various murine models of lupus. By focusing on these differences, we aim to elucidate the intricate relationship between gut microbiota dysbiosis and the development and progression of SLE in preclinical settings. [ABSTRACT FROM AUTHOR]

Purpose: Heterozygous STAT1 Gain-of-Function (GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC) among Inborn Errors of Immunity. Clinically, these mutations manifest as a broad spectrum of immune dysregulation, including autoimmune diseases, vascular disorders, and malignancies. The pathogenic mechanisms of immune dysregulation and its impact on immune cells are not yet fully understood. In treatment, JAK inhibitors have shown therapeutic effectiveness in some patients. Methods: We analyzed clinical presentations, cellular phenotypes, and functional impacts in five Taiwanese patients with STAT1 GOF. Results: We identified two novel GOF mutations in 5 patients from 2 Taiwanese families, presenting with symptoms of CMC, late-onset rosacea, and autoimmunity. The enhanced phosphorylation and delayed dephosphorylation were displayed by the patients' cells. There are alterations in both innate and adaptive immune cells, including expansion of CD38+HLADR +CD8+ T cells, a skewed activated Tfh cells toward Th1, reduction of memory, marginal zone and anergic B cells, all main functional dendritic cell lineages, and a reduction in classical monocyte. Baricitinib showed therapeutic effectiveness without side effects. Conclusion: Our study provides the first comprehensive clinical and molecular characteristics in STAT1 GOF patient in Taiwan and highlights the dysregulated T and B cells subsets which may hinge the autoimmunity in STAT1 GOF patients. It also demonstrated the therapeutic safety and efficacy of baricitinib in pediatric patient. Further research is needed to delineate how the aberrant STAT1 signaling lead to the changes in cellular populations as well as to better link to the clinical manifestations of the disease. [ABSTRACT FROM AUTHOR]

The paper presents a description of a clinical case of Gougerot–Hailey–Hailey disease with proven dysregulation of the immune response. The disease, also known as chronic benign familial pemphigus, is a rare genetic disorder that causes bullous skin lesions with intraepidermal localization. It is named after the authors who first described it. In most cases, Gougerot–Hailey–Hailey disease is caused by a mutation in the ATP2C1 gene that disrupts calcium regulation. Calcium accumulation alters normal intercellular adhesion in the skin, resulting in characteristic bullous skin lesions. Gougerot–Hailey–Hailey disease is inherited in an autosomal dominant pattern. The frequency of distribution in the population is 1:50000 people. However, the variety of clinical phenotypes of the disease without a proven hereditary predisposition and the absence of a mutation in this gene allows us to assert the presence of other pathogenic factors, in particular, disorders in the immune system. In the clinical case we are describing, no clear genetic predisposition was revealed, but serious disorders in the immune system were detected. In particular, TNK cells are virtually non-existent. Analysis of subpopulations of natural killer cells indicates a decrease in the relative and absolute numbers of NK cells expressing CD16 and CD56 antigens, NK cells with high cytolytic activity, NK cells expressing the α chain of the CD8 antigen and having the ability to repeatedly perform their cytolytic function. When assessing B cell subpopulations, there is an increase in the relative content of B2 cells and B1 cells associated with production of autoantibodies, in parallel with an increase in the percentage of regulatory T helper cells with immunosuppressive function. Based on the identified changes in the immune system, we performed immunomodulatory therapy: discrete plasmapheresis, 5 procedures in 2 days, then intravenous drip injection of normal human immunoglobulin 25 mL (50 μg/mL) in 3 days, 5 infusions. The dynamics of cutaneous manifestations indicates a moderate positive effect. Obviously, further in-depth study of immune parameters in Gugerout-Haley-Haley disease, presumably in the innate immune system, is required. Probably, success in treatment and achievement of stable remission will be possible with the rational selection of anticytokine therapy.

Introduction: Lichen planus is a chronic mucocutaneous disease that may affect the skin or any other mucosal surface. Although the etiology is largely unknown, role of stress in initiation or aggravation of the disease is a well-known fact. Apart from respiratory distress, COVID-19 has also been found to be associated with triggering autoimmune reactions such as oral lichen planus (OLP). Apart from its direct ill effect on health, the confusing nature, and the unknown course of COVID-19, the psychological stress of the lockdown and quarantine tremendously increased the stress levels. All this could be a trigger for the onset or exacerbation of existing OLP lesions. Objective: The primary outcome is to understand the likely association between OLP and COVID-19. The secondary outcome is to understand the role of COVID-19 in the pathogenesis of OLP if it is present. Materials and Methods: It was a unicentric cross-sectional study conducted on 57 patients suffering from OLP who had reported to the dental outpatient department of our tertiary health care center from September 2021 to April 2022. The clinical sign and symptoms associated with the OLP was recorded. A detailed history of COVID-19 exposure, vaccination status, and history of hospitalization were recorded. Results: The mean age of study participants was found to be 36.8 years the male:female ratio was found to be 1:2. Out of 57 patients, 45 patients had given a positive history of COVID-19 exposure. Conclusion: Apart from the immune dysregulation, the tremendous increase in stress levels due to COVID-19 has impacted everyone’s life very badly. The sudden increase in cases of OLP in post-COVID patients may be attributable to a combination of factors such as low Vitamin D levels COVID-19 and other comorbidities.

Primary progressive multiple sclerosis (PPMS), the least frequent type of multiple sclerosis (MS), is characterized by a specific course and clinical symptoms, and it is associated with a poor prognosis. It requires extensive differential diagnosis and often a long-term follow-up before its correct recognition. Despite recent progress in research into and treatment for progressive MS, the diagnosis and management of this type of disease still poses a challenge. Considering the modern concept of progression "smoldering" throughout all the stages of disease, a thorough exploration of PPMS may provide a better insight into mechanisms of progression in MS, with potential clinical implications. The goal of this study was to review the current evidence from investigations of PPMS, including its background, clinical characteristics, potential biomarkers and therapeutic opportunities. Processes underlying CNS damage in PPMS are discussed, including chronic immune-mediated inflammation, neurodegeneration, and remyelination failure. A review of potential clinical, biochemical and radiological biomarkers is presented, which is useful in monitoring and predicting the progression of PPMS. Therapeutic options for PPMS are summarized, with approved therapies, ongoing clinical trials and future directions of investigations. The clinical implications of findings from PPMS research would be associated with reliable assessments of disease outcomes, improvements in individualized therapeutic approaches and, hopefully, novel therapeutic targets, relevant for the management of progression. [ABSTRACT FROM AUTHOR]

Rosacea is a complex inflammatory condition characterized by papulopustular lesions and erythema on the central face for which there is no cure. The development of rosacea is influenced by both external triggers and genetics, but the common pathophysiology is overactivation of the immune system. Here, we review the current data on proinflammatory cytokines and dysregulation of the neurovascular system as targetable components of rosacea. Amelioration of cutaneous and gastrointestinal dysbiosis and other external factors impacts the immune state and has been observed to improve rosacea. While multiple treatments exist, many patients do not achieve their goals for rosacea control and highlights an unmet need for dermatologic care. Current interventions encompass topical/oral drugs, light devices, and avoidance of triggers management. Additional understanding of the underlying pathogenesis may help us develop novel targeted therapeutic strategies to improve rosacea. [ABSTRACT FROM AUTHOR]

Sepsis stands as a prominent contributor to sickness and death on a global scale. The most current consensus definition characterizes sepsis as a life-threatening organ dysfunction stemming from an imbalanced host response to infection. This definition does not capture the intricate array of immune processes at play in sepsis, marked by simultaneous states of heightened inflammation and immune suppression. This overview delves into the immune-related processes of sepsis, elaborating about mechanisms involved in hyperinflammation and immune suppression. Moreover, we discuss stratification of patients with sepsis based on their immune profiles and how this could impact future sepsis management. [ABSTRACT FROM AUTHOR]

Background: Inborn Errors of Immunity (IEI) comprise several genetic anomalies that affect different components of the innate and adaptive responses, predisposing to infectious diseases, autoimmunity and malignancy. Different studies, mostly in adults, have reported a higher prevalence of cancer in IEI patients. However, in part due to the rarity of most of these IEI subtypes (classified in ten categories by the Primary Immunodeficiency Committee of the International Union of Immunological Societies), it is difficult to assess the risk in a large number of patients, especially during childhood. Objective: To document the cancer prevalence in a pediatric cohort from a single referral institution, assessing their risk, together with the type of neoplasia within each IEI subgroup. Method: An extensive review of clinical records from 1989 to 2022 of IEI patients who at some point developed cancer before the age of sixteen. Results: Of a total of 1642 patients with IEI diagnosis, 34 developed cancer before 16 years of age, showing a prevalence (2.1%) significantly higher than that of the general age matched population (0.22). Hematologic neoplasms (mostly lymphomas) were the most frequent malignancies. Conclusion: This study represents one of the few reports focused exclusively in pediatric IEI cases, describing not only the increased risk of developing malignancy compared with the age matched general population (a fact that must be taken into account by immunologists during follow-up) but also the association of the different neoplasms with particular IEI subtypes, thus disclosing the possible mechanisms involved. [ABSTRACT FROM AUTHOR]

Simple Summary: To reveal the effects of waterborne copper stress on gene expression changes, molecular pathways, and physiological functions in Coilia nasus, two libraries were constructed from a copper treatment group (Cu) and a control group (C) and sequenced using Illumina sequencing technology. The present study indicates the main view: copper induces the aberrant expression of immune and metabolic aspects of genes, suggesting that copper causes metabolic disorders and insufficient energy supply in the body, and it induces oxidative stress, which results in reduced immune functions. To reveal the effects of waterborne copper stress on gene expression changes, molecular pathways, and physiological functions in Coilia nasus, juvenile fish were equally divided into two experimental groups, and the copper levels were 1.61 ± 0.03 mg/L (copper-exposed group) and 0 mg/L (control group), respectively. After 4 h, gill tissue samples were collected for transcript sequencing analysis, and two libraries were constructed from the copper treatment group (Cu) and the control group (C) and sequenced using Illumina sequencing technology. The results showed that approximately 40.2–46.0 M clean reads were obtained from each library, and the percentage of uniquely mapped transcripts ranged from 80.57 to 84.93%. A total of 3915 differentially expressed genes (DEGs) were identified under waterborne copper stress, among which 1300 genes were up-regulated, and 2615 genes were down-regulated. Twelve DEGs were randomly selected for quantitative RT-PCR (qRT-PCR) analysis, and the results confirmed that the transcriptome analysis was reliable. Furthermore, the DEGs were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the results showed that most of the DEGs were involved in metabolic pathways, including steroid biosynthesis, glutathione metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Furthermore, due to the waterborne copper levels, gsk-3β was significantly up-regulated, while other metabolism-related genes (tor, pi3k, lpl, aqp7, fabp3) were significantly down-regulated. In addition, the copper-exposed group significantly reduced the expression of some immunity genes (ifn-γ, stat1, cxcl10, and tgf-β), and enhanced the expression of il-1β and tnf-α. In summary, these results indicated that copper causes metabolic disorders and insufficient energy supply in the body, and induces oxidative stress, which results in reduced immune functions. [ABSTRACT FROM AUTHOR]

Dengue infection is caused by the dengue virus (DENV) and is transmitted to humans by infected female Aedes aegypti and Aedes albopictus mosquitoes. There are nearly 100 million new dengue cases yearly in more than 120 countries, with a five-fold increase in incidence over the past four decades. While many patients experience a mild illness, a subset suffer from severe disease, which can be fatal. Dysregulated immune responses are central to the pathogenesis of dengue, and haematologic manifestations are a prominent feature of severe disease. While thrombocytopaenia and coagulopathy are major causes of bleeding in severe dengue, leucocyte abnormalities are emerging as important markers of prognosis. In this review, we provide our perspective on the clinical aspects and pathophysiology of haematologic manifestations in dengue. We also discuss the key gaps in our current practice and areas to be addressed by future research. [ABSTRACT FROM AUTHOR]

Monogenic diseases of immune dysregulation should be considered in the evaluation of children presenting with recurrent neutrophilic dermatoses in association with systemic signs of inflammation, autoimmune disease, hematologic abnormalities, and opportunistic or recurrent infections. We report the case of a 2‐year‐old boy presenting with a neutrophilic dermatosis, found to have a novel likely pathogenic germline variant of the IKAROS Family Zinc Finger 1 (IKZF1) gene; the mutation likely results in a loss of function dimerization defective protein based on reports and studies of similar variants. IKZF1 variants could potentially lead to aberrant neutrophil chemotaxis and development of neutrophilic dermatoses. Long‐term surveillance is required to monitor the development of hematologic malignancy, autoimmunity, immunodeficiency, and infection in patients with pathogenic IKZF1 germline variants. [ABSTRACT FROM AUTHOR]

• Multiple sclerosis (MS) predominantly affects young adults, characterized by inflammation, demyelination, and scar tissue formation. • Impaired BBB permeability permits immune cells and inflammatory mediators to infiltrate the CNS. • Immune cells and non-neuronal cells contribute to MS pathogenesis by producing pro-inflammatory cytokines and chemokines. • Contrarily, anti-inflammatory cytokines and chemokines promote remyelination and offer protection against MS. • Immunemodulatory drugs show potential in reducing relapse rates and delaying disease progression. Multiple sclerosis (MS), a prevalent neurological disorder, predominantly affects young adults and is characterized by chronic autoimmune activity. The study explores the immune system dysregulation in MS, highlighting the crucial roles of immune and non-neuronal cells in the disease's progression. This review examines the dual role of cytokines, with some like IL-6, TNF-α, and interferon-gamma (IFN-γ) promoting inflammation and CNS tissue injury, and others such as IL-4, IL-10, IL-37, and TGF-β fostering remyelination and protecting against MS. Elevated chemokine levels in the cerebrospinal fluid (CSF), including CCL2, CCL5, CXCL10, CXCL13, and fractalkine, are analyzed for their role in facilitating immune cell migration across the blood–brain barrier (BBB), worsening inflammation and neurodegeneration. The study also delves into the impact of auto-antibodies targeting myelin components like MOG and AQP4, which activate complement cascades leading to further myelin destruction. The article discusses how compromised BBB integrity allows immune cells and inflammatory mediators to infiltrate the CNS, intensifying MS symptoms. It also examines the involvement of astrocytes, microglia, and oligodendrocytes in the disease's progression. Additionally, the effectiveness of immunomodulatory drugs such as IFN-β and CD20-targeting monoclonal antibodies (e.g., rituximab) in modulating immune responses is reviewed, highlighting their potential to reduce relapse rates and delaying MS progression. These insights emphasize the importance of immune system dysfunction in MS development and progression, guiding the development of new therapeutic strategies. The study underscores recent advancements in understanding MS's molecular pathways, opening avenues for more targeted and effective treatments. [ABSTRACT FROM AUTHOR]

Myeloid neoplasms are a group of bone marrow diseases distinguished by disruptions in the molecular pathways that regulate the balance between hematopoietic stem cell (HSC) self-renewal and the generation of specialized cells. Cytokines and chemokines, two important components of the inflammatory process, also influence hematological differentiation. In this scenario, immunological dysregulation plays a pivotal role in the pathogenesis of bone marrow neoplasms. The STING pathway recognizes DNA fragments in the cell cytoplasm and triggers an immune response by type I interferons. The role of STING in cancer has not yet been established; however, both actions, as an oncogene or tumor suppressor, have been documented in other types of cancer. Therefore, we performed a systematic review (registered in PROSPERO database #CRD42023407512) to discuss the role of STING pathway in the advancement of pathogenesis and/or prognosis for different myeloid neoplasms. In brief, scientific evidence supports investigations that primarily use cell lines from myeloid neoplasms, such as leukemia. More high-quality research and clinical trials are needed to understand the role of the STING pathway in the pathology of hematological malignancies. Finally, the STING pathway suggests being a promising therapeutic molecular target, particularly when combined with current drug therapies. Findings of the STING pathway in hematological malignancies. CML Chronic myeloid leukemia, MDS Myelodysplastic neoplasms, AML Acute myeloid leukemia, BV173 Human chronic myeloid leukemia cell line with Philadelphia chromosome (Ph1) + , RU.521 cGAS inhibitor, dsDNA double-stranded DNA, KO Knock-out. SHR1032 STING agonist, DMXAA STING agonist [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, commonly associated with nosocomial transmission. Gram-negative bacterial species are particularly problematic due to the release of the lipopolysaccharide toxins upon cell death. The lipopolysaccharide toxin of E. coli has a greater immunogenic potential than that of other Gram-negative bacteria. The resultant dysregulation of the immune system is associated with organ failure and mortality, with pregnant women, ICU patients, and neonates being particularly vulnerable. Additionally, sepsis recovery patients have an increased risk of re-hospitalisation, chronic illness, co-morbidities, organ damage/failure, and a reduced life expectancy. The emergence and increasing prevalence of antimicrobial resistance in bacterial and fungal species has impacted the treatment of sepsis patients, leading to increasing mortality rates. Multidrug resistant pathogens including vancomycin-resistant Enterococcus, beta lactam-resistant Klebsiella, and carbapenem-resistant Acinetobacter species are associated with an increased risk of mortality. To improve the prognosis of sepsis patients, predominantly high-risk neonates, advances must be made in the early diagnosis, triage, and control of sepsis. The identification of suitable biomarkers and biomarker combinations, coupled with machine learning and artificial intelligence, show promise in early detection protocols. Rapid diagnosis of sepsis in patients is essential to inform on clinical treatment, especially with resistant infectious agents. This timely review aims to discuss sepsis prevalence, aetiology, and recent advances towards disease mitigation and control. [ABSTRACT FROM AUTHOR]

Down syndrome is the most common genetic cause of intellectual disability and has previously been associated with a variety of autoimmune disorders affecting multiple organ systems. The high prevalence of autoimmune disease, in conjunction with other inflammatory and infectious diseases, in this population suggests an intrinsic immune dysregulation associated with triplication of chromosome 21. Emerging data on the role of chromosome 21 in interferon activation, cytokine production, and activation of B-cell mediated autoimmunity are emerging hypotheses that may explain the elevated prevalence of autoimmune thyroid disease, celiac disease, type I diabetes, autoimmune skin disease, and a variety of autoimmune neurologic conditions. As the life expectancy for individuals with Down syndrome increases, knowledge of the epidemiology, clinical features, management and underlying causes of these conditions will become increasingly important. Disorders such as Hashimoto's thyroiditis are prevalent in between 13 and 34% of individuals with Down syndrome but only 3% of the neurotypical population, a pattern similarly recognized in individuals with Celiac Disease (5.8% v 0.5–2%), alopecia areata (27.7% v. 2%), and vitiligo (4.4% v. 0.05–1.55%), respectively. Given the chronicity of autoimmune conditions, early identification and management can significantly impact the quality of life of individuals with Down syndrome. This comprehensive review will highlight common clinical autoimmune conditions observed in individuals with Down syndrome and explore our current understanding of the mechanisms of disease in this population. [ABSTRACT FROM AUTHOR]

Peri-implantitis, a complex condition that can lead to dental implant failure, is characterized by inflammatory destruction resulting from immune dysregulation. Oral microbial dysbiosis and foreign body stimulation are the main factors contributing to such dysregulation, impairing immune cell function and triggering an inflammatory response. Immune dysregulation plays a critical role in the pathophysiology of peri-implantitis, impacting the balance of T cell subsets, the production of inflammatory factors, and immune-related molecular signaling pathways. Understanding the relationship between immune dysregulation and peri-implantitis is crucial for developing targeted strategies for clinical diagnosis and individualized treatment planning. This review explores the similarities and differences in the immune microenvironment of oral bacterial infections and foreign body rejection, analyzes the relevant molecular signaling pathways, and identifies new key targets for developing innovative immunotherapeutic drugs and effective and personalized treatment modalities for peri-implantitis. Additionally, it addresses the challenges and potential directions for translating immunotherapy into clinical practice for peri-implantitis, offering insights that bridge the gaps in current literature and pave the way for future research.

BackgroundCommon Variable Immunodeficiency (CVID) represents a heterogenic group of primary immunodeficiencies (PID) characterized by impaired antibody production and susceptibility to infections. Non-infectious complications, such as autoimmune diseases, lymphoproliferative disorders, and malignancies, now significantly impact prognosis. Moreover, both hematologic and solid organ malignancies are more frequently observed in CVID patients compared to other PIDs. The risk factors for carcinogenesis in CVID remain largely unknown.ObjectiveThis multicenter study aims to characterize the clinical profile of cancer in CVID patients in Spain and to identify independent risk factors associated with malignancy development, focusing on the role of immune dysregulation.MethodsA nationwide, cross-sectional study was conducted from November 2019 to May 2022, involving 17 hospitals treating PID patients in Spain. Data were collected systematically on demographics, infectious and non-infectious comorbidities, immunological parameters, and treatment. Statistical analysis, including multivariate logistic regression, was performed to identify risk factors associated to malignancy.ResultsOf 250 CVID patients, 38 (15.26%) were diagnosed with cancer, predominantly non-Hodgkin lymphoma, gastric cancer, and lung adenocarcinoma. Cancer patients were significantly older (mean age 60.70 vs. 49.36 years, p

Background: Atopic dermatitis (AD), also known as atopic eczema, is a common, chronic, non-infectious, relapsing-remitting inflammatory skin disease with increasing incidence globally. It results from a complex interaction of immune dysregulation, genetic mutations, and environmental factors, causing severe itchy skin lesions. AD affects 10-20% of children and 2-10% of adults in industrialized countries and often precedes other atopic diseases such as asthma. Aim of the Study: This study aims to summarize the current knowledge on atopic dermatitis, including its epidemiology, etiology, and treatment methods. Materials and Methods: A literature review was conducted using the PubMed database with keywords: "atopic dermatitis," "atopic eczema," "JAK inhibitors," "calcineurin inhibitors," and "AD systematic treatment." Conclusion: AD is a multifactorial disease involving epidermal barrier defects, genetic predispositions, and immune dysregulation. Effective management requires a combination of topical and systemic therapies. First-line treatments include emollients and topical corticosteroids, with newer options like phosphodiesterase inhibitors, JAK inhibitors, and biologics offering promising results. This study provides a comprehensive overview of AD, emphasizing the need for a multifaceted treatment approach.