Dysregulation Of Immune System Research Articles

Exosomal microRNA following severe trauma: Role in bone marrow dysfunction.

Severe trauma disrupts bone marrow function and is associated with persistent anemia and altered hematopoiesis. Previously, plasma-derived exosomes isolated after trauma have been shown to suppress in vitro bone marrow function. However, the cargo contained in these vesicles has not been examined. We hypothesized that trauma plasma-derived exosomes exhibit microRNA (miRNA) changes that impact bone marrow function after severe injury. Plasma was collected from a prospective cohort study of trauma patients (n = 15; 7 males, 8 females) with hip and/or femur fractures and an Injury Severity Score of ≥15; elective total hip arthroplasty (THA) patients (n = 8; 4 males, 4 females) served as operative controls. Exosomes were isolated from plasma with the Invitrogen Total Exosome Isolation Kit (Thermo Fisher Scientific, Waltham, MA), and RNA was isolated using a miRNeasy Mini Kit (Qiagen, Hilden, Germany). Direct quantification of miRNA was performed by NanoString Technologies on a human miRNA gene panel and analyzed with nSolver with significance defined as p < 0.05. There were no differences in age or sex distribution between trauma and THA groups; the average Injury Severity Score was 23. Trauma plasma-derived exosomes had 60 miRNA identities that were significantly downregulated and 3 miRNAs that were upregulated when compared with THA ( p < 0.05). Twelve of the downregulated miRNAs have a direct role in hematopoiesis regulation. Furthermore, male trauma plasma-derived exosomes demonstrated downregulation of 150 miRNAs compared with male THA ( p < 0.05). Female trauma plasma-derived exosomes demonstrated downregulation of only four miRNAs and upregulation of two miRNAs compared with female THA ( p < 0.05). We observed downregulation of 12 miRNAs linked to hematopoiesis along with sexual dimorphism in miRNA expression from plasma-derived exosomes following severe trauma. Understanding sexually dimorphic miRNA expression provides new insight into sex-based changes in postinjury systemic inflammation, immune system dysregulation, and bone marrow dysfunction and will aid us in more precise future potential therapeutic strategies. Prognostic and Epidemiological; Level III.

Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series

BackgroundPatients with post-acute sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (PASC, i.e., Long COVID) have a symptom complex highly analogous to many features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting they may share some aspects of pathogenesis in these similar disorders. ME/CFS is a complex disease affecting numerous organ systems and biological processes and is often preceded by an infection-like episode. It is postulated that the chronic manifestations of illness may result from an altered host response to infection or inability to resolve inflammation, as is being reported in Long COVID. The immunopathogenesis of both disorders is still poorly understood. Here, we show data that suggest Long COVID and ME/CFS may be due to an aberrant response to an immunological trigger-like infection, resulting in a dysregulated immune system with CD8 T-cell dysfunction reminiscent of some aspects of T-cell clonal exhaustion, a phenomenon associated with oxidative stress. As there is an urgent need for diagnostic tools and treatment strategies for these two related disabling disorders, here, in a retrospective case series, we have also identified a potential nebulized antioxidant/anti-pathogen treatment that has evidence of a good safety profile. This nebulized agent is comprised of five ingredients previously reported individually to relieve oxidative stress, attenuate NF-κB signaling, and/or to act directly to inhibit pathogens, including viruses. Administration of this treatment by nebulizer results in rapid access of small doses of well-studied antioxidants and agents with anti-pathogen potential to the lungs; components of this nebulized agent are also likely to be distributed systemically, with potential to enter the central nervous system. Methodsand Findings: We conducted an analysis of CD8 T-cell function and severity of symptoms by self-report questionnaires in ME/CFS, Long COVID and healthy controls. We developed a CD8 T-cell functional assay, assessing CD8 T-cell dysfunction by intracellular cytokine staining (ICS) in a group of ME/CFS (n = 12) and Long COVID patients (n = 8), comparing to healthy controls (HC) with similar age and sex (n = 10). Magnet-enriched fresh CD8 T-cells in both patient groups had a significantly diminished capacity to produce both cytokines, IFNγ or TNFα, after PMA stimulation when compared to HC. The symptom severity questionnaire showed similar symptom profiles for the two disorders. Fortuitously, through a retrospective case series, we were able to examine the ICS and questionnaire data of 4 ME/CFS and 4 Long COVID patients in conjunction with their treatment (3–15 months). In parallel with the treatment pursued electively by participants in this retrospective case series, there was an increase in CD8 T-cell IFNγ and TNFα production and a decrease in overall self-reported symptom severity score by 54%. No serious treatment-associated side effects or laboratory anomalies were noted in these patients. ConclusionsHere, in this small study, we present two observations that appear potentially fundamental to the pathogenesis and treatment of Long COVID and ME/CFS. The first is that both disorders appear to be characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα. The second is that in a small retrospective Long COVID and ME/CFS case series, this immune dysfunction and patient health improved in parallel with treatment with an immunomodulatory, antioxidant pharmacological treatment with anticipated anti-pathogen activity. This work provides evidence of the potential utility of a biomarker, CD8 T-cell dysfunction, and suggests the potential for benefit from a new nebulized antioxidant/anti-pathogen treatment. These immune biomarker data may help build capacity for improved diagnosis and tracking of treatment outcomes during clinical trials for both Long COVID and ME/CFS while providing clues to new treatment avenues that suggest potential efficacy for both conditions.

World Trade Center Exposure, DNA Methylation Changes, and Cancer: A Review of Current Evidence.

Introduction: Known carcinogens in the dust and fumes from the destruction of the World Trade Center (WTC) towers on 9 November 2001 included metals, asbestos, and organic pollutants, which have been shown to modify epigenetic status. Epigenome-wide association analyses (EWAS) using uniform (Illumina) methodology have identified novel epigenetic profiles of WTC exposure. Methods: We reviewed all published data, comparing differentially methylated gene profiles identified in the prior EWAS studies of WTC exposure. This included DNA methylation changes in blood-derived DNA from cases of cancer-free "Survivors" and those with breast cancer, as well as tissue-derived DNA from "Responders" with prostate cancer. Emerging molecular pathways related to the observed DNA methylation changes in WTC-exposed groups were explored and summarized. Results: WTC dust exposure appears to be associated with DNA methylation changes across the genome. Notably, WTC dust exposure appears to be associated with increased global DNA methylation; direct dysregulation of cancer genes and pathways, including inflammation and immune system dysregulation; and endocrine system disruption, as well as disruption of cholesterol homeostasis and lipid metabolism. Conclusion: WTC dust exposure appears to be associated with biologically meaningful DNA methylation changes, with implications for carcinogenesis and development of other chronic diseases.

Quantifying the prevalence and predictors of burnout in emergency medical services personnel.

Recently, burnout has amassed considerable attention because of deleterious effects on workers and the work environment. Frequently, EMS clinicians find themselves prone to experiencing burnout, yet little is known about etiologies in this population. To estimate prevalence and predictors of burnout in EMS clinicians. This was a cross-sectional survey study of nine EMS agencies from North Carolina selected based on geography and population. Emergency medical technicians (EMTs), advanced EMTs, and paramedics were included. Emergency medical responders and air medical personnel were excluded if those positions were a primary occupational function. The Professional Quality of Life (ProQOL) Scale was used to assess burnout. Parametric and nonparametric testing was used to assess factors potentially affecting burnout. Factors significant in univariate analyses were included in a hierarchical linear regression model to determine unique predictors of burnout while controlling for confounders. The area under the curve (AUC) of the receiver operating characteristic (ROC) was used to determine model predictability. A total of 686 EMS clinicians completed the survey. Overall, 57.3% (n = 393) were likely to have burnout. Of the 328 respondents who were likely to have burnout, 254 (77.4%) and 211 (75.1%) also were identified as likely to suffer from compassion fatigue or vicarious trauma, respectively. Overall, 152 (22.2%) were likely to suffer from all three stress disorders, 118 (56.5%) of which scored high enough to potentially produce immune system dysregulation. Prior suicidal thoughts ((sr2 = 0.042, p < 0.001), attempts (sr2 = 0.025, p < 0.001) or the presence of vicarious trauma (sr2 = 0.040, p < 0.001) accounted for 4.2%, 2.5%, and 4.0% of model variance, respectively. Years of field experience (sr2 = 0.035, p < 0.001) and credential level (sr2 = 0.011, p = 0.005) accounted for 4.6% of model variance. Finally, a respondent's experience or knowledge of debriefing (sr2 = 0.008, p = 0.023); experiencing adversity in childhood in the form of familial mental illness, depression, or suicide (sr2 = 0.009, p = 0.016); or the incarceration of a family member (sr2 = 0.010, p = 0.011) accounted for a combined 2.7% of model variance. Model predictability showed an AUCROC of 81.5%. This study showed a nearly 60% prevalence of occupational burnout in the group of EMS clinicians surveyed, making burnout of considerable concern in this population. Further study is needed to address occupational factors that contribute to burnout in EMS clinicians.

Immunomodulation of NK, NKT and B/T cell subtypes in relapsed/refractory multiple myeloma patients treated with pomalidomide along with velcade and dexamethasone and its association with improved progression-free survival.

Multiple Myeloma (MM) patients exhibit dysregulated immune system, which is further weakened by chemotherapeutic agents. While cereblon-modulating agents, such as pomalidomide and lenalidomide, have been found to improve the immune profile, the efficacy of their impact in combination with other treatments is yet unknown. We conducted an immune-profiling of a longitudinal cohort of 366 peripheral blood samples from the CC4047-MM-007 (OPTIMISMM, NCT01734928) study. This study followed relapsed/refractory Multiple Myeloma (RRMM) patients who were treated with Velcade + dexamethasone (Vd), or Vd with pomalidomide (PVd). 366 blood samples from 186 patients were evaluated using multi-color flow cytometry at 3 timepoints: screening, day 8 of cycle 1, and cycle 3. Among NK and NKT cell populations, adding pomalidomide showed no inhibition in the frequency of NK cells. When expression of double positivity for activation markers like, p46/NKG2D, on NK cells was higher than the median, PVd treated patients showed significantly better (p=0.05) progression-free survival (PFS) (additional 15 months) than patients with lower than the median expression of p46/NKG2D on NK cells. PVd treated patients who expressed CD158a/b below the median at cycle 1 demonstrated a significantly better PFS (more than 18months). Among B cell subtypes, PVd treatment significantly increased the abundance of B1b cells (p<0.05) and decreased Bregs (p<0.05) at day 8 of both cycle 1 and cycle 3 when compared to screening samples. Of all the B cell-markers evaluated among paired samples, a higher expression of MZB cells at day 8 of cycle 1 has resulted in enhanced PFS in PVd treated patients. Within T cells, pomalidomide treatment did not decrease the frequency of CD8 T cells when compared with screening samples. The higher the surface expression of OX-40 on CD8 T cells and the lower the expression of PD-1 and CD25 on CD4 T cells by PVd treatment resulted in improved PFS. The prognostic significance for the number of immune markers is only seen in the PVd arm and none of these immune markers exhibit prognostic values in the Vd arm. This study demonstrates the importance of the immunomodulatory effects and the therapeutic benefit of adding pomalidomide to Vd treatment.

Diagnosis and Treatment of Immune Heamolytic Aneamia

Immune hemolytic anemia (IHA) stands as a multifaceted hematologic disorder characterized by accelerated destruction of red blood cells due to immune system dysregulation. This paper aims to elucidate the nuanced landscape of IHA, focusing on its diverse diagnostic approaches and evolving treatment strategies. Diagnostic considerations encompass a range of laboratory tests, including direct and indirect Coombs tests, hemolysis markers, and autoimmune antibody panels, elucidating their roles in confirming IHA etiology and subtype classification. Additionally, advancements in imaging modalities aid in identifying underlying causative factors contributing to hemolysis. The paper further scrutinizes therapeutic interventions, spanning corticosteroids, immunosuppressive agents, and monoclonal antibodies, while also appraising emerging modalities like rituximab and splenectomy. Moreover, the role of supportive care and transfusion strategies in managing IHAassociated complications is delineated. Challenges in IHA management, including refractory cases and adverse effects of therapies, are deliberated alongside the potential of future advancements in precision medicine and targeted therapies. By assimilating the latest diagnostic methodologies and treatment paradigms, this review provides a comprehensive outlook on navigating the complexities of immune hemolytic anemia to optimize patient care and outcomes. Keywords: haemolytic anaemia, anaemia, immunity, diagnosis, treatment

Long term high‐fat feeding induces cognitive impairment, alterations in microglial morphology, and spatial transcriptomic changes

AbstractBackgroundObesity and metabolic dysfunction (Metabolic Syndrome, prediabetes, and diabetes) increase the risk of later life cognitive impairment, including dementias such as Alzheimer’s Disease1‐3. One common etiology that might underly this increased risk is immune system dysregulation and inflammation4, 5. Specifically, microglial dependent mechanisms are thought to play an important role in pathology6‐8. However, the precise immune and inflammatory mechanisms promoting cognitive decline secondary to obesity and metabolic dysfunction are unclear.MethodBL6 male mice were fed 60% HFD (high fat diet) or 10% SD (standard diet) for 1 year. Body weight and glucose tolerance were assessed longitudinally. Cognition was repeatedly evaluated using Morris water maze, social recognition, and puzzle box. At study termination, mice were given either an intraperitoneal injection of lipopolysaccharide as an immune challenge or saline as a control. Activation of hippocampal microglia was assessed via immunohistochemistry (IHC) and analysis of microglial morphology. Changes in brain gene expression were measured via spatial transcriptomics using the 10X Visium platform.ResultHFD feeding caused increased weight, impaired glucose tolerance, and cognitive deficits which persisted throughout the study period. Body weight in particular was predictive of cognitive changes, especially for later time points. In response to immune challenge, hippocampal microglia in SD mice had a normal morphological response indicative of activation. However, microglia of HFD mice had no change in their morphology in response to lipopolysaccharide injection. Additionally, changes in morphology significantly correlated with cognition and indicated that a higher percentage of activated hippocampal microglia is associated with a worse cognitive phenotype. Spatial transcriptomics analysis showed changes in gene expression in multiple brain regions of HFD mice, including the hippocampus, many of which were related to neurodegenerative and inflammatory pathways.ConclusionThese data support that HFD feeding causes an early and persistent cognitive impairment, which is associated with obesity. Our data also confirm a role for microglia in HFD‐induced cognitive impairment. Indeed, microglial and transcriptomic data strongly indicate a role for inflammation and inflammatory pathways in HFD‐induced cognitive impairment.

Characterization of peripheral immune cell populations in stable and progressive Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia which results in debilitating memory loss as the disease advances. In addition to the amyloid plaques, tau tangles, and neuronal inflammation characteristic of AD, there is strong evidence of dysregulation in the peripheral immune system, including decreased naïve T cells and increased memory T cells among older adults with AD. However, the involvement of the peripheral immune system in the neurodegenerative cascade leading to AD is poorly understood. Furthermore, among older adults with AD, some may experience rapid cognitive decline while others may maintain a stable cognitive status for years. It is currently unknown whether dysfunction in the peripheral immune system is associated with neuronal inflammation and cognitive decline.MethodIn our ongoing work, we are longitudinally characterizing resting peripheral immune system cells by flow cytometry and here present data from a subset of those with AD (n = 19) or no dementia (ND, n = 93) whom we have followed for &gt;1 year.ResultWe have identified an increase in B cells (percent all lymphocytes, AD 6.4 (SD 8.6) vs ND 4.0 (SD 2.4) p = 0.031) and CD4+/CD62L+ naïve T cells (percent CD4+ lymphocytes, AD 33.4 (SD 18.4) vs ND 25.4 (SD 14.1) p = 0.034) among AD patients. Among the population of AD patients experiencing cognitive decline (n = 4) determined by increasing ADAS‐Cog score &gt;6 points over one year compared to stable scores (n = 11), we have discovered a decrease in CD4+/CD62L+ naïve T cells (percent CD4+ lymphocytes, stable 33.9 (SD 14.5) vs declining 20.5 (SD 16.1) p = 0.049), increase in effector memory CD4+ T cells (percent CD4+ lymphocytes, stable 28.2 (SD 4.8) vs declining 47.0 (SD 6.5) p&lt;0.001), and increase in B cells (percent all lymphocytes, stable 2.6 (SD 1.5) vs declining 5.3 (SD 1.8) p = 0.010), when compared to older adults with AD and stable cognitive status.ConclusionThis longitudinal clinical study identifies changes in resting peripheral B and T cell populations in AD patients and among AD patients with cognitive decline.

Abstract B030: Intracerebral and intraventricular hemorrhage due to severe thrombocytopenia: A rare case of Evans syndrome

Abstract Introduction: Evans syndrome (ES) is a rare autoimmune disorder characterized by the development of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and/or immune neutropenia (AIN) without an identifiable cause. It is believed to involve immune system dysregulation, leading to the destruction of red blood cells, platelets, and neutrophils. Case Presentation: A 68-year-old male with a history of coronary artery disease, hypertension, diabetes, and atrial fibrillation presented with abdominal pain and diarrhea. Laboratory tests revealed a platelet count of 3k, suggesting ITP. Initial treatment with dexamethasone and platelet transfusion provided limited improvement. A bone marrow biopsy showed mildly hypercellular bone marrow with trilineage hematopoiesis. However, the patient's condition rapidly deteriorated, and he returned to the emergency department with severe symptoms, including headache, gum bleeding, and lower extremity petechiae. A CT scan revealed a large intraparenchymal hematoma with intraventricular hemorrhage, highlighting the risk of life-threatening bleeding in ES patients. Discussion: The patient was managed with platelet transfusions, high-dose steroids, and intravenous immunoglobulin (IVIG), which provided temporary relief but failed to maintain stable platelet levels. Further investigations revealed a positive antinuclear antibody (ANA), suggesting an underlying rheumatological condition and confirming the diagnosis of secondary ES. This finding necessitated the exploration of treatment options. Of interest is Romiplostim (Promacta), a thrombopoietin receptor agonist, which has shown promise in increasing platelet counts and reducing bleeding episodes in refractory ITP. Considering the positive ANA and the suspected rheumatological etiology, Romiplostim may serve as a viable long-term treatment option to stabilize platelet levels and mitigate bleeding risks in this case. Conclusion: This case highlights the complexity of Evans syndrome and emphasizes the need to promptly recognize and manage life-threatening bleeding complications, particularly in older patients. The presence of a positive ANA suggests an underlying rheumatological condition, necessitating comprehensive evaluation, and tailored therapeutic approaches. Although further research is needed to understand the pathogenesis and optimal management strategies for ES, Romiplostim holds promise as a potential treatment for patients with secondary ES who are unresponsive to conventional therapies. Citation Format: Kiersten R. Patterson, Aliya M. Khan, Raj Patel. Intracerebral and intraventricular hemorrhage due to severe thrombocytopenia: A rare case of Evans syndrome [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B030.

H. Pylori and Autoimmune Disorders: Unraveling the Links between Chronic Infection and Immune Dysfunction: Review Paper

The human stomach is home to the Gram-negative bacterium Helicobacter pylori, which has been connected to several gastrointestinal disorders. There may be a link between H. pylori infection and the start of autoimmune disorders, according to recent research. This review examines the intricate connections between persistent H. pylori infection, immune system dysregulation, and their possible role in initiating autoimmune disorders. The study begins with a summary of H. pylori infection and its prevalence worldwide, emphasizing the mounting data that connects this bacterium to autoimmune disorders. Then, using experimental data from animal models and epidemiological research as support, it undertakes a thorough review of autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, and autoimmune gastritis linked to H. pylori infection. The review looks at the clinical consequences and existing treatments, emphasizing how important it is to screen for and diagnose H. pylori infection in patients with autoimmune disorders. Moreover, current studies are looking into possibly using H. pylori removal as a therapeutic approach to lessen autoimmune symptoms.

Clonal Hematopoiesis of Indeterminate Potential (CHIP) Related to the Etiology of Ischemic Stroke

Introduction: Clonal Hematopoiesis of Indeterminate Potential (CHIP) is associated with cardiovascular disease, including acute myocardial infarction and ischemic stroke, due to immune system dysregulation leading to increased atherosclerotic plaque formation and inflammation. Approximately 25-40% of ischemic strokes have an unknown cause even after a comprehensive etiological study and are eventually categorized as cryptogenic strokes. Our hypothesis is that the presence of CHIP could represent a biomarker for atherosclerotic or cardioembolic ischemic stroke and help to clarify the origin of cryptogenic strokes. Therefore, the objective of this study was to analyze the prevalence of CHIP in patients with different subtypes of ischemic stroke and its prognostic impact on cardiovascular risk. Methods: This prospective observational study included consecutive patients over 60 years of age with no prior history of neoplasia or cytotoxic treatment, who experienced embolic ischemic stroke between September 2021 and August 2022. Ischemic strokes were classified into cardioembolic (CE), atherothrombotic (AT) or cryptogenic (CRYP) etiologies after performing a systematic etiological study. During the stroke admission, peripheral blood samples were obtained in order to analyze the 13 genes most frequently associated with CHIP ( DNMT3A, TET2, ASXL1, JAK2, PPM1D, TP53, SF3B1, GNB1, SRSF2, CHEK2, CBL, GNAS, NRAS) through targeted next generation sequencing. Libraries were prepared using the KAPA HyperPlus capture chemistry (Roche) and were sequenced on a MiSeq platform (Illumina) following a 2x150bp paired-end read standard protocol, allowing the detection of variants with a variant allelic frequency (VAF) of ≥1%. The analysis was conducted using an in-house developed pipeline. Patients with one or more mutations in these genes with a VAF ≥2% were considered CHIP carriers. Cardiovascular risk factors including: hypertension, diabetes mellitus, dyslipidemia, smoking and obesity, were also analyzed. Results: Seventy-eight patients with stroke were included (50% female, median age 72 years (range: 59-90). Ischemic strokes were classified etiologically as: 36 CE (46.2%), 34 AT (43.6%) and 8 CRYP (10.3%) (Table 1). CHIP was detected in 21/78 (31.3%) patients, with the following gene mutation frequencies among CHIP carriers: DNMT3A (47.6%), TET2 (28.5%), SRSF2 (14.2%), PPM1D (9.5%), ASXL1 (4.8%), CBL (4.8%), CHEK2 (4.8%) and JAK2 (4.8%). The median VAF detected was 4.85% (range: 2.1%-43.7%), and 23.8% (5/21) of cases presented more than one mutation. The incidence of CHIP varied according to stroke etiology: CE etiology: 38.9% (14/36); AT etiology: 17.6% (6/34) and CRYP etiology: 12.5% (1/8) (p=0.046) (Figure 1). Moreover, only CE strokes showed mutations in TET2 (16.7% (6/36)) compared to AT (0/34) and CRYP (0/8) (p=0.015). No significant differences were observed in the blood counts (Hb, MCV, RDW, neutrophil count, monocytes, platelets or PCR) between stroke patients with CHIP and non-CHIP (Table 1). Finally, in the multivariate analysis, TET2 mutations were associated with CE stroke independently of age, coronary artery disease and classic cardiovascular risk factors (OR 8.1; Cl: 1.35-48.47; p=0.012). Conclusions: Our findings identify that CHIP is common in patients with ischemic strokes, especially in those of cardioembolic etiology, with TET2 being the most frequently mutated gene. The presence of CHIP TET2 could represent a novel cardiovascular risk factor, contributing to a more precise etiological distinction between the different etiologies of ischemic stroke. Funding source: this project is supported by health research fund of Carlos III health institute. FIS PI20/00881

A perspective on the role of physiological stresses in cancer, diabetes and cognitive disease as environmental diseases.

With rapid industrialization, urbanization, and climate change, the impact of environmental factors on human health is becoming increasingly evident and understanding the complex mechanisms involved is vital from a healthcare perspective. Nevertheless, the relationship between physiological stress resulting from environmental stressors and environmental disease is complex and not well understood. Chronic exposure to environmental stressors, such as air and water contaminants, pesticides, and toxic metals, has been recognized as a potent elicitor of physiological responses ranging from systemic inflammation to immune system dysregulation causing or progressing environmental diseases. Conversely, physiological stress can exacerbate susceptibility to environmental diseases. Stress-induced alterations in immune function and hormonal balance may impair the ability to detoxify harmful substances and combat pathogens. Additionally, prolonged stress can impact lifestyle choices, leading to harmful behaviors. Understanding the link between physiological stress and environmental disease requires a systematic, multidisciplinary approach. Addressing this complex relationship necessitates the establishment of a global research network. This perspective discusses the intricate interplay between physiological stress and environmental disease, focusing on common environmental diseases, cancer, diabetes, and cognitive degeneration. Furthermore, we highlight the intricate and reciprocal nature of the connection between physiological stress and these environmental diseases giving a perspective on the current state of knowledge as well as identifying where further information is necessary. Recognizing the role of physiological stress in environmental health outcomes will aid in the development of comprehensive strategies to safeguard public health and promote ecological balance.

Systemic onset juvenile idiopathic arthritis associated with Agammaglobulinemia: A brief report

Systemic onset Juvenile Idiopathic Arthritis (SJIA) is defined as a systemic inflammatory disease. Innate immune system dysregulation and systemic inflammation are the autoinflammatory pathogenesis of this disease. The clinical manifestations are fever, arthritis, lymphadenopathy, rash, and serositis. Of the manifestation of immune deficiency is recurrent otitis media. Recurrent otitis media should be evaluated for immune components. In this report, we presented a boy with recurrent otitis media, pain and swelling in both knees, and fever which fever was exacerbated at nights and he had no fever during day. After immune system evaluations, autosomal recessive agammaglobulinemia was observed in genetic test.

Identification of immune-related genes in diagnosing retinopathy of prematurity with sepsis through bioinformatics analysis and machine learning.

Background: There is increasing evidence indicating that immune system dysregulation plays a pivotal role in the pathogenesis of retinopathy of prematurity (ROP) and sepsis. This study aims to identify key diagnostic candidate genes in ROP with sepsis. Methods: We obtained publicly available data on ROP and sepsis from the gene expression omnibus database. Differential analysis and weighted gene correlation network analysis (WGCNA) were performed to identify differentially expressed genes (DEGs) and key module genes. Subsequently, we conducted functional enrichment analysis to gain insights into the biological functions and pathways. To identify immune-related pathogenic genes and potential mechanisms, we employed several machine learning algorithms, including Support Vector Machine Recursive Feature Elimination (SVM-RFE), Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest (RF). We evaluated the diagnostic performance using nomogram and Receiver Operating Characteristic (ROC) curves. Furthermore, we used CIBERSORT to investigate immune cell dysregulation in sepsis and performed cMAP analysis to identify potential therapeutic drugs. Results: The sepsis dataset comprised 352 DEGs, while the ROP dataset had 307 DEGs and 420 module genes. The intersection between DEGs for sepsis and module genes for ROP consisted of 34 genes, primarily enriched in immune-related pathways. After conducting PPI network analysis and employing machine learning algorithms, we pinpointed five candidate hub genes. Subsequent evaluation using nomograms and ROC curves underscored their robust diagnostic potential. Immune cell infiltration analysis revealed immune cell dysregulation. Finally, through cMAP analysis, we identified some small molecule compounds that have the potential for sepsis treatment. Conclusion: Five immune-associated candidate hub genes (CLEC5A, KLRB1, LCN2, MCEMP1, and MMP9) were recognized, and the nomogram for the diagnosis of ROP with sepsis was developed.

New insights on the mechanisms of myocardial injury in hypertensive patients with COVID-19

Abstract Introduction Cardiac comorbidities, particularly hypertension, are highly prevalent in patients hospitalized with COVID-19 and are related directly to the risk of clinical disease progression. Cardiac injury is the most frequently reported cardiac abnormality in these patients. Diverse forms and mechanisms of myocardial injury, including acute myocardial ischemia due to plaque rupture, oxygen supply/demand imbalance, non-ischemic injuries such as myocarditis, direct virus-mediated injury, and immune system dysregulation, have been described in patients with COVID-19. Purpose The mechanism of the association among hypertension, COVID-19 and cardiac injury and the reasons for worse clinical progression in these patients have not been elucidated clearly. Considering that myocardial injury due to direct SARS-CoV-2 infection is rare and that the immune system is often dysregulated in patients with COVID-19, and also that cytokine storm and lymphopenia are important immune markers of progression to severe disease, the present study aimed to investigate the immune profile of hypertensive patients with COVID-19 and myocardial injury to obtain a better understanding of the immune dysregulation and to provide new insights on the mechanism of myocardial injury in hypertensive patients with this disease. Methods All patients were selected prospectively from a multicenter registry of adults hospitalized with confirmed COVID-19. Cases had hypertension and myocardial injury, defined by troponin levels above the 99th percentile upper reference limit, and controls were hypertensive patients with no myocardial injury. Biomarkers and immune cell subsets were quantified and compared between the two groups. A multiple logistic regression model was used to analyze the associations of clinical and immune variables with myocardial injury. Results The sample comprised 193 patients divided into two groups: 47 cases and 146 controls. Relative to controls, cases had lower total lymphocyte count, percentage of T lymphocytes, CD8+CD38+ mean fluorescence intensity (MFI), and percentage of CD8+ human leukocyte antigen DR isotope (HLA-DR)+ CD38–cells and higher percentage of natural killer lymphocytes, natural killer group 2A (NKG2A)+ MFI, percentage of CD8+CD38+cells, CD8+HLA-DR+MFI, CD8+NKG2A+MFI, and percentage of CD8+HLA-DR–CD38+cells. On multivariate regression, the CD8+HLA-DR+MFI, CD8+CD38+MFI, and total lymphocyte count were associated significantly with myocardial injury. Conclusion Our findings suggest that lymphopenia, CD8+CD38+MFI, and CD8+HLA-DR+MFI are immune biomarkers of myocardial injury in hypertensive patients with COVID-19. The immune signature described here may aid in understanding the mechanisms underlying myocardial injury in these patients. The study data might open a new window for improvement in the treatment of hypertensive patients with COVID-19 and myocardial injury.

Bupropion Associated Immunomodulatory Effects on Peripheral Cytokines in Male with Major Depressive Disorder

Background: Experimental and clinical studies have reported increased levels of pro-inflammatory cytokines in patients with major depressive disorder (MDD), suggesting that immune system dysregulation may contribute to MDD pathophysiology. Aim: Due to the lack of knowledge about the immune potential of antidepressants, this study investigated the immunomodulatory effects of bupropion, a norepinephrine–dopamine reuptake inhibitor. Methods: This study involved 18 patients with MDD treated with bupropion (150 mg/d) for 4 weeks and 23 healthy volunteers. All participants underwent multiplex bead-based cytokine assessment before and after bupropion treatment to quantify the following cytokines: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-γ, tumor necrosis factor-α, granulocyte colony-stimulating factor, granulocyte-macrophage CSF, monocyte chemotactic protein-1, and macrophage inflammatory protein-1β. Results: Four-week treatment with bupropion significantly increased the levels of IL-1β (P = 0.011), IL-4 (P = 0.019), IL-5 (P = 0.019), IL-7 (P = 0.021), and IL-8 (P = 0.023) compared to the control group. Furthermore, the percentage change in most cytokines, including anti-inflammatory cytokines such as IL-4, IL-5, IL-10, and IL-13, was significantly increased after bupropion treatment. Conclusion: The promoted synthesis of anti-inflammatory cytokines to surpass the pro-inflammatory cytokines may be a crucial step in the treatment of MDD patients with bupropion.

Soluble urokinase Plasminogen Activator Receptor (suPAR) is associated with educational attainment in patients with coronary artery disease

Abstract Background Biological mediators of adverse social determinants of health may include chronic low-grade inflammation. Elevation of circulating soluble urokinase Plasminogen Activator Receptor (suPAR) levels indicates activation of inflammatory and immune pathways and is associated with cardiovascular outcomes, independent of C-reactive protein (CRP) levels. Purpose We investigated whether the adverse impact of lower educational attainment on all-cause and cardiovascular mortality is mediated by elevated suPAR levels in patients with coronary artery disease (CAD). Methods In 3,164 patients undergoing coronary angiography, we investigated multivariable associations, including demographic characteristics, behavioral and clinical risk factors, between suPAR levels collected at the time of angiography and self-reported educational attainment, and assessed the relationship between lower educational level (defined as high school degree or less as highest educational qualification) and outcomes using Cox proportional hazard and Fine and Gray’s sub-distribution competing risk models. Mediation analyses were performed to assess the total effect of education on mortality, and the indirect effects through hs-CRP and suPAR on survival stratified by education using accelerated failure time models under exponential distribution. Results Mean age of the cohort was 64.5±11.9 years, with 32% women and 8.1±3.8 years follow-up. SuPAR levels were 9.0% [95% CI 6.3–11.8, p &amp;lt;0.0001] higher in patients achieving a lower (≤high school) compared to a higher (≥college) education after full covariate adjustment including hs-CRP levels. Lower educational attainment was associated with a higher risk of cardiovascular death (HR 1.39 [95% CI 1.15–1.68, p=0.0008]). After adjustment for demographic, clinical and behavioral covariates, and hs-CRP levels, this effect remained significant (HR 1.29 [95% CI 1.06–1.57, p=0.01]). However, after adjustment for suPAR levels, the effect of a lower educational level on cardiovascular mortality became insignificant. Values were similar for all-cause death. SuPAR levels mediated 49% and hs-CRP levels 17% of the association between lower educational attainment and cardiovascular mortality. Conclusion SuPAR importantly mediates the effects of lower educational attainment on mortality, indicating the importance of systemic inflammation and immune dysregulation as biologic mediators of adverse social determinants of health.Figure 1Central Illustration

Association between anti-cardiac autoantibodies in acute myocarditis and downstream clinical outcomes

Abstract Introduction Myocarditis is an inflammatory heart muscle disease that can result in cardiac dysfunction and arrhythmias. Its aetiology includes infectious, toxic or autoimmune causes. Myocarditis is responsible for sudden cardiac death in young adults (1) and can result in heart failure due to dilated cardiomyopathy in 20% of patients (2). The pathogenesis of myocarditis may involve immune system dysregulation leading to a cascade of inflammation and myocardial damage (3). For those patients that rapidly progress to end-stage dilated cardiomyopathy, an important dilemma is whether there is any prospect of heart function recovery. Therefore, there is an unmet need for a better understanding of key causal pathways and for developing a biological signature of disease progression. Hypothesis The progression of acute myocarditis depends on a persistent adaptive immune response against the heart, leading to ongoing inflammation, myocardial fibrosis and ultimately tissue destruction and remodelling. Aims We sought to explore anti-cardiac IgG serum levels, their temporal profile throughout follow up and their association with clinical and imaging data, in patients presenting with acute myocarditis. Methods We prospectively recruited 80 patients with a clinical diagnosis of acute myocarditis. We measured their total anti-cardiac IgG levels at admisssion, 3- and 12-months follow-up using an enzyme-linked immunosorbent assay (ELISA). We explored the association between the anti-cardiac IgG levels, cardiac MRI parameters (CMR) and clinical data. Results We detect an adaptive immune response against the heart in a subgroup of patients with acute myocarditis. 20% of patients develop high systemic titres of anti-cardiac IgG (OD threshold &amp;gt;0.65), within the first 7 days of presentation (Figure 1a). These patients continue to have persistent and significantly higher anti-cardiac IgG levels at 12 months (Figure 1b). Importantly, patients that mount a strong initial adaptive immune response against the heart, are more likely to show evidence of persistent oedema on CMR at 12 months(Figure 1c). Clinical event rates in our cohort have remained low at five-year follow-up. A small signal exists to indicate potentially higher rates of persistent symptoms (70% vs 47%), hospitalisations for heart failure (12% vs 8%) and new heart failure diagnosis (18% vs 11%), in patients that mount a strong adaptive immune response compared to those that do not. Conclusion A subset of patients with acute myocarditis develops a strong and persistent adaptive immune response against the heart. This may be associated with more myocardial oedema on cardiac MRI, persistent symptoms and higher rates of heart failure diagnoses and hospitalisations. Further work Plasma proteomics (targeted and un-targeted discovery) with validation in myocardial tissue. Analysis of CMR data with a focus on fibrosis assessment. ELISA for IgG subtypes and total IgG against myosin and troponin I.

Decreased levels of plasmacytoid dendritic cells predict survival in critically ill patients

Abstract Background Critically ill patients admitted to intensive care units (ICUs) exhibit high mortality rates and suffer from a broad variety of life-threatening conditions. Irrespective of the initial cause of hospitalization, many of them experience systemic immune dysregulation accompanied by strong inflammatory activation and subsequent anti-inflammatory response resulting in immune paralysis. Dendritic cells (DCs) are the most potent antigen-presenting cells and play a pivotal role in regulating the immune response by linking the innate to the adaptive immune system. Previous studies already highlighted their prognostic value in sepsis and infectious diseases. Purpose DCs may be useful as a biomarker in intensive care medicine. Thus, the aim of this study was to analyse whether DCs or their respective subsets are associated with 30-day mortality in a cohort of unselected patients admitted to a medical ICU with cardiovascular focus. Methods 231 patients admitted to a tertiary care medical ICU were consecutively included in this single-centre prospective observational study. Patient characteristics and vital parameters were assessed within 24 hours following ICU admission and 72 hours thereafter. Additionally, blood was drawn at both time points. Subsequently, flow cytometry was utilized for the analysis of DCs and their respective subsets. Patients were prospectively followed up for 30 days or until the primary study endpoint, defined as mortality, was reached. Results In the study cohort, low percentages of total DCs were significantly associated with sepsis, respiratory failure, and the presence of shock. Percentages of plasmacytoid dendritic cells (pDCs) were inversely correlated with routinely assessed markers of inflammation, organ dysfunction and hemodynamic derangement. In particular, pDCs at admission showed the most robust association with survival in univariate analysis with a hazard ratio (HR) of 6.5 (95% confidence interval [CI]: 2.5 – 17.2, p &amp;lt; 0.001) comparing the first to the third tertile. In multivariate analysis, pDCs remained a strong and independent predictor of 30-day mortality after adjustment for demographic and clinical variables with an adjusted HR of 4.20 (1.3 - 13.3, p = 0.015). Corresponding Kaplan-Meier curves showing survival according to tertiles of pDCs at day 0 are displayed in figure 2 (log-rank test: p &amp;lt; 0.001). Conclusion We observed low percentages of DCs in patients admitted to an ICU suffering from sepsis, respiratory failure, and cardiogenic shock, which potentially contributes to the excessive immune response in critically ill patients. In our cohort, pDCs were identified as the most robust subset to predict 30-day mortality.Figure 1Figure 2

Abstract 15864: Genetic Findings of Cardiac Sarcoidosis in a Case of Apical Variant Hypertrophic Cardiomyopathy With Recurrent Ventricular Tachyarrhythmias

Background: Genetic sequencing is changing the way physicians practice medicine. Hypertrophic cardiomyopathy (HCM) is one of the most common inheritable cardiac diseases. Sarcoidosis is a multisystem disease involving granulomatous infiltration of the lungs, heart, and other organs thought to be caused by a dysregulated immune system, influenced by genetic factors. Here, we present a case where an individual initially diagnosed with HCM was experiencing frequent episodes of ventricular tachycardia (VT). Further workup, including advanced imaging along with whole genome screening (WGS), revealed an unlikely diagnosis of concurrent cardiac sarcoidosis (CS). Clinical History: A 62-year-old man had ventricular fibrillation with workup notable for an ECG with deeply inverted T-waves, normal coronary angiography, and an echocardiogram and MRI showing apical HCM. An ICD was placed. Six years later, he had VT requiring a shock and was started on sotalol. He has now developed recurrent exercise-induced VT. While VT is seen HCM, the increasing frequency prompted further evaluation. A CT coronary angiogram showed normal coronaries and mediastinal lymphadenopathy. Lymph node biopsy revealed noncaseating granulomas and a PET/CT revealed hypermetabolic basal myocardium meeting HRS criteria for CS. Given minimal apical FDG uptake and a low likelihood that he had CS for 9 years without significant fibrosis, he likely has both HCM and CS. Using WGS, four genetic variants previously described in CS and HCM were identified confirming this diagnosis, HLA-DRB1, HLA-DQA1, ALPK3, and TTN. Discussion: HLA-DRB1 and HLA-DQA1 are both major histocompatibility complexes associated with CS. ALPK3 encodes alpha kinase 3 while TTN encodes titin. Truncating variants of ALPK3 are associated with HCM while pathogenic TTN variants have been described to cause HCM, DCM, and ARVC. This case reflects the potential of WGS in aiding clinicians in confirming an unlikely diagnosis.