Immune-mediated Research Articles

A Review: Ophiocordycep Sinensis (Berk.) as a Traditional Tibetan Medicine and its Potential in the Treatment of Various Human Ailments

Abstract: Nature’s never-ending gift, which counts as one of the most valuable medicines in the entire world, the Ophiocordyceps sinensis, also known as caterpillar fungus, is a traditional Chinese medicine found in Tibetan plateaus. During the season of spring, many shepherd search for this caterpillar fungus as its value in the market is very high. Moreover, due to the effects of climatic change on its population and increasing demand, O. sinensis is now an endangered species. It can treat almost many diseases, such as cardiovascular disease, respiratory diseases, immune dysfunction etc. The chemical composition of this fungus includes amino acids, glutamic acid, polyamines, cordycepic acid, saccharides, sterols, nucleotides, sugar derivatives, fatty acids, vitamins, and oleic acid.

Molecular patterns of microbial and metabolic interactions in septic patients with persistent lymphopenia

BackgroundPersistent lymphopenia can be regarded as an important index of acquired immune dysfunction in sepsis. Whether the specific immune factor changes in septic patients with lymphopenia and the correlation to gut microbiota and metabolites remain unclear. MethodsThis single-center prospective observation conducted lymphocyte subgroup analysis of blood samples and 16S rRNA gene amplicons sequencing and untargeted metabolomics analysis of fecal samples from 36 subjects with the persistent (≥3d) (n=21) and non-persistent lymphopenia (<3d) (n=15). ResultsThe persistent lymphopenia showed higher the 28d mortality and 90d mortality, while significantly lower CD3+T/LY, CD3+T cells, CD3+CD4+T cells, CD3+CD8+T cells, Th1 cells, Th2 cells, CD45RA+Treg cells. The 16S rRNA results showed that Staphylococcus, Peptostreptococcus, Bulleidia, Leuconostoc were significant enriched in the persistent lymphopenia. The metabolomics analysis showed that α-Ketoisovaleric acid was increased and 7-DHCA, α-MCA, β-MCA, HCA, LCA-3S, CA, UCA and Citramalic acid were decreased in the persistent lymphopenia. ConclusionIn the process of interaction between host receptors and gut microbiota in patients with persistent lymphopenia sepsis, with a significant reduction in gut microbiota diversity and bile acid metabolites. That can affect various inflammatory pathways of gut immune cells, causing immune dysfunction in the body, which may be one of the main causes of death.

The Gut Microbiota and Major Depressive Disorder: Current Understanding and Novel Therapeutic Strategies.

Major depressive disorder (MDD) is a common neuropsychiatric challenge that primarily targets young females. MDD as a global disorder has a multifactorial etiology related to the environment and genetic background. A balanced gut microbiota is one of the most important environmental factors involved in human physiological health. The interaction of gut microbiota components and metabolic products with the hypothalamic-pituitary-adrenal system and immune mediators can reverse depression phenotypes in vulnerable individuals. Therefore, abnormalities in the quantitative and qualitative structure of the gut microbiota may lead to the progression of MDD. In this review, we have presented an overview of the bidirectional relationship between gut microbiota and MDD, and the effect of pre-treatments and microbiomebased approaches, such as probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and a new generation of microbial alternatives, on the improvement of unstable clinical conditions caused by MDD.

304 Plasma metabolomic profile of psoriasis and immune-mediated inflammatory diseases

304 Plasma metabolomic profile of psoriasis and immune-mediated inflammatory diseases

Generation of two isogenic human iPSC lines (ZIPi013-B-1, ZIPi013-B-2) carrying a CRISPR/Cas9-mediated deletion of TRPM4

Two isogenic hiPSC lines, ZIPi013-B-1 and ZIPi013-B-2, were generated by CRISPR/Cas9-mediated indels in the TRPM4 gene of the previously published ZIPi013-B. TRPM4 belongs to the evolutionarily conserved family of transient receptor potential (TRP) channels. It is expressed ubiquitously and its activity is regulated by intracellular calcium binding, changes in membrane potential, phosphoinositide lipids in the plasma membrane and the local concentration of cytoplasmic ATP and ADP. TRPM4 has been implicated in various diseases, including neurological and immune system disorders, cardiac diseases and cancer. Both new cell lines offer the opportunity to model human diseases and test therapeutic modalities addressing these

Pediatric MOG-Ab-Associated Encephalitis: Supporting Early Recognition and Treatment.

Antibodies to myelin oligodendrocyte glycoprotein (MOG-Ab) have recently been reported in patients with encephalitis who do not fulfill criteria for acute disseminated encephalomyelitis (ADEM). We evaluated a cohort of these children and compared them with children with ADEM. This retrospective, multicenter cohort study comprised consecutive patients <18 years of age with MOG-Ab who fulfilled criteria for autoimmune encephalitis. These patients were stratified into (1) children not fulfilling criteria for ADEM (encephalitis phenotype) and (2) children with ADEM. Clinical/paraclinical data were extracted from the electronic records. Comparisons were made using the Mann-Whitney U test and χ2 Fisher exact test for statistical analysis. From 235 patients with positive MOG-Ab, we identified 33 (14%) with encephalitis and 74 (31%) with ADEM. The most common presenting symptoms in children with encephalitis were headache (88%), seizures (73%), and fever (67%). Infective meningoencephalitis was the initial diagnosis in 67%. CSF pleocytosis was seen in 79%. Initial MRI brain was normal in 8/33 (24%) patients. When abnormal, multifocal cortical changes were seen in 66% and unilateral cortical changes in 18%. Restricted diffusion was demonstrated in 43%. Intra-attack new lesions were seen in 7/13 (54%). When comparing with children with ADEM, children with encephalitis were older (median 8.9 vs 5.7 years, p = 0.005), were more likely to be admitted to intensive care (14/34 vs 4/74, p < 0.0001), were given steroid later (median 16.6 vs 9.6 days, p = 0.04), and were more likely to be diagnosed with epilepsy at last follow-up (6/33 vs 1/74, p = 0.003). MOG-Ab should be tested in all patients with suspected encephalitis even in the context of initially normal brain MRI. Although exclusion of infections should be part of the diagnostic process of any child with encephalitis, in immunocompetent children, when herpes simplex virus CSF PCR and gram stains are negative, these features do not preclude the diagnosis of immune mediated disease and should not delay initiation of first-line immunosuppression (steroids, IVIG, plasma exchange), even while awaiting the antibody results.

Cortistatin exerts an immunomodulatory and neuroprotective role in a preclinical model of ischemic stroke

Ischemic stroke is the result of a permanent or transient occlusion of a brain artery, leading to irreversible tissue injury and long-term sequelae. Despite ongoing advancements in revascularization techniques, stroke remains the second leading cause of death worldwide. A comprehensive understanding of the complex and interconnected mechanisms, along with the endogenous mediators that modulate stroke responses is essential for the development of effective interventions. Our study investigates cortistatin, a neuropeptide extensively distributed in the immune and central nervous systems, known for its immunomodulatory properties. With neuroinflammation and peripheral immune deregulation as key pathological features of brain ischemia, cortistatin emerges as a promising therapeutic candidate. To this aim, we evaluated its potential effect in a well-established middle cerebral artery occlusion (MCAO) preclinical stroke model. Our findings indicate that the peripheral administration of cortistatin at 24h post-stroke significantly reduces neurological damage and enhances recovery. Importantly, cortistatin-induced neuroprotection was multitargeted, as it modulated the glial reactivity and astrocytic scar formation, facilitated blood-brain barrier recovery, and regulated local and systemic immune dysfunction. Surprisingly, administration of cortistatin at immediate and early post-stroke time points proved to be not beneficial and even detrimental. These results emphasize the importance of understanding the spatio-temporal dynamics of stroke pathology to develop innovative therapeutic strategies with appropriate time windows. Premature interruption of certain neuroinflammatory processes might inadvertently compromise neuroprotective mechanisms. In summary, our study highlights cortistatin as a novel pleiotropic therapeutic approach against ischemic stroke, offering new treatment options for patients for whom early revascularization intervention is unsuccessful.

Valence-dependent immune responses of earthworm coelomocytes: Toxicity pathways and molecular mechanisms of As (III) and As (V)-induced immunotoxicity

Epidemiological studies in inorganic arsenic (iAs) exposure populations have offered convincing evidence that exposure to arsenite (As (III)) and arsenate (As (V)) are linked to immune dysfunction and immunosuppression. However, the valence-dependent immunotoxicity mechanism of iAs has not been explored. In this work, we conducted a thorough investigation and comparison of lysosome dysfunction in As (III) and As (V) induced earthworm typical immune cells coelomocytes, and the binding reaction between As (III)/As (V) and immunoprotein lysozyme (LZM). Results indicated As (III) and As (V) induced severe alterations in NR uptake and caused serious damage to lysosomal membrane, particularly As (III). As (III) (21.24 %) had a stronger inhibitory effect on LZM activity in coelomocytes than As (V) (67.40 %), which showed a similar toxic trend as enzyme activity in vitro (As (III)-68.66 % and As (V)-78.50 %). LZM skeleton relaxation, secondary structural transformation, fluorescence sensitization and particle alteration provided evidence for As (III) trigger more grievous immunoprotein dysfunction. In conclusion, As (III) and As (V) triggered lysosomal membrane destruction in coelomocytes, as well as induced structural changes in LZM result in lysosomal hydrolase dysfunction in coelomocytes. Ultimately, cellular lysosome dysfunction and destruction, which leads to the normal immune system of the cells is disrupted. As (III) induced stronger immunosuppression through lysosome pathway than As (V). Our work reveals the degree of lysosome dysfunction triggered by As (III) and As (V) probably responsible for the valence-dependent immunosuppression patterns of iAs, and provide new insights for As toxicity assessment.

Axial Spondyloarthritis in Black Americans: An Observational Study From Five Centers in Shelby County, Tennessee.

Axial spondyloarthritis (axSpA) is an immune-mediated disease that predominantly affects the axial skeleton. The objective of this study was to describe the frequency and clinical characteristics of axSpA in Black Americans in Shelby County. We also aimed to report diagnostic delays, disease severity, and health disparities in this population. This was a retrospective observational study in which electronic records of patients with axSpA were reviewed across five centers in Shelby County. Patients were identified using International Classification of Diseases codes. Data on demographics, clinical characteristics, and imaging were collected. The frequency was reported. Two-group comparisons were done using the chi-square test and two-sample t-test. Multivariable logistic and linear regression methods were used to compare sacroiliitis grades and delay in diagnosis, respectively, after adjusting for confounders. Black Americans constituted 32% (n = 78) of the 244 patients with axSpA identified. Black Americans had significantly more hip involvement, more elevations in C-reactive protein, less HLA-B27 positivity, and less family history positivity when compared with White patients. After adjusting for age, sex, and HLA-B27, Black Americans had twice as higher odds of having advanced grades of sacroiliitis on x-rays compared to White Americans (odds ratio 2.32 [95% confidence interval 1.23-4.44]). AxSpA was associated with significant diagnostic delays in both races. A significant proportion of patients with axSpA in Shelby County were Black Americans. The study identified that Black Americans have more odds of having advanced sacroiliitis on x-rays, more hip involvement, and higher markers of inflammation. It also showed that, regardless of race or ethnicity, there is a significant diagnostic delay.

RhoGDI in RBL-2H3 cells acts as a negative regulator of Rho GTPase signaling to inhibit granule exocytosis.

Mast cells are hematopoietic-derived immune cells that possess numerous cytoplasmic granules containing immune mediators such as cytokines and histamine. Antigen stimulation triggers mast cell granule exocytosis, releasing granule contents in a process known as degranulation. We have shown that Rho GTPase signaling is an essential component of granule exocytosis, however, the proteins that regulate Rho GTPases during this process are not well defined. Here we examined the role of Rho guanine-nucleotide dissociation inhibitors (RhoGDIs) in regulating Rho GTPase signaling using RBL-2H3 cells as a mast cell model. We found that RBL-2H3 cells express two RhoGDI isoforms which are primarily localized to the cytosol. Knockdown of RhoGDI1 and RhoGDI2 greatly reduced the levels of all Rho GTPases tested: RhoA, RhoG, Rac1, Rac2, and Cdc42. The reduction in Rho GTPase levels was accompanied by an increase in their membrane-localized fraction and an elevation in the levels of active Rho GTPases. All RhoGDI knockdown strains had altered resting cell morphology, although each strain was activation competent when stimulated. Live cell imaging revealed that the RhoGDI1/2 double knockdown (DKD) strain maintained its activated state for prolonged periods of time compared to the other strains. Only the RhoGDI1/2 DKD strain showed a significant increase in granule exocytosis. Conversely, RhoGDI overexpression in RBL-2H3 cells did not noticeably affect Rho GTPases or degranulation. Based on these results, RhoGDIs act as negative regulators of Rho GTPases during mast cell degranulation, and inhibit exocytosis by sequestering Rho GTPases in the cytosol.

LINE-1 hypomethylation characterizes the inflammatory response in coeliac disease associated-intestinal mucosa and small bowel adenocarcinomas.

Long interspersed nuclear elements 1 (LINE-1) are the most abundant and the only autonomous mobile elements in the human genome. When their epigenetic repression is removed, it can lead to disease, such as autoimmune diseases and cancer. Coeliac disease (CeD) is an immune-mediated disease triggered by an abnormal T-cell response to dietary gluten and a predisposing condition of small bowel adenocarcinoma (SBA), frequently characterized by epigenetic alterations. The aim of this work was to assess LINE-1 methylation by bisulphite pyrosequencing and NanoString® gene transcription analysis in 38 CeD-SBAs compared with 25 SBAs associated with Crohn's disease (CrD-SBAs) and 25 sporadic SBAs (S-SBA). Both analyses were also performed in duodenal mucosae from 12 untreated CeD patients (UCD) and 19 treated CeD patients (TCD), and in 11 samples of normal intestinal mucosa to better investigate the role of LINE-1 deregulation in CeD and in CeD-SBA. A significant loss of LINE-1 methylation was observed in CeD-SBAs and in mucosae from UCD patients (with very similar methylation levels) compared with controls. By contrast, a restoration of normal LINE-1 methylation levels was found in TCD mucosae after a strict gluten-free diet. LINE-1 hypomethylation does not lead to expression of ORF1 and ORF2, with the only exception being for one CeD-SBA. The expression analysis of enzymes modulating DNA methylation and inflammatory genes confirmed that CeD-SBA shared a very similar expression profile of UCD mucosae showing a strong upregulation of genes involved in inflammation, immune response, and T-cell activity compared with TCD mucosae. For the first time, this work demonstrates that loss of DNA methylation is an intrinsic epigenetic feature of CeD, accompanying the immune response as a reversible mechanism in patients following a strict gluten-free diet, and suggests the possible role of LINE-1 hypomethylation in promoting cell adaptability during the gliadin-related inflammatory process. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Identification of Plasma Metabolites and Dipeptides as Diagnostic Biomarkers for Psoriasis Vulgaris through Liquid Chromatography-High Resolution Mass Spectrometry-Based Metabolomics.

Psoriasis, an immune-mediated chronic inflammatory skin disease, is primarily diagnosed through clinical assessment. Currently, specific markers for the accurate diagnosis and prediction of psoriatic disease are lacking. Here, we employed a three-step designed study to perform untargeted metabolomics, with the aim of identifying candidate biomarkers for psoriasis. Through comprehensive multivariate and univariate statistical analyses, we screened eight potential biomarkers specific to psoriasis, with five structurally identified. Two dipeptide biomarkers, γ-GluSer and ThrGly, along with a lysine glycation metabolite, Nα-fructosyl-lysine (Fruc-Lys), were found to be psoriasis biomarkers for the first time. Receiver operating characteristic curve analysis revealed that the area under the curve (AUC) values of these eight metabolites/features ranged from 0.68 to 0.94. A biomarker panel comprising ThrGly and feature m/z 120.0656 (C4H9NO3) demonstrated high diagnostic accuracy (AUC = 0.97) in distinguishing psoriasis patients from healthy controls. Overall, our study identified and validated a panel of plasma metabolites/features that could serve as potential biomarkers for the diagnosis of psoriasis, providing new insights into the diagnosis and pathogenesis of this disease.

PERSISTENCE, EFFECTIVENESS, AND SAFETY OF UPADACITINIB IN CROHN'S DISEASE AND ULCERATIVE COLITIS IN REAL LIFE: RESULTS FROM A SPANISH NATIONWIDE STUDY (UREAL STUDY): Upadacitinib for IBD.

Real-world data on the effectiveness of upadacitinib for inflammatory bowel disease (IBD) are limited. To assess upadacitinib persistence, effectiveness, and safety in a real-world scenario. Retrospective multicentre study of IBD patients who received upadacitinib before 31st December 2022 and at least 12 weeks before the recruitment date. Clinical effectiveness was assessed based on partial Mayo score for ulcerative colitis (UC) and Harvey-Bradshaw index for Crohn's disease (CD). We included 100 patients (68 with CD, and 32 with UC). Patients had previously received a median of four advanced therapies. Twenty-three discontinued the treatment (median follow-up 7.6 months). CD (vs. UC) (Hazard Ratio[HR] 3.7;95%Confidence Interval (CI):1.04-12.9), and age below 40 years at upadacitinib initiation (HR 2.4;95%CI:1.0-5.8) were associated with treatment discontinuation in multivariable analysis. Clinical remission for IBD was achieved in 59% of patients at week 8, 64% at week 12, and 42% at week 52. The proportion of patients with UC previously exposed to tofacitinib (n=25) who achieved clinical remission was 78% at week 12, and 50% at week 52. Factors associated with clinical remission at week 12 were UC diagnosis (Odds Ratio[OR] 4.6;95%CI:1.3-17), mild or moderate activity at baseline (OR 8;95%CI:1.1-56) and not smoking (OR 4.4;95%CI:1.5-13). Dose escalation recaptured remission in 60% of patients with relapse. Eighty percent of patients with active immune-mediated diseases or extraintestinal manifestations improved with upadacitinib. Forty-three patients reported adverse events, 11 of them serious. Upadacitinib is effective and safe for treating highly refractory IBD patients, even in previously treated with JAK inhibitors.

Seoul orthohantavirus evades innate immune activation by reservoir endothelial cells

Seoul orthohantavirus evades innate immune activation by reservoir endothelial cells

Small cell lung cancer with liver metastases: from underlying mechanisms to treatment strategies.

Small cell lung cancer (SCLC) represents an aggressive neuroendocrine (NE) tumor within the pulmonary region, characterized by very poor prognoses. Druggable targets for SCLC remain limited, thereby constraining treatment options available to patients. Immuno-chemotherapy has emerged as a pivotal therapeutic strategy for extensive-stage SCLC (ES-SCLC), yet it fails to confer significant efficacy in cases involving liver metastases (LMs) originating from SCLC. Therefore, our attention is directed towards the challenging subset of SCLC patients with LMs. Disease progression of LM-SCLC patients is affected by various factors in the tumor microenvironment (TME), including immune cells, blood vessels, inflammatory mediators, metabolites, and NE substances. Beyond standard immuno-chemotherapy, ongoing efforts to manage LMs in SCLC encompass anti-angiogenic therapy, radiotherapy, microwave ablation (MWA) / radiofrequency ablation (RFA), trans-arterial chemoembolization (TACE), and systemic therapies in conjunction with local interventions. Prospective experimental and clinical investigations into SCLC should prioritize precise and individualized approaches to enhance the prognosis across distinct patient cohorts.

Endoplasmic reticulum stress-related signatures: a game-changer in prognostic stratification for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has limited therapeutic options and a poor prognosis. The endoplasmic reticulum (ER) plays a crucial role in tumor progression and response to stress, making it a promising target for HCC stratification. This study aimed to develop a risk stratification model using ER stress-related signatures. We utilized transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus, which encompass whole-genome expression profiles and clinical annotations. Machine learning algorithms, including the least absolute shrinkage and selection operator, random forest, and support vector machine recursive feature elimination, were applied to the key genes associated with HCC prognosis. A prognostic system was developed using univariate Cox hazard analysis and least absolute shrinkage and selection operator Cox regression, followed by validation using Kaplan-Meier analysis and receiver operating characteristic curves. Tumor immune dysfunction and exclusion tools were used to predict immunotherapy responsiveness. Two distinct clusters associated with ER stress were identified in HCC, each exhibiting unique clinical and biological features. Using a computational approach, a prognostic risk model, namely the ER stress-related signature, was formulated, demonstrating enhanced predictive accuracy compared with that of existing prognostic models. An effective clinical nomogram was established by integrating the risk model with clinicopathological factors. Patients with lower risk scores exhibited improved responsiveness to various chemotherapeutic, targeted, and immunotherapeutic agents. The critical role of ER stress in HCC is highlighted. The ER stress-related signature developed in this study is a powerful tool to assess the risk and clinical treatment of HCC.

Measuring Disease Progression in Multiple Sclerosis Clinical Drug Trials and Impact on Future Patient Care.

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterised by inflammation, demyelination and neurodegeneration. Although several drugs are approved for MS, their efficacy in progressive disease is modest. Addressing disease progression as a treatment goal in MS is challenging due to several factors. These include a lack of complete understanding of the pathophysiological mechanisms driving MS and the absence of sensitive markers of disease progression in the short-term of clinical trials. MS usually begins at a young age and lasts for decades, whereas clinical research often spans only 1-3 years. Additionally, there is no unifying definition of disease progression. Several drugs are currently being investigated for progressive MS. In addition to new medications, the rise of new technologies and of adaptive trial designs is enabling larger and more integrated data collection. Remote assessments and decentralised clinical trials are becoming feasible. These will allow more efficient and large studies at a lower cost and with less burden on study participants. As new drugs are developed and research evolves, we anticipate a concurrent change in patient care at various levels in the foreseeable future. We conducted a narrative review to discuss the challenges of accurately measuring disease progression in contemporary MS drug trials, some new research trends and their implications for patient care.

&lt;b&gt;IMPACT OF DIABETES ON TUBERCULOSIS TREATMENT OUTCOMES: EDITORIAL PERSPECTIVE&lt;/b&gt;

Diabetes mellitus (DM) significantly alters tuberculosis (TB) treatment outcomes due to immune dysfunction, drug interactions, and limited access to integrated care. The coexistence of these conditions exacerbates global health disparities, particularly in low-resource settings. Diabetic patients with TB frequently exhibit delayed sputum conversion, higher relapse rates, and poorer cure outcomes than non-diabetic counterparts. Addressing these challenges requires an interdisciplinary approach combining better glycemic control, robust healthcare integration, and patient education. This editorial evaluates the interplay between DM and TB, discusses barriers to effective treatment, and highlights strategies to improve cure rates, advocating for targeted interventions to reduce the dual disease burden globally.

Immunological Profiles, Oxidative Stress Biomarkers and Plasma Cholinesterase Activities in Patients with Immune-Mediated Inflammatory Diseases Treated in a Clinic in Duhok, Iraq

Abstract Aim The purpose of the present study was to measure the levels of selected plasma biochemical variables among cases of immune-mediated inflammatory diseases (IMIDs), other than rheumatoid arthritis, treated in a clinic in the city of Duhok, Iraq, since such information is scarce in the region. Materials and Methods A case-control study on IMIDs patients treated in a clinic in Duhok, Iraq, was performed from February 2022 to June 2023. A total of 29 patients of both genders with IMIDs and 61 healthy controls were recruited at the Duhok Center for Rheumatic Diseases and Medical Rehabilitation, Duhok, Iraq. The laboratory tests conducted on plasma samples from IMIDs patients and healthy controls included measurements of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, malondialdehyde (MDA), total antioxidant status (TAS) and cholinesterase (ChE) activity. Results No significant differences were found in gender distribution, age, and body mass index between the IMIDs patients and healthy controls. The majority of patients (69%) received conventional therapy combined with biologic agents, whereas the remaining patients (31%) received only conventional medications. The IMIDs identified among the 29 patients were Behcet’s disease (27.6%), ankylosing spondylitis (24.1%), inflammatory bowel diseases (24.1%), psoriatic arthritis (10.3%), systemic lupus erythematosus (6.9%) and psoriasis (6.9%). Conventional therapy used was mostly azathioprine (44.8%) and methotrexate (17.2%), whereas biological therapy included mostly etanercept (27.6%) and adalimumab (24.1%). The values of CRP, IL-6 and TNF-Į among the IMIDs patients were not significantly different from those of the controls. The oxidative stress biomarker MDA was elevated in IMID patients (2.93 ± 1.106 —mol/L vs. 2.52 ± 0.478) at a p value of 0.064 (though not significant). The TAS level (1.21 ± 0.422 mmol Trolox Equiv./L vs. 1.00 ± 0.338, p = 0.022) and plasma ChE activity (1.18 ± 0.50 ¨ pH/20 min vs. 0.83 ± 0.30, p = 0.001) were significantly higher in IMIDs patients compared to controls. Conclusions The data suggest that oxidative stress and changes in plasma ChE activity might be a part of the pathophysiological alterations among IMIDs patients. Therapeutic drug monitoring and its clinical outcome as well as response of IMIDs patients to anti-ChE agents are worth of further in depth exploration and pursuing. They are essential for better diagnosis, treatment, and management of IMIDs.

TET2 promotes tumor antigen presentation and T cell IFN-γ, which is enhanced by vitamin C.

Immune evasion by tumors is promoted by low T cell infiltration, ineffective T cell activity directed against the tumor, and reduced tumor antigen presentation. The TET2 DNA dioxygenase gene is frequently mutated in hematopoietic malignancies and loss of TET enzymatic activity is found in a variety of solid tumors. We showed previously that vitamin C (VC), a cofactor of TET2, enhances tumor-associated T cell recruitment and checkpoint inhibitor therapy responses in a TET2-dependent manner. Using single-cell RNA sequencing (scRNA-seq) analysis performed on B16-OVA melanoma tumors, we have shown here that an additional function for TET2 in tumors is to promote expression of certain antigen presentation machinery genes, which is potently enhanced by VC. Consistently, VC promoted antigen presentation in cell-based and tumor assays in a TET2-dependent manner. Quantifying intercellular signaling from the scRNA-seq dataset showed that T cell-derived IFN-γ-induced signaling within the tumor and tumor microenvironment requires tumor-associated TET2 expression, which is enhanced by VC treatment. Analysis of patient tumor samples indicated that TET activity directly correlates with antigen presentation gene expression and with patient outcomes. Our results demonstrate the importance of tumor-associated TET2 activity as a critical mediator of tumor immunity, which is augmented by high-dose VC therapy.