Background: Chronic systemic inflammation in individuals with moderate-to-severe atopic dermatitis (AD) potentially predisposes them to metabolic and cardiovascular diseases. Nevertheless, evidence with regard to such association is limited. Objective: To assess the association between metabolic and cardiovascular outcomes and moderate-to-severe AD. Methods: A systematic search was performed through PubMed, Scopus, EMBASE, and Cochrane for population-based studies that addressed the effects of moderate-to-severe AD on metabolic and cardiovascular outcomes compared with the general population from inception to August 31, 2023. Meta-analysis was performed using the random effects model. The pooled odds ratio (OR) and certainty of evidence for each outcome were reported. Results: We included 11 studies, 4 retrospective cohorts, 1 prospective cohort, 4 cross-sectional, and 2 case-control studies involving 405,170 moderate-to-severe AD patients compared to 4,591,478 unaffected controls. Moderate-to-severe AD was associated with a higher risk of myocardial infarction with an OR (95% CI) of 1.33 (1.07, 1.65), angina 1.33 (1.06, 1.66), heart failure 1.56 (1.28, 1.90), stroke 1.45 (1.21, 1.74), hypertension 1.38 (1.18, 1.63), dyslipidemia 1.27 (1.15, 1.41), and metabolic syndrome 1.24 (1.05, 1.42) with very low certainty of evidence. No significantly increased risk of cardiovascular death with an odds ratio (95% CI) of 1.81 (0.96, 3.44) and diabetes of 1.24 (0.91, 1.68) was observed. High heterogeneity was observed in most studies for all of the outcomes. Conclusion: Our meta-analysis demonstrated a modest but significant association between moderate-to-severe AD and increased susceptibility to metabolic and cardiovascular diseases. Initial assessment of cardiovascular and metabolic risk for patients with moderate-to-severe AD should be considered to enable early management strategies.
Lung cancer is the most common malignant tumor in the world. Presently, there are still problems, including a high recurrence rate, resistance, and serious toxic side effects, even if conventional treatments like chemotherapy, radiotherapy, and targeted therapy have somewhat improved patient survival. Even though immune checkpoint inhibitors that target programmed cell death-1/programmed cell death ligand 1 have fundamentally altered the therapeutic paradigm, the core mechanism is strongly linked to tumor immune escape, and some patients continue to have poor response rates or treatment resistance. The mechanisms of immune escape in the immunological microenvironment of lung cancer, involving metabolic reprogramming, overexpression of immune checkpoint molecules, and abnormalities in antigen presentation, are systematically summarized in this review. The article also sums up new therapeutic targets and promising clinical trials. The goal is to provide a solid theoretical foundation for further research into the immune escape mechanism, the creation of new immunotherapeutic targets, and personalized therapeutic strategies.
Safwaan H. Khan, Safwaan H. Khan, Yeonjoo Choi
et al.
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, achieving remarkable clinical success with FDA-approved therapies targeting CD19 and BCMA. However, the extension of these successes to solid tumors remains limited due to several intrinsic challenges, including antigen heterogeneity and immunosuppressive tumor microenvironments. In this review, we provide a comprehensive overview of recent advances in CAR T cell therapy aimed at overcoming these obstacles. We discuss the importance of antigen identification by emphasizing the identification of tumor-specific and tumor-associated antigens and the development of CAR T therapies targeting these antigens. Furthermore, we highlight key structural innovations, including cytokine-armored CARs, protease-regulated CARs, and CARs engineered with chemokine receptors, to enhance tumor infiltration and activity within the immunosuppressive microenvironment. Additionally, novel manufacturing approaches, such as the Sleeping Beauty transposon system, mRNA-based CAR transfection, and in vivo CAR T cell production, are discussed as scalable solution to improve the accessibility of CAR T cell therapies. Finally, we address critical therapeutic limitations, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and suboptimal persistence of CAR T cells. An examination of emerging strategies for countering these limitations reveals that CRISPR-Cas9-mediated genetic modifications and combination therapies utilizing checkpoint inhibitors can improve CAR T cell functionality and durability. By integrating insights from preclinical models, clinical trials, and innovative engineering approaches, this review addresses advances in CAR T cell therapies and their performance in solid tumors.
Uppala Radhakrishna, Uppala Ratnamala, Devendrasinh D. Jhala
et al.
BackgroundHidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects hair follicles in areas with apocrine sweat glands, such as the underarms, groin, and buttocks. The pathogenesis of HS is not fully understood, but considering the key role played by the biological clock in the control of immune/inflammatory processes the derangement of circadian and ultradian pathways could be hypothesized.MethodsWe analyzed genome-wide DNA methylation patterns in peripheral blood from 24 HS cases and 24 controls using the Infinium HumanMethylation450 BeadChip array (Illumina), followed by bioinformatics and statistical analyses.ResultsWe found that several circadian and ultradian genes were differentially methylated in HS patients, predominantly exhibiting hypomethylation. These genes were enriched in pathways such as MAPK and WNT cascades, acute phase response, cytokine release, inflammation, innate immune response, xenobiotic detoxification, and oxidative stress response.ConclusionAltered DNA methylation patterns of genes related to circadian and ultradian pathways could contribute to immune system derangement and inflammatory processes chronicization in addition to other comorbidities hallmarking HS onset and progression, at the same time representing possible druggable targets.
Abstract Background Ankylosing spondylitis (AS) has been known to have auto-inflammatory nature; hence, the efficacy of autoantibodies is low. However, studies on autoantibodies are ongoing, with some studies showing associations. Previous studies showed that anti-protein phosphatase magnesium-dependent 1A (PPM1A) IgG was increased in patients with AS and associated with radiographic progression. However, the diagnostic usefulness was limited due to relatively low sensitivity and specificity. This pilot study evaluated the diagnostic utility of anti-PPM1A-IgM and anti-PPM1A-IgG in patients with active AS. Methods Serum samples were obtained from the registry cohort of a single tertiary center in Korea. Serum levels of anti-PPM1A-IgG/IgM were measured by direct ELISA. Receiver operating characteristic (ROC) analysis was used to predict the diagnostic sensitivity and specificity of serum anti-PPM1A-IgG/IgM. Results Samples were collected from 28 patients with active AS, 16 healthy controls (HCs), and 28 patients with rheumatoid arthritis (RA). Although total serum IgM was lower in the RA and AS groups than in the HC group, anti-PPM1A-IgM was significantly lower in the AS group than in the other groups. In evaluating the diagnostic utility of anti-PPM1A-IgG/IgM for AS patients compared with HCs, the area under the curve (AUC) of anti-PPM1A-IgM was 0.998 (sensitivity 96.4%, specificity 100.0%). When ROC analysis of anti-PPM1A-IgM for AS patients compared with RA patients was conducted, sensitivity was 78.6% and specificity was 71.4%, with an AUC of 0.839. Conclusion Decreased anti-PPM1A-IgM levels in AS patients suggests a potential role for anti-PPM1A-IgM in the diagnosis of active AS.
Diseases of the musculoskeletal system, Immunologic diseases. Allergy
Jin-Chuan Liu, Jin-Chuan Liu, Qunxiong Zeng
et al.
B cells constitute a diverse and adaptable immune cell population with functions that can vary according to the environment and circumstances. The involvement of B cells in pregnancy, as well as the associated molecular pathways, has yet to be investigated. This review consolidates current knowledge on B cell activities and regulation during pregnancy, with a particular focus on the roles of various B cell subsets and the effects of B cell-derived factors on pregnancy outcomes. Moreover, the review examines the significance of B cell-associated autoantibodies, cytokines, and signaling pathways in relation to pregnancy complications such as pregnancy loss, preeclampsia, and preterm birth.
Coagulopathy is a critical pathophysiological mechanism of acute pancreatitis (AP), arising from the complex interplay between innate immune, endothelial cells and platelets. Although initially beneficial for the host, uncontrolled and systemic activation of coagulation cascade in AP can lead to thrombotic and hemorrhagic complications, ranging from subclinical abnormalities in coagulation tests to severe clinical manifestations, such as disseminated intravascular coagulation. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, is impaired by pro-inflammatory cytokines. Also, fibrin removal is severely obstructed by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1. Finally, increased fibrin generation and impaired break down lead to deposition of (micro) vascular clots, which may contribute to tissue ischemia and ensuing organ dysfunction. Despite the high burden of coagulopathy that have a negative impact on AP patients’ prognosis, there is no effective treatment yet. Although a variety of anticoagulants drugs have been evaluated in clinical trials, their beneficial effects are inconsistent, and they are also characterized by hemorrhagic complications. Future studies are called to unravel the pathophysiologic mechanisms involved in coagulopathy in AP, and to test novel therapeutics block coagulopathy in AP.
Abstract Hepatitis B virus (HBV) infection remains a global health challenge. Despite the availability of effective preventive vaccines, millions of people are at risk of cirrhosis and hepatocellular carcinoma. Current drug therapies inhibit viral replication, slow the progression of liver fibrosis and reduce infectivity, but they rarely remove the covalently sealed circular DNA (cccDNA) of the virus that causes HBV persistence. Alternative treatment strategies, including those based on CRISPR/cas9 knockout virus gene, can effectively inhibit HBV replication, so it has a good prospect. During chronic infection, some virus gene knockouts based on CRISPR/cas9 may even lead to cccDNA inactivation. This paper reviews the progress of different HBV CRISPR/cas9, vectors for delivering to the liver, and the current situation of preclinical and clinical research.
Mast Cell Activation Syndrome (MCAS) is a severe relapsing disease requiring inpatient treatment, with clinical pattern including the features of anaphylaxis. The article presents diagnostic criteria aimed for differentiation of MCAS from similar severe conditions as well as discusses local forms of mast cell activation. The consensus group has established distinct criteria for diagnosing MCAS. The agreed criteria include episodic (recurrent) occurrence of typical systemic symptoms caused by release of mast cell mediators and involve, at least, two organs; an increase in serum tryptase level by, at least, 20% over individual baseline tryptase plus 2 ng/mL tryptase during 3-4 hours of the pathological reaction; a positive response to drugs that either target mast cells mediators, or their effects. In principle, the classification of MCAS is based on its etiology being subdivided into primary (clonal) MCAS, secondary MCAS, and idiopathic MCAS. The primary MCAS is determined by clonal expansion of mast cells and is considered systemic mastocytosis. In secondary MCAS, normal mast cells are activated by the known triggers, e.g., IgE. If neither clonal expansion nor a trigger for mast cells activation are identified, the condition is defined as idiopathic MCAS.The new COVID-19 infection has attracted particular interest in MCAS, since the severe course of COVID-19 was thought to develop due to latent MCAS, but the criteria for MCAS in these patients were not reproduced. In the presence of local symptoms, such as urticaria, or in cases of single-organ involvement, e.g., isolated gastrointestinal symptoms, and suspected mast cell activation being basic to pathogenesis, the term mast cell activation disorder was introduced. Moreover, the article discusses several different mediators that are proposed as markers in the diagnosis of MCAS.However, over-diagnosis of MCAS entails the risk of missing the underlying pathology, which is not associated with MCAS, and requires differential diagnosis with a number of diseases. In the absence of severe attacks (with hypotension and shock), the likelihood of MCAS is generally very low. Of course, the patients with mastocytosis and/or confirmed IgE-dependent allergy are at higher risk of developing MCAS, but a key diagnostic marker is an event-related increase in mast cells tryptase from baseline determined over the asymptomatic period. The diagnosis of MCAS is highly likely if the tryptase level rises above a certain threshold (20% of baseline plus 2 ng/mL).
Bacillus thuringiensis (Bt) produces different insecticidal proteins effective for pest control. Among them, Cry insecticidal proteins have been used in transgenic plants for the control of insect pests. However, evolution of resistance by insects endangers this technology. Previous work showed that the lepidopteran insect Plutella xylostella PxHsp90 chaperone enhanced the toxicity of Bt Cry1A protoxins by protecting them from degradation by the larval gut proteases and by enhancing binding of the protoxin to its receptors present in larval midgut cells. In this work, we show that PxHsp70 chaperone also protects Cry1Ab protoxin from gut proteases degradation, enhancing Cry1Ab toxicity. We also show that both PxHsp70 and PxHsp90 chaperones act cooperatively, increasing toxicity and the binding of Cry1Ab439D mutant, affected in binding to midgut receptors, to cadherin receptor. Also, insect chaperones recovered toxicity of Cry1Ac protein to a Cry1Ac-highly resistant P. xylostella population, NO-QAGE, that has a disruptive mutation in an ABCC2 transporter linked to Cry1Ac resistance. These data show that Bt hijacked an important cellular function for enhancing its infection capability, making use of insect cellular chaperones for enhancing Cry toxicity and for lowering the evolution of insect resistance to these toxins.
Angus T Stock, Sarah Parsons, Varun J Sharma
et al.
Abstract Objective Vasculitis is characterised by inflammation of the blood vessels. While all layers of the vessel can be affected, inflammation within the intimal layer can trigger thrombosis and arterial occlusion and is therefore of particular clinical concern. Given this pathological role, we have examined how intimal inflammation develops by exploring which (and how) macrophages come to populate this normally immune‐privileged site during vasculitis. Methods We have addressed this question for Kawasaki disease (KD), which is a type of vasculitis in children that typically involves the coronary arteries. We used confocal microscopy and flow cytometry to characterise the macrophages that populate the coronary artery intima in KD patient samples and in a mouse model of KD, and furthermore, have applied an adoptive transfer system to trace how these intimal macrophages develop. Results In KD patients, intimal hyperplasia coincided with marked macrophage infiltration of the coronary artery intima. Phenotypic analysis revealed that these ‘intimal macrophages’ did not express markers of resident cardiac macrophages, such as Lyve‐1, and instead, were uniformly positive for the chemokine receptor Ccr2, suggesting a monocytic lineage. In support of this origin, we show that circulating monocytes directly invade the intima via transluminal migration during established disease, coinciding with the activation of endothelial cells lining the coronary arteries. Conclusions During KD, intimal macrophages develop from circulating monocytes that infiltrate the inflamed coronary artery intima by transluminal migration.
Ciro Romano, Olga Tortorella, Liliana Dalla Mora
et al.
BackgroundChronic immune stimulation by hepatitis C virus (HCV) may cause occurrence of several autoantibodies in infected patients, with or without features of clinically overt autoimmune diseases. The recent introduction of direct-acting antivirals (DAAs) has dramatically changed the natural history of chronic HCV infection. The aim of this study was to assess the effects of DAA therapy on serum autoantibodies in chronic hepatitis C (CHC) patients.MethodsThe medical records of 113 CHC patients were reviewed to assess autoantibody behavior following DAA-directed HCV eradication. Statistical analysis was performed to assess correlations between DAA treatment and autoantibody titers, HCV genotypes, and viral loads.ResultsAnti-nuclear (ANA), anti-smooth muscle cell (ASMA) and anti-mitochondrial (AMA) antibody testing was available in 77 patients; 31 out of 77 patients (40%) had one or more serum autoantibodies prior to treatment. Measurement of autoantibody titers before and after HCV eradication was performed in 20 of 31 patients. DAA treatment significantly affected ANA and ASMA titers, leading to disappearance or reduction of autoantibody titers; conversely, AMA were not influenced by DAA treatment. No correlations were observed between autoantibody specificity and both HCV genotypes and viral loads at baseline. Likewise, serum autoantibody titers were independent of HCV genotypes.ConclusionsDAA-directed HCV clearance may interrupt chronic immune stimulation by removing the drive for autoantibody induction. The isolated persistence of autoantibodies in the small fraction of patients who did not show clearance following DAA treatment may require long-term vigilance.
Food allergy is a significant public health burden affecting around 10% of adults and 8% of children. Although the first peanut oral immunotherapy product received Food and Drug Administration approval in 2020, there is still an unmet need for more effective therapeutic options that minimize the risk of anaphylaxis, nutritional deficiencies, and patient's quality of life. Biologics are promising modalities, as they may improve compliance, target multiple food allergies, and treat other concomitant atopic diseases. Although omalizumab has been evaluated extensively, most biologics are more novel and have broader immunologic impact. Careful evaluation of their safety profile should therefore be conducted.