Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hypereosinophilic syndrome. Core disease mechanisms, molecular and cellula...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 19
• Snippets retrieved: 20

Relevant Papers

[1] Eosinophilic disorders: evaluation of current classification and diagnostic criteria, proposal of a practical diagnostic algorithm

• Authors: P. Leru
• Year: 2019
• Venue: Clinical and Translational Allergy
• URL: https://www.semanticscholar.org/paper/6e8da4097abf058d39cc9a659ef65fb8802cd363
• DOI: 10.1186/s13601-019-0277-4
• PMID: 31367340
• PMCID: 6657042
• Citations: 78
• Influential citations: 4
• Summary: The aim of this paper is to review recent data from the literature regarding definition, classification and diagnosis criteria of eosinophilic diseases and to propose a revised and updated diagnostic algorithm useful in clinical practice.
• Evidence snippets:
• Snippet 1 (score: 0.528) > Eosinophilic diseases represent a broad range of pathologic conditions characterized by various degree of persistent blood and/or tissue hypereosinophilia, with potential for end-organ dysfunction [1]. Interest in this group of disorders has recently increased with consistent progress made regarding understanding of molecular mechanisms, refining of diagnostic criteria, classification and evaluation of therapeutic options. The pathophysiology and clinical presentation of eosinophilic disorders are highly heterogeneous and disease outcome may vary from asymptomatic or mild, to severe and fatal, with variable time course patterns. There are significant geographical influences regarding the most prevalent causes of hypereosinophilia, with reported parasitic infectious in tropical settings and allergic diseases in more developed and occidental countries. Many other hematologic (primary) and non-hematologic (reactive or secondary) hypereosinophilic syndromes and diseases, as well as associated or idiopathic forms have been described, making this topic a complex and difficult medical entity to unravel. There are still many gaps and difficulties in evaluating eosinophilic syndromes and diseases in medical practice, despite recommendations from consensus papers regarding diagnostic criteria and management. An important aim of the experts in the field is agreement upon diagnosis criteria and better characterization of various phenotypes, a clearer and more practically useful classification, with a focus on distinguishing isolated or asymptomatic eosinophilias from diseases with specific and potentially severe eosinophil-related organ damage, identification of novel biomarkers and more effective therapies [2]. Another important aspect in medical practice is the need for multidisciplinary and personalized approach of the patient with hypereosinophilia and evaluation of disease burden for patients and health systems.

[2] A Rare Presentation of Hypereosinophilic Syndrome With Loffler’s Endomyocarditis, Encephalopathy, and Multiple Thromboembolic Strokes

• Authors: Hassan Hussain, Kvc Janaka, N. Amarasena, Sudeshan Senanayake, Dhanuka Sudam
• Year: 2023
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/376467c8c1ea8a0a9d24b87cccbbfe8800fa27c1
• DOI: 10.7759/cureus.46050
• PMID: 37900362
• PMCID: 10604507
• Citations: 1
• Summary: A 47-year-old male with a background history of hypereosinophilia presented with sudden onset altered level of consciousness and drowsiness for 1 day duration associated with a gradual onset progressive memory loss for 1-month duration, and made a successful recovery after 2 months of treatment.
• Evidence snippets:
• Snippet 1 (score: 0.441) > Hypereosinophilia is caused by various pathophysiological mechanisms [3]. They can be broadly classified as primary and secondary based on the causative mechanisms. In the event that no causative factor is evident, it is classified as idiopathic. Primary causes of hypereosinophilia include neoplastic causes where there is clonal expansion of underlying stem cells or myeloid precursors. In secondary hypereosinophilia, there is overproduction of eosinophil poetic cytokines by other cell types and their polyclonal. This is classically associated with parasitic infection, certain solid tumors, and T-cell disorders [4]. Hypereosinophilic variants can be further divided into several clinically relevant subtypes namely myeloproliferative variants, T lymphocytic variants, familial idiopathic, organ-restricted hypereosinophilic conditions, and specific syndromes associated with hypereosinophilia [4]. The differential diagnoses that are usually considered are acute eosinophilic leukemia, chronic myeloid or myelomonocytic leukemia, and systemic macrocytosis with eosinophilia [1]. > Eosinophilic overproduction occurs as a result of a primary molecular defect that involves hemopoietic cells or defects in signal transduction from the receptors that mediate eosinophilopoiesis. Considering the pathophysiology behind hypereosinophilic syndrome, there is eosinophil-mediated significant damage to the tissues that they infiltrate. The major target organs include the skin, lungs, gastrointestinal tract, and less commonly cardiovascular system and brain which are known to be life-threatening conditions if left untreated. Among the commonly involved organs skin plays a major role [5]. The skin manifestations include eczema, erythroderma, and generalized thickening of the skin, and when evaluated with biopsy it shows perivascular infiltrations without vasculitis. Mucosal involvement is extremely rare in hypereosinophilic syndrome.

[3] Biological therapies targeting the type 2 inflammatory pathway in severe asthma (Review)

• Authors: A. Fildan, R. Râjnoveanu, R. Cîrjaliu, Ionela Pohrib, E. Tudorache et al.
• Year: 2021
• Venue: Experimental and Therapeutic Medicine
• URL: https://www.semanticscholar.org/paper/a72ce3dd46565f46e885f228a44282778699e7ef
• DOI: 10.3892/etm.2021.10698
• PMID: 34603531
• PMCID: 8453334
• Citations: 21
• Influential citations: 1
• Summary: The effectiveness and safety profile of the currently approved biological drugs are reviewed and an overview of the assessment of patients with severe asthma who are potentially suitable for biological therapy is provided in order to help clinicians to select the most appropriate biological agent.
• Evidence snippets:
• Snippet 1 (score: 0.424) > Asthma is a heterogeneous, chronic inflammatory airway disease with complex pathophysiological mechanisms that impact clinical outcomes, including drug response (14,15). Knowledge of the various asthma phenotypes and their different pathophysiology is continuously growing. Nevertheless, the pathways and underlying mechanisms of severe asthma pathogenesis are not yet completely understood. > There are two major groups of asthma phenotypes that can be differentiated by the inflammatory pathway involved, namely T2 or T2-high (eosinophilic) and non-T2 or T2-low phenotypes (16). T2 or T2-high asthma is characterized by T2 inflammation involving T helper 2 (Th2) lymphocytes (CD4 + ), which drives eosinophilic airway inflammation by producing abundant quantities of proteins such as IL-4, IL-5, IL-13 and IgE. In the past decade, evidence has demonstrated that the innate lymphoid cells group 2 (ILC2) plays an early key role in augmenting T2 inflammatory responses in the airway (6,8,9,17). Thus, the terminology has changed from 'Th2-high' to 'T2-high', reflecting the role of innate immunity, along with CD4 + cells, in the pathophysiology of asthma. T2-high asthma encompasses several subtypes in both children and adults, such as early-onset allergic and late-onset eosinophilic asthma, and aspirin-exacerbated respiratory disease (18). > Non-T2 or T2-low asthma is less well characterized (10); Th1 and Th17 cells, neutrophils and proteins, such as IL-1β, IL-6, IL-8, IL-17A/F, TNF-α and IFN-γ, are involved in its pathobiology. In addition to inflammatory biomarkers, non-T2 asthma may also be driven by irregular neuronal activation as well as structural abnormalities involving airway smooth muscle (10).

[4] The evolving burden of asthma and contemporary advances in management: Implications for clinical practice in Southern Africa

• Authors: A. Kiboneka
• Year: 2020
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/0ba536bc7dbea898dcaabe247c92c7897c7e059c
• DOI: 10.30574/wjarr.2020.8.3.0315
• Citations: 1
• Summary: The development of novel asthma phenotyping & endo typing plus better classification of patients using machine learning and big data have markedly improved asthma treatment outcomes in both children and Adults, and several research groups have developed cluster analyses of phenotypes in severe asthma.
• Evidence snippets:
• Snippet 1 (score: 0.423) > Research Program (SARP) I and II cohorts to study mechanisms differentiating severe from non-severe asthma. SARP investigators characterized severe asthma as a heterogeneous syndrome with diverse molecular, biochemical, and cellular inflammatory features and structure-function abnormalities. > Adults and children with severe asthma were further categorized by unbiased statistical methods into clusters based on distinguishing clinical features. These studies have not been done in Sub-Sahara Africa. Research performed over the past one to two decades has sought to better understand the heterogeneous clinical nature of asthma. Whereas older attempts at phenotyping asthma emphasized the duality of allergic vs. non-allergic asthma, more recent non-biased analyses have attempted to cluster patients by a multitude of possible features, including age of onset, atopy, severity of airways obstruction, and requirement for medication. Examples of these phenotypes include early-onset mild allergic asthma, later-onset asthma associated with obesity, and severe non-atopic asthma with frequent exacerbations. The elucidation of asthma phenotypes has been further refined by including information regarding pathophysiologic mechanisms present in different groups. These groups, called endo-types, include examples such as aspirin-exacerbated respiratory disease and allergic bronchopulmonary mycosis. > A phenotype covers the clinically relevant properties of the disease, but does not show the direct relationship to disease etiology and pathophysiology. Different patho-genetic mechanisms might cause similar asthma symptoms and might be operant in a certain phenotype. These putative mechanisms are addressed by the term 'endotype'. > Classification of asthma based on endo-types provides advantages for epidemiological, genetic, and drug-related studies. A successful definition of endo-types should link key pathogenic mechanisms with the asthma phenotype. Thus, the identification of corresponding molecular biomarkers for individual pathogenic-mechanism underlying phenotypes or subgroups within a phenotype is important. > The term asthma encompasses a disease spectrum with mild to very severe disease phenotypes whose traditional common characteristic is reversible airflow limitation. Unlike milder disease, severe asthma is poorly controlled by the current standard of care.

[5] Radioclinical Profile of Eosinophilic Lung: A Case Series

• Authors: Abir Bouhamdi, Fatima Saddouki, Badreddine Alami, Mounia Serraj, Mohamed Biaz et al.
• Year: 2024
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/9b54d6500ded3b73647a61a39c82d9425ea6bc90
• DOI: 10.7759/cureus.62579
• PMID: 39036186
• PMCID: 11258676
• Summary: Findings from an analysis of 17 patients diagnosed with eosinophilic lung disease are presented, with a majority (64.70%) being male and the main etiologies identified were chronic eosinophilic pneumonia, followed by eosinophilic granulomatosis with polyangiitis and drug-induced hypereosinophilia.
• Evidence snippets:
• Snippet 1 (score: 0.413) > Eosinophilic lung diseases are a complex group of diffuse parenchymal lung diseases characterized by eosinophilic infiltration of lung tissue [1].Although rare, these conditions are of significant clinical importance due to their diagnostic and therapeutic implications.Eosinophils, immune cells involved in allergic and inflammatory responses, are often found in excessive quantities in lung tissue, associated with alveolar eosinophilia exceeding 25%.However, blood eosinophilia can vary, sometimes being absent or temporary [2]. > These conditions share similarities in pathophysiology, radiology, and response to corticosteroid treatment, but they differ considerably in terms of etiology, clinical presentation, and disease progression.The underlying mechanisms involved in these pathologies often remain complex and poorly understood, making their diagnosis and clinical management a challenge for practitioners. > Eosinophilic lung diseases can be classified into primary and secondary categories [1].Primary eosinophilic lung diseases originate directly from eosinophilic infiltration of the lung tissue, often without a clear underlying cause.Examples include eosinophilic pneumonia and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome).Secondary eosinophilic lung diseases arise due to underlying conditions or triggers such as parasitic infections, allergic reactions, certain medications, or other systemic diseases.These include conditions like allergic bronchopulmonary aspergillosis and hypereosinophilic syndrome.Primary forms typically have a more direct association with eosinophilic infiltration, while secondary forms are often linked to external factors or underlying diseases. > Our research aims to thoroughly investigate the epidemiological, clinical, biological, and radiological characteristics of patients with eosinophilic lung disease.By emphasizing the varied and often insidious clinical presentations of these conditions, as well as the diagnostic challenges faced by clinicians, our study aspires to contribute to improving the management of patients with eosinophilic lung disease.By providing relevant data on the different subtypes of this pathology and analyzing responses to available treatments, we aim to contribute to a better understanding of these conditions and guide therapeutic decisions in daily clinical practice.

[6] Transcript- and protein-level analyses of the response of human eosinophils to glucocorticoids

• Authors: Manasi Gadkari, M. Makiya, F. Legrand, Kindra Stokes, Thomas Brown et al.
• Year: 2018
• Venue: Scientific Data
• URL: https://www.semanticscholar.org/paper/577aaf7f606b4608f7254f4fd7f5bf533dc2723e
• DOI: 10.1038/sdata.2018.275
• PMID: 30512017
• PMCID: 6278693
• Citations: 10
• Summary: RNA sequencing was performed on purified blood eosinophils obtained before and 30, 60, and 120 minutes after administration of a single dose of oral prednisone to three unrelated healthy subjects with hypereos inophilia of unknown significance to gain an unbiased, genome-wide view of the early transcriptional effects of glucocorticoids on human eosInophils in vivo.
• Evidence snippets:
• Snippet 1 (score: 0.409) > Glucocorticoids effectively suppress eosinophilia and its clinical manifestations, and they are first-line agents in a variety of eosinophil-associated disorders, including hypereosinophilic syndromes 1 and eosinophilic granulomatosis with polyangiitis 2 . Although commonly used to treat these and other disorders, glucocorticoids have non-specific effects and their use is associated with significant toxicity. Glucocorticoids act primarily through the induction of changes in gene expression. The glucocorticoid receptor is a transcription factor that binds glucocorticoids in the cytoplasm, after which the complex translocates to the nucleus. The ligand-bound glucocorticoid receptor complex then binds genomic DNA directly, or indirectly via tethered interactions with other proteins 3,4 . The glucocorticoid receptor complex also interferes with the activity of other transcription factors, notably NF-κB and AP-1 4 . Although the molecular biology of glucocorticoid receptor signaling has been the subject of intensive study, the specific mechanisms responsible for the clinically beneficial actions of glucocorticoids in different cell types and disease states remain poorly understood 5 . In the case of eosinophils, one of the difficulties in studying the glucocorticoid response in vivo is the fact that systemic administration of glucocorticoids consistently leads to a transient but profound drop in the number of circulating eosinophils 6,7 . Consequently, serial sampling of sufficient numbers of eosinophils after glucocorticoid administration in healthy volunteers with normal eosinophil counts (o500/μL) is problematic. Although patients with hypereosinophilic syndromes (HES) have adequate numbers of blood eosinophils for study, glucocorticoid responses in these patients vary considerably and may not reflect normal pathways.

[7] Exploring the molecular mechanisms of subarachnoid hemorrhage and potential therapeutic targets: insights from bioinformatics and drug prediction

• Authors: Yi Liu, Yang Zhang, Huan Wei, Li Wang, Lishang Liao
• Year: 2025
• Venue: Scientific Reports
• URL: https://www.semanticscholar.org/paper/19a91d9c8cabec6a5a186729d545077e252ecb67
• DOI: 10.1038/s41598-025-97642-8
• PMID: 40229542
• PMCID: 11997208
• Summary: The findings not only elucidate the molecular mechanisms underlying SAH but also provide robust bioinformatics and experimental evidence supporting IRN as a promising therapeutic candidate, offering novel insights for future intervention strategies in SAH.
• Evidence snippets:
• Snippet 1 (score: 0.405) > involved in SAH pathology. As a result, our understanding of the cellular composition and microenvironment in SAH remains incomplete 8 . > Advances in bioinformatics provide powerful tools to analyze large-scale gene expression data and understand complex biological processes. By integrating transcriptomic data with immune cell infiltration analysis, we can gain a deeper understanding of the molecular mechanisms underlying SAH and identify potential key genes as therapeutic targets 9,10 . Previous studies have indicated that inflammation, oxidative stress, and cell death play crucial roles in the development of SAH, processes that are often closely associated with changes in specific cell types and immune responses 11 . > The goal of this study is to explore the molecular mechanisms of SAH, with a focus on immune cell infiltration and its role in disease progression. We aim to identify key genes and signaling pathways associated with SAH and investigate potential therapeutic strategies. Specifically, we will examine Isorhynchophylline (IRN) as a potential treatment for SAH and analyze its effects on relevant targets and signaling pathways. Through a comprehensive understanding of the pathological features of SAH, this study aims to provide valuable insights into future clinical interventions and treatment strategies.

[8] Idiopathic hypereosinophilic syndromes and rare dysimmune conditions associated with hyper-eosinophilia in practice: An innovative multidisciplinary approach

• Authors: M. Caminati, Lucia Federica Carpagnano, Chiara Alberti, F. Amaddeo, R. Bixio et al.
• Year: 2024
• Venue: The World Allergy Organization Journal
• URL: https://www.semanticscholar.org/paper/4837fea94c05dae659793b3701ce91ca98187f32
• DOI: 10.1016/j.waojou.2024.100928
• PMID: 39156600
• PMCID: 11327453
• Citations: 7
• Influential citations: 1
• Summary: The present review aims at providing an overview about the current challenges and unmet needs in the practical approach to HES and rare hypereosinophilic allergo-immunological diseases, including a proposal for an innovative multidisciplinary organizational model.
• Evidence snippets:
• Snippet 1 (score: 0.404) > Despite their limited epidemiological "size" rare diseases are characterized by relevant burden in terms of patients' quality of life and morbidity, which is further amplified by their difficult early recognition, the diagnostic challenges and by the poor availability of specific or targeted treatments. 1 In the field of Allergy and Clinical Immunology the recent advances in the knowledge of pathobiological mechanisms and the development of new-targeted drugs are contributing to polarize the interest and attention of clinicians about rare immunological conditions characterized by hyper-eosinophilia and sharing a common T2 inflammatory background. That is the case of hypereosinophilic syndrome (HES), eosinophilic esophagitis (EoE) and other eosinophilic disorders of the digestive tract (EGIDs), eosinophilic lung diseases (allergic bronchopulmonary aspergillosis -ABPA, acute/chronic eosinophilic pneumonia -EP), and eosinophilic granulomatosis with polyangiitis (EGPA) 2 (Fig. 1). > Under a pathobiological perspective, the central role of eosinophils in all the above-mentioned conditions has supported the "eosinophilic march" concept, describing the potential trajectory of T2 disorders, from allergic rhinitis to hypereosinophilic syndrome according to the amount and burden of blood and/or tissue eosinophils. 3 hat perspective, although valuing on a clinical ground the pleiotropic clinical expression of eosinophilic inflammation, only partially reflects the complexity of the different immunological scenarios sharing an increased eosinophilia. In fact, the well-known T2 inflammation may overlap with a typical autoimmune environment, like in the case of EGPA, 4 or with an epithelial-driven cascade expressing a functional and anatomical barrier dysfunction, as in the case of EoE. 5 A combined inflammatory and cytotoxic eosinophilic-mediated impairment along with potential impact of eosinophils on coagulation homeostasis probably characterize HES dis-immunity 6,7 (Fig. 2).
• Snippet 2 (score: 0.383) > In fact, the well-known T2 inflammation may overlap with a typical autoimmune environment, like in the case of EGPA, 4 or with an epithelial-driven cascade expressing a functional and anatomical barrier dysfunction, as in the case of EoE. 5 A combined inflammatory and cytotoxic eosinophilic-mediated impairment along with potential impact of eosinophils on coagulation homeostasis probably characterize HES dis-immunity 6,7 (Fig. 2). > However, the strong evidence in favour of highly selective monoclonal antibodies targeting T2 inflammation and previously licensed for severe asthma has paved the way to the investigation and approval of some of those options for EGPA, EoE, and I-HES. 8 e availability of targeted treatments certainly contributes to improve the overall management of rare hypereosinophilic allergo-immunological diseases, which are no more orphan, but at the same time, further sustains the need for appropriate and updated healthcare pathways in order to shorten the patient's journey, properly manage the disease complexity and overall improving the standard of care for affected patients. > The present review aims at providing an overview about the current challenges and unmet needs in the practical approach to HES and Fig. 1 Overview of the most relevant immunological conditions sharing a T2-eosinophilic inflammation in their pathobiological background still with different clinical manifestations and burden. Red colour indicates systematic association with blood hypereosinophilia. ABPA: allergic bronchopulmonary aspergillosis. CRSwNP: chronic rhinosinusitis with nasal polyps. EGPA: eosinophilic granulomatosis with polyangiitis. > rare hypereosinophilic allergo-immunological diseases, including a proposal for an innovative multidisciplinary organizational model.

[9] Fatal Outcome of Imatinib in a Patient with Idiopathic Hypereosinophilic Syndrome

• Authors: Ashraf Abugroun, Ahmed Chaudhary, G. Rodriguez
• Year: 2018
• Venue: Case Reports in Oncological Medicine
• URL: https://www.semanticscholar.org/paper/dde6d2dcb66ff5fbf8b47f417cce84ba247efdd1
• DOI: 10.1155/2018/6291614
• PMID: 29780651
• PMCID: 5892290
• Citations: 2
• Summary: A 77-year-old male with a past medical history of hypereosinophilic syndrome who developed acute fatal cytokine storm following treatment with imatinib is presented, highlighting a life-threatening complication of the medication that may be underrecognized.
• Evidence snippets:
• Snippet 1 (score: 0.397) > According to the World Health Organization (WHO) classification, hypereosinophilic syndrome (HES) is classified into three distinct subsets caused by different 2 Case Reports in Oncological Medicine pathogenic mechanisms including chronic eosinophilic leukemia caused by fusion protein (FIP1L1-PDGFRA) with tyrosine kinase activities, lymphoproliferative HES caused by clonal IL-5/ 2 lymphocyte-mediated hypereosinophilia, and idiopathic or myeloproliferative HES where no evidence of clonal hypereosinophilia is identified [1]. Patients with HES present with variable clinical manifestations related to the target organ involved by eosinophils. Although all body parts can be involved, the disease commonly involves the skin, heart, digestive tract, and nervous system [1]. e pathogenesis of HES is related to various molecular and cytogenetic abnormalities that ultimately result in overactivity of tyrosine kinase causing dysregulated clonal overproduction of eosinophils [2]. e goal of therapy in HES is to prevent eosinophilinduced progressive end-organ damage and irreversible complications of sustained hypereosinophilia. Available therapeutic options include corticosteroids, hydroxyurea, interferon-alpha, bone marrow transplant, and other cytotoxic and immunomodulatory agents [1,3]. Due to low incidence of HES and increased heterogeneity of presenting symptoms, there are paucity of available data and limited numbers of studies on treatment options. Most studies on treatment are restricted to case reports and case series. e tyrosine kinase inhibitor imatinib was recently proposed as a rescue medication with high response rate among patients with HES refractory to medical therapy [4]. Imatinib was found to be particularly useful among patients with positive (FIP1L1-PDGFRA) phenotypes.

[10] Are there environmental forms of systemic autoimmune diseases?

• Authors: E. Hess
• Year: 1999
• Venue: Environmental Health Perspectives
• URL: https://www.semanticscholar.org/paper/a02203af72c6c6565fa996ecaceb76c0926278a2
• DOI: 10.1289/EHP.99107S5709
• PMID: 10502535
• PMCID: 1566256
• Citations: 12
• Summary: It is important for physicians and others involved in health care to recognize the potential associations of these diseases of unknown cause or causes.
• Evidence snippets:
• Snippet 1 (score: 0.394) > The mechanisms by which these drugs and/or their metabolites, the chemicals and their breakdown products, and the other environ- mental factors and their various structures are as diverse as the entire immune system itself. Literally hundreds of papers have examined the drugs and other factors listed in this arti- cle and about every conceivable effect has been noted. It is not possible to define a spe- cific role or pathway that would result in the varied immunologic and clinical syndromes seen. For drugs such as hydralazine and pro- cainamide, the specific metabolites that react with specific immune cells have been well demonstrated (18,19). Other proposed mechanisms for a number of the compounds include the possibility of cross-reactive anti- gens, interference with various tolerance mechanisms, potential alteration of DNA by the drugs or their metabolites, and the role of the genetics of the various metabolic pathways of the compounds, in particular the P450 enzyme system. Studies of the actual drug structures for any commonality have not been very productive. Basically, the various drugs often fall under three different struc- tural groups: hydrazines, aromatic amines, and phenols. Studies to date of the various environmental factors again have not revealed any major commonality. > Another factor that has to be considered in humans and experimental animals is the possible inciting or potentiating effect of infectious agents. Myxoviruses, retroviruses, measles, rubella, parainfluenza, Epstein-Barr, Type C oncarnoviruses, and Type C retro- viruses could all play a role and must be con- sidered when looking at mechanisms of cross-reactive antigens (20). Among the bac- teria under consideration are streptococcal cell wall products, lipopolysaccharides, and adjuvant components. > The genetics of the immune system in autoimmune diseases and phenomena is increasingly complex. It would appear that for any one compound or environmental agent, genetic factors may differ. There is also the added complication of the genetics of the host response as manifested in the expression of different disease states.

[11] Differential Regulation of Interferon Signaling Pathways in CD4+ T Cells of the Low Type-2 Obesity-Associated Asthma Phenotype

• Authors: Fahd Alhamdan, L. Marsh, F. Pedersen, B. A. Alhamwe, C. Thölken et al.
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/64e368bc44d989aa672152b1812fa77c44e3189c
• DOI: 10.3390/ijms221810144
• PMID: 34576307
• PMCID: 8469911
• Citations: 23
• Summary: The specific activation of interferon (IFN)-stimulated genes associated with IFN-related signaling and viral infection pathways might provide a novel view of the molecular mechanisms associated with the development of the low type-2 obesity-associated asthma phenotype, which is a step ahead in theDevelopment of new stratified therapeutic approaches.
• Evidence snippets:
• Snippet 1 (score: 0.390) > Over the last decades, non-communicable diseases (NCDs) have become the major cause of death worldwide, especially after the development of effective anti-infectious measures of prevention (vaccines) and treatment (antibiotics) [1][2][3]. Moreover, they represent a huge burden on the healthcare system and economic situation [4,5]. Prevalence and incidence of NCDs are still further increasing along with ongoing urbanization, industrialization, and globalization of unhealthy diet and lifestyles [6,7]. According to the World Health Organization (WHO), the rapid increase in the NCDs is mainly driven by various risk factors including tobacco, harmful use of alcohol, and obesity [8]. Furthermore, different NCDs and their major risk factors seem to have substantially overlapping underlying mechanisms, often involving immunometabolic alterations [9,10]. Combinations of certain NCDs and associated risk factors can create separate specific disease entities, classified as a clinical subtype or phenotype [11]. > Obesity is a key risk factor underlying a variety of major NCDs, including asthma [10,12]. The comorbidity of obesity and asthma is referred to as obesity-associated asthma [13,14]. Various associated clinical characteristics of obesity and asthma have been described. The major obesity-associated asthma phenotype is characterized as "late-onset, severe and difficult to treat, type-2 low inflammation disease and presenting mostly in women" [15][16][17]. While these detailed clinical characteristics strictly define this particular phenotype of asthma, the specific underlying cellular and molecular mechanisms of this phenotype are still only poorly understood. > Gene expression alterations, especially in cells critically involved in disease development, represent a major molecular contributor to the pathophysiology of chronic inflammatory diseases such as asthma. Subsets of CD4 + T cells, such as Th1, Th2, and Th17 have been shown to differentially contribute to the initiation and perpetuation of specific asthma phenotypes [18,19]. Certain biological pathways and cellular processes play an essential role in the polarization of the CD4 + T cells subtypes [20].

[12] Idiopathic Hypereosinophilia and Venous Thromboembolism: Is There a Pathophysiological or Clinical Link? Description of an Intriguing Clinical Case

• Authors: P. di Micco, O. Scudiero, B. Lombardo, C. Lodigiani
• Year: 2020
• Venue: Journal of Blood Medicine
• URL: https://www.semanticscholar.org/paper/2b0abe4a7c119df1b9f1cf3435363c6f83e27dce
• DOI: 10.2147/JBM.S229074
• PMID: 32184691
• PMCID: 7055521
• Citations: 4
• Summary: A case of idiopathic hypereosinophilia associated to venous thromboembolism without any other associated prothrombotic condition is reported.
• Evidence snippets:
• Snippet 1 (score: 0.380) > Incidence and prevalence of hypereosinophilic syndromes are still not well known. In the majority of cases males seem to be more affected, in particular, in middle age, but case series have been reported in all decades of life. 4 Clinical signs and symptoms may be different and may appear as contemporaneous features or at different times. Usually, skin symptoms such as urticaria or eczema or digestive symptoms such as nausea, vomiting, and diarrhea or respiratory symptoms such as asthma are the most common symptoms described by patients, but thromboses are not rare, comprising 20% or more of affected patients. 5,6 These symptoms may also be present in clonal eosinophilia and may be associated with peripheral nervous dysfunctions or thromboembolic complications. 8 Venous thromboembolism is the one of the most commonly described thromboses in hypereosinophilia and it may influence long-term treatment and prognosis of hypereosinophilic patients. 5,6 Several pathophysiological mechanisms have been described in the last decades to explain the hypercoagulable state induced by hypereosinophilia that may lead to thrombosis. Of course the most commonly known has been related to chronic inflammation as in the Churg-Strauss vasculitis that may cause a real thromboangiitis. 1 However, other clinical forms of hypereosinophilia may be associated with thrombosis by other noninflammatory pathways. > The proteolytic actions induced by eosinophil granules may activate the kallikrein system and so the clotting cascade by factor XII activation; the factor XII activation, increasing the activation of other proteases of clotting system, induces hypercoagulable state. 9 Protease systems, in particular, matrix metalloproteinases are also involved in cleavage of extracellular matrix proteins that also participate in myocardial remodelling during cardiac diseases as heart failure and\or pulmonary hypertension. 10,11 Moreover, this pathway is also overexpressed by the cytokine network and the balance protease-antiprotease is able to hyperactivate clotting system per se.

[13] LifeTime and improving European healthcare through cell-based interceptive medicine

• Authors: N. Rajewsky, G. Almouzni, S. Gorski, S. Aerts, I. Amit et al.
• Year: 2020
• Venue: Nature
• URL: https://www.semanticscholar.org/paper/d626a4acb560c1ef16ea394cb4dccf277882d119
• DOI: 10.1038/s41586-020-2715-9
• PMID: 32894860
• PMCID: 7656507
• Citations: 138
• Influential citations: 2
• Summary: The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe over the next decade.
• Evidence snippets:
• Snippet 1 (score: 0.380) > , a major challenge is a lack of understanding of the early events in disease onset to enable the development of disease-modifying therapies. The lack of access to longitudinal samples from patients necessitates the establishment of cohorts of patient-derived disease models to understand the cellular heterogeneity associated with disease. The discovery of pathways and biomarkers that will allow the stratification of patients on the basis of the cellular mechanisms that drive a disease will make it possible to design new clinical trials to reevaluate drugs that were previously tested without such stratification, and to broaden the drug target portfolio. > As seen during the coronavirus disease 2019 (COVID-19) pandemic, it is important to be able to understand infection mechanisms and the host response in order to rapidly identify the most likely effective treatment for an infection. At the same time, the continuous rise of antimicrobial resistance requires the discovery of new therapeutic strategies. A key medical challenge for infectious diseases is to understand the cellular response to infections and to develop precision, immune-based therapeutic strategies to combat infections. > Chronic inflammatory diseases impose a high burden owing to their long-term debilitating consequences, which result from the structural destruction of affected organs or tissues. Current therapies treat the symptoms but do not cure or fully control the chronic inflammatory pathophysiology. While different targeted therapies exist, they are expensive and their success is limited by high rates of non-response to treatment. Consequently, there is an urgent need to explore and understand how cellular heterogeneity contributes to the pathology of inflammatory diseases 61 and how this relates to the predicted course of disease and the response of a patient to one of the numerous available therapies. > Many cardiovascular and metabolic diseases lack effective therapies owing to a lack of knowledge of their underlying causes and the link between abnormal cardiac cell structure or function and pathophysiology. The identified medical priority is to understand the cellular and molecular mechanisms involved, in order to enable early diagnosis and the design of new mechanism-based therapies for precise clinical treatment. > The LifeTime disease roadmaps can be divided broadly into three phases 7 : first, immediate research into the identified medical challenges using established, scaled single-cell technologies, computational tools and disease models; second, the development of new technologies that are required

[14] Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

• Authors: H. Breiteneder, Z. Diamant, T. Eiwegger, W. Fokkens, C. Traidl‐Hoffmann et al.
• Year: 2019
• Venue: Allergy
• URL: https://www.semanticscholar.org/paper/e19b0755c4f4903f68377333676edebf9bd73c89
• DOI: 10.1111/all.13851
• PMID: 31056763
• PMCID: 6973012
• Citations: 90
• Influential citations: 3
• Summary: Recent developments in research and patient care and future trends in the discipline are reviewed and topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen‐specific immunotherapy for airway disease are highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.378) > The past decades have witnessed extensive progress in unraveling cellular and molecular mechanisms of immune regulation in asthma, allergic diseases, organ transplantation, autoimmune diseases, tumor biology, and chronic infections. 1,2 Consequently, a better understanding of the functions, the reciprocal regulation, and the counterbalance of subsets of immune and inflammatory cells but also structural cells-for example, epithelial and vascular cells, airway smooth muscle cells, neuroendocrine system-that interact via various intercellular messengers will indicate avenues for immune interventions and novel treatment modalities of allergic diseases and immunological disorders. It is generally expected that drug development in the next decades will show a significant shift from chemicals to biologicals. > After more than 20 years without any breakthrough drug becoming available for patients, several disciplines including allergology are now experiencing extraordinary times with the recent licensing of several major biological drugs and novel allergen-specific immunotherapy (AIT) vaccines. Several biological modifiers of the immune response targeting intracellular messengers or their receptors have been developed to date. [3][4][5][6][7][8] In addition, a number of promising small molecule drugs and vaccines are in the development pipeline. [9][10][11] This new era is now calling for the development of biomarkers and phenoand endotyping of diseases for customized patient care, which is termed stratified medicine, precision medicine, or personalized medicine. 4 Distinguishing phenotypes of a complex disease covers the observable clinically relevant properties of the disease but does not show a direct relationship to disease etiology and pathophysiology. In a complex condition, such as asthma, different pathogenetic mechanisms can induce similar clinical manifestations; however, they may require different treatment approaches. 12,13 These pathophysiological mechanisms underlying disease subgroups are addressed by the term "endotype." [12][13][14] Classification of complex diseases based on the concept of endotypes provides advantages for epidemiological, genetic, and drug-related studies. Accurate endotyping by using reliable biomarkers reflects the natural history of the disease and aims to predict the response to (targeted) treatments. 15 Recent studies have focused on better understanding

[15] Eosinophil responses during COVID-19 infections and coronavirus vaccination

• Authors: Andrew W. Lindsley, Justin T. Schwartz, Marc E. Rothenberg
• Year: 2020
• Venue: The Journal of Allergy and Clinical Immunology
• URL: https://www.semanticscholar.org/paper/79b50d57a7fc199e717b94d4ca9bd7ed4de292cb
• DOI: 10.1016/j.jaci.2020.04.021
• PMID: 32344056
• PMCID: 7194727
• Citations: 304
• Influential citations: 15
• Summary: Abstract

Eosinophils are circulating and tissue-resident leukocytes that have potent pro-inflammatory effects in a number of diseases. Recently, eosinophils have been shown to have a variety of other functions, including immunoregulation and antiviral activity. Eosinophil levels vary dramatically in a number of clinical settings, especially following eosinophil-targeted therapy, which is now available to selectively deplete these cells. There are key COVID-19–related questions concerning... - Evidence snippets: - Snippet 1 (score: 0.378) > Eosinophils normally account for only a small percentage of circulating leukocytes (1%-3%), but their levels can vary in various disease states. [1][2][3] Their level is clinically relevant because eosinophils are potent proinflammatory cells, primarily due to their preformed granules, which are packed with cytotoxic proteins, including major basic protein (one of the most basically charged molecules in the body), eosinophil peroxidase, and 2 RN-Ases (eosinophil cationic protein and eosinophil neurotoxin). In addition to their proinflammatory effects, evidence is emerging, albeit primarily in mice, that eosinophils have pleotropic roles as regulatory cells involved in protective immunity, including antiviral responses and shaping diverse physiological responses, such as organ development and metabolism. Although eosinophils are normally considered blood cells, they reside in various tissues. Most notably, eosinophils reside in the gastrointestinal tract, which is their primary residence, and the lung, where a population of regulatory eosinophils, which have unique features compared with inflammatory eosinophils, has been identified. 4 There are a number of diseases associated with eosinophil expansion in which eosinophils are causally related to the disease pathology, such as subsets of moderate and severe asthma. Accordingly, a number of clinically approved biological antibody-based precision therapies are now available that directly target eosinophils, resulting in eosinophil depletion. 5 These drugs include those that neutralize the eosinophil growth and activating factor IL-5 (eg, mepolizumab and reslizumab) and drugs that directly induce eosinophil depletion by antibody-dependent cellular cytotoxicity (eg, the anti-IL-5 receptor drug benralizumab). 6 These drugs have remarkable beneficial effects in a growing number of diseases, including asthma, hypereosinophilic syndrome, and eosinophilic granulomatous polyangiitis (formerly known as Churg

[16] In vitro systems to study inborn errors of immunity using human induced pluripotent stem cells

• Authors: Eirini Nikolouli, Janne Reichstein, G. Hansen, N. Lachmann
• Year: 2022
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/50f330ee9584168734b8cc8a22dc702c4cbe8ec5
• DOI: 10.3389/fimmu.2022.1024935
• PMID: 36466870
• PMCID: 9713844
• Citations: 1
• Summary: This review aims to provide an overview of the current available in vitro models used to study IEI and which could lay the foundation for new therapeutic approaches and elaborate in particular on the use of induced pluripotent stem cell-based systems.
• Evidence snippets:
• Snippet 1 (score: 0.377) > of drug-resistant pathogens, which can cause lifethreatening infections. In some cases, like in the severe combined immunodeficiency (SCID) syndrome, allogenic hematopoietic stem cell transplantation (HSCT) (or autologous HSC-gene therapy) is the only curative therapy (6,7). However, HSCT always lurks the risk of immunological rejection or development of graft versus host disease with devastating consequences for the patient, pointing towards the need of suitable alternatives. > For these reasons, more targeted therapeutic approaches, which can directly modulate specific cell types or intracellular pathways, are preferred. These approaches include the use of specific inhibitors or biologics (antibodies or recombinant proteins). For the safe use of these emerging therapeutic agents, a detailed study of the pathophysiological mechanisms of the diseases is necessary. Given the rarity of IEI and the technical difficulties (obtaining sufficient samples from children or the low number of affected cells), the study of IEI-related diseases remains challenging. Thus, the development of novel systems to unravel the cellular and molecular mechanisms involved in the pathophysiology of the various IEI is of great importance.

[17] Prioritizing Molecular Biomarkers in Asthma and Respiratory Allergy Using Systems Biology

• Authors: Lucía Cremades-Jimeno, M. D. de Pedro, M. López-Ramos, J. Sastre, P. Mínguez et al.
• Year: 2021
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/d8ca6e130adec2dfa39545eb1763827d9450e4f5
• DOI: 10.3389/fimmu.2021.640791
• PMID: 33936056
• PMCID: 8081895
• Citations: 13
• Influential citations: 1
• Summary: This study has enabled it to prioritize biomarkers depending on the functionality associated with each disease and with specific molecular motifs, which could improve the definition and usefulness of new molecular biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.377) > Firstly, the molecular characterization of the three pathophysiological processes of interest (respiratory allergy, allergic asthma, and nonallergic asthma) was performed using the Therapeutic Performance Mapping System (TPMS) technology (Anaxomics Biotech, Barcelona, Catalonia, Spain) (31). Briefly, systems biology generates models that are able to reproduce the behavior of a disease in a patient, thus identifying the key genes, proteins, or metabolites in the development of the disease. A dictionary has been created to translate clinical and medical terms into molecular biology data, effectively linking the molecular and the clinical words. This dictionary, called the Biological Effectors Database (BED), relates biological processes (adverse events of drugs, drug indications, diseases, etc.) with the proteins most closely associated with them. Thus, the dictionary acts as a translator of clinical phenotypes into terms comprehensible for protein networks, and conversely allows for the translation of molecular measures toward clinical outcomes. The BED is structured hierarchically, where the biggest level is the entire disease, which is divided into different pathophysiological molecular motifs, which in turn contain the proteins involved in the development of the disease. The motifs are classified into two levels depending on their respective implication, i.e. causal motifs, which are directly related to the onset or pathophysiology of the condition, and symptomatic (manifestative) motifs, which are a consequence of the disease. > In the present study, respiratory allergy, allergic asthma, and non-allergic asthma have been characterized at the molecular level. Therefore, the analysis of high throughput data by means of TPMS allows for identification of those proteins closely associated with the disease of interest and can provide a mechanistic rationale for their involvement. The effector proteins of the manifestative and causal molecular motifs of these three diseases have been identified through bibliographic review and curate data. Figure 1 summarizes the workflow used for this study.

[18] ICON: Eosinophil Disorders

• Authors: P. Valent, A. Klion, L. Rosenwasser, M. Arock, B. Bochner et al.
• Year: 2012
• Venue: The World Allergy Organization Journal
• URL: https://www.semanticscholar.org/paper/78b4ec44c74422cd2eeca36257e877cbba54450d
• DOI: 10.1097/WOX.0b013e31827f4192
• PMID: 23282419
• PMCID: 3651188
• Citations: 29
• Influential citations: 1
• Summary: The pathogenesis and mechanisms of HE and of HE-induced organ damage are complex, and expert opinions remain divided.
• Evidence snippets:
• Snippet 1 (score: 0.376) > SUMMARY Eosinophil disorders and related syndromes are a heterogeneous group of conditions characterized by marked persistent blood eosinophilia and involvement of one or more organ systems. The hypereosinophilic (HE) state is defined by a persistent eosinophil count exceeding 1.5 · 10 9 /L blood. Several different neoplastic, paraneoplastic, infectious, and allergic disorders may underlie HE. Eosinophil-induced organ damage with more or less typical symptoms may develop in these patients. The final diagnosis is based on clinical, molecular, and histopathologic criteria, and the presence of signs and symptoms indicative of HE-induced organ damage, the latter often manifesting as hypereosinophilic syndrome. The clinical course, prognosis, and response to certain drugs vary greatly among patients and among disease variants. During the last few years, several new markers and targets have been identified, improving diagnosis, prognostication, and therapy for patients with HErelated disorders. Moreover, several attempts have been made to establish robust disease-related criteria and a global classification for HE-related diseases. However, the pathogenesis and mechanisms of HE and of HE-induced organ damage are complex, and expert opinions remain divided.

[19] Navigating Drug-Induced Lung Disease (DILD): A Comprehensive Review on Management and Prevention Strategies

• Authors: Srinivasulareddy Annareddy, B. Ghewade, Ulhas S Jadhav, Pankaj B Wagh
• Year: 2024
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/0b389cda78d09ed43d6169972b6b2948590d3a59
• DOI: 10.7759/cureus.69954
• PMID: 39445304
• PMCID: 11496594
• Citations: 1
• Influential citations: 1
• Summary: This review provides a comprehensive overview of DILD, focusing on its definition, pathophysiology, and clinical implications, and examines future research directions and emerging therapies, aiming to enhance the understanding and management of DILD.
• Evidence snippets:
• Snippet 1 (score: 0.376) > The pathophysiology of drug-induced lung injury (DILI) is complex, involving various mechanisms that can lead to pulmonary complications. These mechanisms can be broadly categorized into two main types: direct toxicity and immune-mediated toxicity [1]. Direct toxicity occurs when a drug or its metabolites cause cellular damage without involving the immune system. This can happen through several pathways, such as producing reactive metabolites, oxidative stress, and direct cellular injury. For example, drugs like bleomycin can generate reactive oxygen species (ROS), leading to oxidative stress, cell injury, and apoptosis. Additionally, certain drugs can directly damage alveolar epithelial cells or endothelial cells, causing inflammation and pulmonary edema [13]. Immune-mediated lung injury involves an abnormal immune response triggered by drug exposure. This can manifest through allergic reactions, where drugs act as haptens and bind to proteins, eliciting an immune response. This can result in drug-induced pneumonitis, characterized by the infiltration of immune cells and cytokine release. Some medications can also induce systemic cytokine release, causing lung inflammation and damage, such as capillary leakage and pulmonary edema [14]. Genetic factors significantly influence susceptibility to drug-induced lung injury. Variability in drug metabolism and immune response can lead to idiosyncratic reactions, which are unpredictable and not dose-dependent. Genetic polymorphisms in genes encoding drug-metabolizing enzymes can affect the production of toxic metabolites, while preexisting lung conditions or genetic predispositions may increase the risk of developing DILI. Differences in immune system function among individuals can also result in varying responses to drugs, with some patients experiencing severe immune-mediated lung injury while others do not [15]. Understanding the pathophysiology of drug-induced lung injury, including the influence of genetic predisposition and idiosyncratic reactions, is crucial for identifying at-risk patients and developing effective prevention and management strategies. Ongoing research is essential to elucidate these mechanisms further and improve clinical outcomes for patients affected by drug-induced lung injury [16].

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.