1,721,003 research outputs found
Towards precision medicine in COPD: Targeting type 2 cytokines and alarmins
No full text: Chronic obstructive pulmonary disease (COPD) is a main global epidemic increasing as population age and affecting approximately 10% of subjects over 45 years. COPD is a heterogeneous inflammatory disease with several endo-phenotypes and clinical presentations. Although neutrophilic inflammation is canonically considered a hallmark of COPD, eosinophilic inflammation can also be present in a subgroup of patients. Several other immune cells and cytokines play a key role in orchestrating and perpetuating the inflammatory pathways in COPD, making them attractive targets for treating this disorder. Recent studies have started to evaluate the possible role of type 2 (T2) inflammation and epithelial-derived alarmins (TSLP and IL-33) in COPD. Two phase III randomized clinical trials (RCTs) showed a modest reduction in exacerbations in COPD patients with eosinophilic phenotype treated with mepolizumab (anti-IL-5) or benralizumab (anti-IL-5Rα). A phase III RCT showed a 30% reduction in exacerbations in COPD patients with ≥ 300 eosinophils/μL treated with dupilumab (anti-IL-4Rα). These results suggest that blocking a single cytokine (e.g., IL-5) or its main target (i.e., IL-5Rα) is less promising than blocking a wider spectrum of cytokines (i.e., IL-4 and IL-13) in COPD. TSLP and IL-33 are upstream regulators of T2-high and T2-low immune responses in airway inflammation. Several ongoing RCTs are evaluating the efficacy and safety of anti-TSLP (tezepelumab), anti-IL-33 (itepekimab, tozorakimab), and anti-ST2 (astegolimab) in patients with COPD, who experience exacerbations. In conclusion, targeting T2 inflammation or epithelial-derived alarmins might represent a step forward in precision medicine for the treatment of a subset of COPD
Mast cells: a novel therapeutic avenue for cardiovascular diseases?
No full text: Mast cells are tissue-resident immune cells strategically located in different compartments of the normal human heart (the myocardium, pericardium, aortic valve and close to nerves) as well as in atherosclerotic plaques. Cardiac mast cells produce a broad spectrum of vasoactive and proinflammatory mediators, which have potential roles in inflammation, angiogenesis, lymphangiogenesis, tissue remodeling and fibrosis. Mast cells release preformed mediators (e.g., histamine, tryptase, chymase) and de novo synthesized mediators [e.g., cysteinyl leukotriene C4 (LTC4) and prostaglandin D2 (PGD2)], as well as cytokines and chemokines, which can activate different resident immune cells (e.g., macrophages) and structural cells (e.g., fibroblasts, endothelial cells) in the human heart and aorta. The transcriptional profiles of various mast cell populations highlight their potential heterogeneity and distinct gene and proteome expression. Mast cell plasticity and/or heterogeneity enable these cells the potential for performing different, even opposite, functions in response to changing tissue contexts. Human cardiac mast cells display significant differences compared to mast cells isolated from other organs. These characteristics make cardiac mast cells intriguing, given their dichotomous potential roles of inducing or protecting against cardiovascular diseases. Identification of cardiac mast cell subpopulations represents a prerequisite for understanding their potential multifaceted roles in health and disease. Several new drugs specifically targeting human mast cell activation are under development or in clinical trials. Mast cells and/or their subpopulations can potentially represent novel therapeutic targets for cardiovascular disorders
Unleashing the power of formyl peptide receptor 2 in cardiovascular disease
No full text: N-formyl peptide receptors (FPRs) are seven-transmembrane, G protein-coupled receptors with a wide distribution in immune and non-immune cells, recognizing N-formyl peptides from bacterial and mitochondrial origin and several endogenous signals. Three FPRs have been identified in humans: FPR1, FPR2, and FPR3. Most FPR ligands can activate a pro-inflammatory response, while a limited group of FPR agonists can elicit anti-inflammatory and homeostatic responses. Annexin A1 (AnxA1), a glucocorticoid-induced protein, its N-terminal peptide Ac2-26, and lipoxin A4 (LXA4), a lipoxygenase-derived eicosanoid mediator, exert significant immunomodulatory effects by interacting with FPR2 and/or FPR1. The ability of FPRs to recognize both ligands with pro-inflammatory or inflammation-resolving properties places them in a crucial position in the balance between activation against harmful events and maintaince of tissue integrity. A new field of investigation focused on the role of FPRs in the setting of heart injury. FPRs are expressed on cardiac macrophages, which are the predominant immune cells in the myocardium and play a key role in heart diseases. Several endogenous (AnxA1, LXA4) and synthetic compounds (compound 43, BMS-986235) reduced infarct size and promoted the resolution of inflammation via the activation of FPR2 on cardiac macrophages. Further studies should evaluate FPR2 role in other cardiovascular disorders
Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events
Full text linkImmune checkpoint inhibitors (ICIs) block inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1) and enhance antitumor T-cell activity. ICIs provide clinical benefits in a percentage of patients with advanced cancers, but they are usually associated with a remarkable spectrum of immune-related adverse events (irAEs) (e.g., rash, colitis, hepatitis, pneumonitis, endocrine, cardiac and musculoskeletal dysfunctions). Particularly patients on combination therapy (e.g., anti-CTLA-4 plus anti-PD-1/PD-L1) experience some form of irAEs. Different mechanisms have been postulated to explain these adverse events. Host factors such as genotype, gut microbiome and pre-existing autoimmune disorders may affect the risk of adverse events. Fatal ICI-related irAEs are due to myocarditis, colitis or pneumonitis. irAEs usually occur within the first months after ICI initiation but can develop as early as after the first dose to years after ICI initiation. Most irAEs resolve pharmacologically, but some appear to be persistent. Glucocorticoids represent the mainstay of management of irAEs, but other immunosuppressive drugs can be used to mitigate refractory irAEs. In the absence of specific trials, several guidelines, based on data from retrospective studies and expert consensus, have been published to guide the management of ICI-related irAEs
TL1A: a novel alarmin in airway, intestinal, and autoimmune disorders
No full text: The term alarmin denotes a broad class of molecules rapidly released to alert the immune system through the engagement of specific receptors on immune cells. Three alarmin cytokines, thymic stromal lymphopoietin (TSLP), IL-33, IL-25), are released from epithelial and certain stromal cells. TNF-like cytokine 1A (TL1A) is a member of the TNF cytokine superfamily, first identified in human endothelial cells. TL1A is now considered a novel alarmin expressed by human and mouse bronchial and intestinal epithelial cells. TL1A exerts its biological activities by binding to a trimeric receptor DR3 (death receptor-3), expressed on a wide spectrum of immune and structural cells (e.g., lung fibroblasts, endothelial cells, and bronchial epithelial cells). TL1A has been implicated in experimental and human inflammatory bowel diseases (IBD), airway inflammation and remodeling in severe asthma. A monoclonal antibody anti-TL1A (tulisokibart) is effective in inducing clinical remission in ulcerative colitis patients. Increasing evidence suggests that TL1A is also involved in certain autoimmune disorders (e.g., rheumatoid arthritis, psoriasis). These emerging findings broaden the role of TL1A in various human inflammatory conditions. Several clinical trials are currently evaluating the safety and efficacy of monoclonal antibodies targeting TL1A in asthma or IBD patients
Imaging of chronic rhinosinusitis with nasal polyps in the era of biological therapies
No full textPurpose of review: Chronic rhinosinusitis (CRS) is a chronic inflammatory disorder of the sinonasal cavities classified into two major phenotypes: CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP). The diagnosis of CRS is based on clinical symptoms associated with imaging and/or nasal endoscopy findings of mucosal inflammation. Recent findings: Recently, novel biological therapies have emerged as therapeutic options for CRSwNP. Imaging is helpful in deciding whether surgery is likely to be beneficial and in guiding surgery. It can also help demonstrate a clinical response to medical therapy. However, specific guidelines concerning the role of imaging in CRwNP are lacking. Summary: This article provides a comprehensive and critical multidisciplinary review of the role of conventional radiology, computed tomography (CT), and magnetic resonance imaging (MRI) in the diagnosis and characterization of CRSwNP. Since the complete characterization of nasal polyps on CT or MR images is very challenging, we provide a critical review of the best imaging methods and essential reporting elements used to assess nasal polyps
Advancing precision medicine for asthma by focusing on type 2 cytokines and alarmins
No full textPurpose of reviewAsthma is a heterogeneous disease encompassing distinct phenotypes and endotypes. Advances in elucidating the pathogenic role of type 2 (T2) cytokines and epithelial-derived alarmins have profoundly reshaped our understanding of airway inflammation in asthma. This review provides an updated perspective on how these mediators contribute to asthma pathobiology and examines their integration into emerging precision medicine strategies.Recent findingsBiologic agents targeting T2 cytokines (IL-4, IL-5, and IL-13) and alarmins (TSLP and IL-33) have demonstrated efficacy across a broad spectrum of severe asthma phenotypes. Recent evidence underscores the central role of alarmins in orchestrating both innate and adaptive immune responses within the airways. In parallel, the development of alarmin-associated molecular and clinical biomarkers is expanding patient stratification beyond traditional eosinophilic and allergic profiles.SummaryAdvancing our understanding of alarmins and T2 cytokines offers new opportunities to refine asthma endotyping, personalize therapeutic decisions, and pursue sustained disease remission. Future directions include the integration of multiomics, real-world evidence, and novel biomarker platforms to consolidate the next phase of precision medicine in asthma and optimize long-term disease modification strategies.</p
Basophils from allergy to cancer
No full textHuman basophils, first identified over 140 years ago, account for just 0.5-1% of circulating leukocytes. While this scarcity long hampered basophil studies, innovations during the past 30 years, beginning with their isolation and more recently in the development of mouse models, have markedly advanced our understanding of these cells. Although dissimilarities between human and mouse basophils persist, the overall findings highlight the growing importance of these cells in health and disease. Indeed, studies continue to support basophils as key participants in IgE-mediated reactions, where they infiltrate inflammatory lesions, release pro-inflammatory mediators (histamine, leukotriene C(4): LTC(4)) and regulatory cytokines (IL-4, IL-13) central to the pathogenesis of allergic diseases. Studies now report basophils infiltrating various human cancers where they play diverse roles, either promoting or hampering tumorigenesis. Likewise, this activity bears remarkable similarity to the mounting evidence that basophils facilitate wound healing. In fact, both activities appear linked to the capacity of basophils to secrete IL-4/IL-13, with these cytokines polarizing macrophages toward the M2 phenotype. Basophils also secrete several angiogenic factors (vascular endothelial growth factor: VEGF-A, amphiregulin) consistent with these activities. In this review, we feature these newfound properties with the goal of unraveling the increasing importance of basophils in these diverse pathobiological processes
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