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Frontiers in Immunology 2024Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with skin barrier defects and a misdirected type 2 immune response against harmless antigens....
BACKGROUND
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with skin barrier defects and a misdirected type 2 immune response against harmless antigens. The skin microbiome in AD is characterized by a reduction in microbial diversity with a dominance of staphylococci, including ().
OBJECTIVE
To assess whether antigens play a role in AD, we screened for candidate allergens and studied the T cell and humoral immune response against the extracellular serine protease (Esp).
METHODS
To identify candidate allergens, we analyzed the binding of human serum IgG4, as a surrogate of IgE, to extracellular proteins using 2-dimensional immunoblotting and mass spectrometry. We then measured serum IgE and IgG1 binding to recombinant Esp by ELISA in healthy and AD individuals. We also stimulated T cells from AD patients and control subjects with Esp and measured the secreted cytokines. Finally, we analyzed the proteolytic activity of Esp against IL-33 and determined the cleavage sites by mass spectrometry.
RESULTS
We identified Esp as the dominant candidate allergen of . Esp-specific IgE was present in human serum; AD patients had higher concentrations than controls. T cells reacting to Esp were detectable in both AD patients and healthy controls. The T cell response in healthy adults was characterized by IL-17, IL-22, IFN-γ, and IL-10, whereas the AD patients' T cells lacked IL-17 production and released only low amounts of IL-22, IFN-γ, and IL-10. In contrast, Th2 cytokine release was higher in T cells from AD patients than from healthy controls. Mature Esp cleaved and activated the alarmin IL-33.
CONCLUSION
The extracellular serine protease Esp of can activate IL-33. As an antigen, Esp elicits a type 2-biased antibody and T cell response in AD patients. This suggests that can aggravate AD through the allergenic properties of Esp.
Topics: Humans; Staphylococcus epidermidis; Dermatitis, Atopic; Serine Proteases; Adult; Male; Female; Immunoglobulin E; Bacterial Proteins; Immunoglobulin G; Cytokines; T-Lymphocytes; Allergens; Interleukin-33; Middle Aged
PubMed: 38895118
DOI: 10.3389/fimmu.2024.1352704 -
International Journal of Molecular... May 2024Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33.... (Review)
Review
Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33. Functionally, TSLP is a key player in the immune response to environmental insults, initiating a number of downstream inflammatory pathways. TSLP performs its role by binding to a high-affinity heteromeric complex composed of the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα. In recent years, the important role of proinflammatory cytokines in the etiopathogenesis of various chronic diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), chronic obstructive pulmonary diseases (COPDs), and chronic spontaneous urticaria has been studied. Although alarmins have been found to be mainly implicated in the mechanisms of type 2 inflammation, studies on monoclonal antibodies against TSLP demonstrate partial efficacy even in patients whose inflammation is not definable as T2 and the so-called low T2. Tezepelumab is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. Several clinical trials are evaluating the safety and efficacy of Tezepelumab in various inflammatory disorders. In this review, we will highlight major recent advances in understanding the functional role of TSLP, its involvement in Th2-related diseases, and its suitability as a target for biological therapies.
Topics: Humans; Cytokines; Thymic Stromal Lymphopoietin; Antibodies, Monoclonal, Humanized; Animals; Receptors, Cytokine; Molecular Targeted Therapy; Respiratory Tract Diseases; Asthma
PubMed: 38892164
DOI: 10.3390/ijms25115972 -
International Journal of Molecular... May 2024Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. Rises in the epithelial barrier permeability of airways alter... (Review)
Review
Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. Rises in the epithelial barrier permeability of airways alter tissue homeostasis and allow the penetration of allergens and other external agents. Different factors contribute to barrier impairment, such as eosinophilic infiltration and allergen protease action-eosinophilic cationic proteins' effects and allergens' proteolytic activity both contribute significantly to epithelial damage. In the airways, allergen proteases degrade the epithelial junctional proteins, allowing allergen penetration and its uptake by dendritic cells. This increase in allergen-immune system interaction induces the release of alarmins and the activation of type 2 inflammatory pathways, causing or worsening the main symptoms at the skin, bowel, and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic protease-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance, and progression. Moreover, we will explore potential clinical and radiological biomarkers of airway remodeling in allergic asthma patients.
Topics: Humans; Asthma; Allergens; Animals; Airway Remodeling
PubMed: 38891935
DOI: 10.3390/ijms25115747 -
Nature Communications Jun 2024IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus...
IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host by inhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison shows that this overlaps with the binding site on IL-33 for its receptor, ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack the large loop from CCP3 are not able to block IL-33-mediated signalling in a cell-based assay and in an in vivo female mouse model of asthma. This shows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses.
Topics: Animals; Interleukin-33; Nematospiroides dubius; Helminth Proteins; Mice; Female; Interleukin-1 Receptor-Like 1 Protein; Asthma; Humans; Signal Transduction; Strongylida Infections; Protein Binding; Disease Models, Animal; Binding Sites; Mice, Inbred BALB C; Mice, Inbred C57BL
PubMed: 38890291
DOI: 10.1038/s41467-024-49550-0 -
Frontiers in Immunology 2024Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease primarily affecting premature neonates, marked by poorly understood pro-inflammatory signaling... (Review)
Review
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease primarily affecting premature neonates, marked by poorly understood pro-inflammatory signaling cascades. Recent advancements have shed light on a subset of endogenous molecular patterns, termed chromatin-associated molecular patterns (CAMPs), which belong to the broader category of damage-associated molecular patterns (DAMPs). CAMPs play a crucial role in recognizing pattern recognition receptors and orchestrating inflammatory responses. This review focuses into the realm of CAMPs, highlighting key players such as extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), cell-free DNA, neutrophil extracellular traps (NETs), histones, and extracellular RNA. These intrinsic molecules, often perceived as foreign, have the potential to trigger immune signaling pathways, thus contributing to NEC pathogenesis. In this review, we unravel the current understanding of the involvement of CAMPs in both preclinical and clinical NEC scenarios. We also focus on elucidating the downstream signaling pathways activated by these molecular patterns, providing insights into the mechanisms that drive inflammation in NEC. Moreover, we scrutinize the landscape of targeted therapeutic approaches, aiming to mitigate the impact of tissue damage in NEC. This in-depth exploration offers a comprehensive overview of the role of CAMPs in NEC, bridging the gap between preclinical and clinical insights.
Topics: Humans; Enterocolitis, Necrotizing; Alarmins; Chromatin; Animals; Signal Transduction; Infant, Newborn; HMGB1 Protein
PubMed: 38881893
DOI: 10.3389/fimmu.2024.1403018 -
Immunologic Research Jun 2024Adjuvants were used to modulate response towards relevant immune cells. The present study aims to investigate FlaA-conjugated Per a 10 and T cell peptides in...
Adjuvants were used to modulate response towards relevant immune cells. The present study aims to investigate FlaA-conjugated Per a 10 and T cell peptides in amelioration of allergic airway disease in mice. Mice given Per a 10 showed allergic features with higher cellular infiltration, IgE, Th-2 cytokines and alarmins. Fusion protein treatment reduced lung inflammation (p < 0.0001) and cellular infiltrates (p < 0.001) with higher IgG2a/IgE indicating resolution of disease. Immunotherapy with FPT1 and FPT3 reduces IL-4, IL-5 and IL-13 levels (p < 0.0001) with a fourfold increase in IFN-γ secretion in BALF. FPT1- and FPT3-treated mice have increased IL-10 and TGF-β levels (p < 0.001) with CD4Foxp3 T cells (p < 0.01) indicating Treg response. There was enhanced expression of claudin-1 (1.7-fold) and occludin (fourfold) in lungs of FPT1- and FPT3-treated mice with reduced TSLP (p < 0.01) and IL-33 (p < 0.0001) secretion in BALF indicating recovery of epithelial function. Peptide-conjugated FlaA proteins showed protective immunity in mice and have potential for immunotherapy with restoration of cellular function.
PubMed: 38879717
DOI: 10.1007/s12026-024-09507-3 -
Inflammation Research : Official... Jun 2024We have previously shown that asthma-like airways inflammation may be induced by topical exposure to respiratory tract pathogens such as S. pneumoniae (SP) in concert...
Airways epithelial exposure to Streptococcus pneumoniae in the presence of the alarmin IL-33 induces a novel subset of pro-inflammatory ILC2s promoting a mixed inflammatory response.
BACKGROUND
We have previously shown that asthma-like airways inflammation may be induced by topical exposure to respiratory tract pathogens such as S. pneumoniae (SP) in concert with epithelial alarmins such as IL-33. Details of the pathogenesis of this murine surrogate remain however unexplored.
METHODS
Airways inflammation was induced by repeated, intranasal exposure of Il-4, Rag1 and Rag2Il2rg mice (in which B lymphocyte IgE switching, adaptive and innate immunity are respectively ablated) as well as wild type mice to inactivated SP, IL-33 or both. Airways pathological changes were analysed, and the subsets and functions of locally accumulated ILC2s investigated by single cell RNA sequencing and flow cytometry.
RESULTS
In the presence of IL-33, repeated exposure of the airways to inactivated SP caused marked eosinophil- and neutrophil-rich inflammation and local accumulation of ILC2s, which was retained in the Il-4 and Rag1 deficient mice but abolished in the Rag2Il2rg mice, an effect partly reversed by adoptive transfer of ILC2s. Single cell sequencing analysis of ILC2s recruited following SP and IL-33 exposure revealed a Klrg1Ly6asubset, expressing particularly elevated quantities of the pro-inflammatory cytokine IL-6, type 2 cytokines (IL-5 and IL-13) and MHC class II molecules, promoting type 2 inflammation as well as involved in neutrophil-mediated inflammatory responses.
CONCLUSION
Local accumulation of KLRG1Ly6a ILC2s in the lung tissue is a critical aspect of the pathogenesis of airways eosinophilic and neutrophil-rich inflammation induced by repeated exposure to SP in the presence of the epithelial alarmin IL-33.
PubMed: 38844678
DOI: 10.1007/s00011-024-01896-3 -
Cureus May 2024Background There is little evidence that pesticide exposure is the primary cause of acquired aplastic anemia (AAA), even though the prevalence of aplastic anemia (AA) is...
Background There is little evidence that pesticide exposure is the primary cause of acquired aplastic anemia (AAA), even though the prevalence of aplastic anemia (AA) is substantially higher in underdeveloped countries than in affluent countries. AA caused by pesticides has not yet been fully understood. This study aimed to examine the potential link between plasma levels of malondialdehyde (MDA) and organochlorine pesticides (OCPs) as risk factors for developing AAA in the North Indian population. Methods This case-control study was conducted at a tertiary care hospital in North India. A total of 99 participants were chosen for the study, of whom 45 were cases of AA. These cases attended the Clinical Hematology department over a period of 1.5 years (May 2018 to November 2019). Forty-five controls were age and sex-matched, apparently healthy subjects. Written informed consent was obtained from each subject before performing the study. Exclusion criteria included patients unwilling to give consent, those using medication to treat AA, those genetically predisposed to AA, those with characteristics including granuloma and dysplasia of bone marrow, any other systemic illness, and subjects with a history of smoking, drinking, or using tobacco in any form. Gas chromatography-tandem mass spectrometry (GC-MS/MS) was used to evaluate the plasma levels of organochlorines. The estimation of plasma MDA, i.e., the lipid peroxide content, was measured. Results The severity of AA is significantly associated with plasma levels of α-Hexachlorocyclohexane (p = 0.040), Heptachlor (p = 0.006), Aldrin (p < 0.001), p,p'-Dichlorodiphenyldichloroethane (p = 0.004), Endosulfan sulfate (p = 0.010), and Methoxychlor (p = 0.001). There was a statistically non-significant difference in MDA levels between cases and controls (p = 0.145); however, a statistically significant linear increase in MDA levels (p < 0.001) was observed according to the severity of AA. Conclusion Our study suggests that oxidative stress may be linked to the severity of AA. Pesticide exposure (plasma organochlorine levels) could act as a stressor, potentially initiating an alarmin response of oxidative stress in the form of lipid peroxidation (MDA) from damaged tissue, which could then lead to suppression of hematopoiesis and be a possible factor in the development of AA.
PubMed: 38841016
DOI: 10.7759/cureus.59698 -
Parasite Immunology Jun 2024Ticks are notorious blood-sucking ectoparasites that affect both humans and animals. They serve as a unique vector of various deadly diseases. Here, we have shown the... (Review)
Review
Ticks are notorious blood-sucking ectoparasites that affect both humans and animals. They serve as a unique vector of various deadly diseases. Here, we have shown the roles of the receptor for advanced glycation end products (RAGE) during repeated infestations by the tick Haemaphysalis longicornis using RAGE mice. In primary infestation, a large blood pool developed, which was flooded with numerous RBCs, especially during the rapid feeding phase of the tick both in wild-type (wt) and RAGE mice. Very few inflammatory cells were detected around the zones of haemorrhage in the primary infestations. However, the number of inflammatory cells gradually increased in the subsequent tick infestations, and during the third infestations, the number of inflammatory cells reached to the highest level (350.3 ± 16.8 cells/focus). The site of attachment was totally occupied by the inflammatory cells in wt mice, whereas very few cells were detected at the ticks' biting sites in RAGE mice. RAGE was highly expressed during the third infestation in wt mice. In the third infestation, infiltration of CD44 lymphocytes, eosinophils and expression of S100A8 and S100B significantly increased at the biting sites of ticks in wt, but not in RAGE mice. In addition, peripheral eosinophil counts significantly increased in wt but not in RAGE mice. Taken together, our study revealed that RAGE-mediated inflammation and eosinophils played crucial roles in the tick-induced inflammatory reactions.
Topics: Animals; Ixodidae; Receptor for Advanced Glycation End Products; Mice; Inflammation; Mice, Knockout; Tick Infestations; Mice, Inbred C57BL; Female; Feeding Behavior; Haemaphysalis longicornis
PubMed: 38838041
DOI: 10.1111/pim.13039 -
Frontiers in Immunology 2024Activated lung ILC2s produce large quantities of IL-5 and IL-13 that contribute to eosinophilic inflammation and mucus production following respiratory syncytial virus...
Activated lung ILC2s produce large quantities of IL-5 and IL-13 that contribute to eosinophilic inflammation and mucus production following respiratory syncytial virus infection (RSV). The current understanding of ILC2 activation during RSV infection, is that ILC2s are activated by alarmins, including IL-33, released from airway epithelial cells in response to viral-mediated damage. Thus, high levels of RSV neutralizing maternal antibody generated from maternal immunization would be expected to reduce IL-33 production and mitigate ILC2 activation. Here we report that lung ILC2s from mice born to RSV-immunized dams become activated despite undetectable RSV replication. We also report, for the first time, expression of activating and inhibitory Fcgamma receptors on ILC2s that are differentially expressed in offspring born to immunized versus unimmunized dams. Alternatively, ex vivo IL-33-mediated activation of ILC2s was mitigated following the addition of antibody: antigen immune complexes. Further studies are needed to confirm the role of Fcgamma receptor ligation by immune complexes as an alternative mechanism of ILC2 regulation in RSV-associated eosinophilic lung inflammation.
Topics: Animals; Respiratory Syncytial Virus Infections; Mice; Female; Mice, Inbred BALB C; Lung; Interleukin-33; Respiratory Syncytial Viruses; Lymphocytes; Immunization; Receptors, IgG; Antibodies, Viral; Pregnancy; Respiratory Syncytial Virus Vaccines
PubMed: 38827738
DOI: 10.3389/fimmu.2024.1374818