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Annual Review of Immunology Jun 2024IgE-mediated food allergy (IgE-FA) occurs due to a breakdown in immune tolerance that leads to a detrimental type 2 helper T cell (T2) adaptive immune response. While... (Review)
Review
IgE-mediated food allergy (IgE-FA) occurs due to a breakdown in immune tolerance that leads to a detrimental type 2 helper T cell (T2) adaptive immune response. While the processes governing this loss of tolerance are incompletely understood, several host-related and environmental factors impacting the risk of IgE-FA development have been identified. Mounting evidence supports the role of an impaired epithelial barrier in the development of IgE-FA, with exposure of allergens through damaged skin and gut epithelium leading to the aberrant production of alarmins and activation of T2-type allergic inflammation. The treatment of IgE-FA has historically been avoidance with acute management of allergic reactions, but advances in allergen-specific immunotherapy and the development of biologics and other novel therapeutics are rapidly changing the landscape of food allergy treatment. Here, we discuss the pathogenesis and immunobiology of IgE-FA in addition to its diagnosis, prognosis, and treatment.
Topics: Humans; Food Hypersensitivity; Animals; Immunoglobulin E; Allergens; Desensitization, Immunologic; Th2 Cells; Immune Tolerance; Disease Susceptibility
PubMed: 38360544
DOI: 10.1146/annurev-immunol-090122-043501 -
Journal of Investigational Allergology... Feb 2024
EPI-SURVEY. Grade of awareness of Spanish allergist, hospital pharmacist, and pulmonologists on the relevance of bronchial epithelium and alarmins in the pathogenesis and management of severe asthma.
PubMed: 38353099
DOI: 10.18176/jiaci.0997 -
International Journal of Molecular... Jan 2024MCs are tissue-resident immune cells that strategically reside in barrier organs and respond effectively to a wide range of stimuli, such as IL-33, a mediator released...
MCs are tissue-resident immune cells that strategically reside in barrier organs and respond effectively to a wide range of stimuli, such as IL-33, a mediator released upon epithelial damage. Adenosine triphosphate (ATP) accumulates at sites of tissue injury and is known to modulate MC activities. This study investigated how an inflammatory tissue environment rich in IL-33 modulates the ATP-mediated activation of MCs. Human primary MCs primed with IL-33 displayed a strongly increased response to ATP but not ADP. This resulted in increased degranulation, IL-8 release, and pERK1/2 signalling. Such effects are unique to IL-33 stimulation and not shared by the epithelial alarmin, TSLP. MC exposure to IL-33 also increased membrane expression of purinergic and ATP-binding P2X receptors. The use of selective P2X receptor inhibitors identified P2X7 receptor as the key mediator of the enhanced ATP-induced ERK1/2 signalling and degranulation in IL-33-primed MCs. Whilst the inhibition of P2X1 and P2X4 receptors had no effect on MC degranulation, inhibiting these receptors together with P2X7 resulted in further decreased MC-mediated degranulation. These data therefore point toward the potential mechanisms by which IL-33 contributes to the modulation of ATP-mediated activation in human MCs.
Topics: Humans; Adenosine Triphosphate; Cell Degranulation; Interleukin-33; Mast Cells; Receptors, Purinergic P2X7; Signal Transduction
PubMed: 38339008
DOI: 10.3390/ijms25031730 -
Nature Communications Feb 2024Chemokine heterodimers activate or dampen their cognate receptors during inflammation. The CXCL12 chemokine forms with the fully reduced (fr) alarmin HMGB1 a...
Chemokine heterodimers activate or dampen their cognate receptors during inflammation. The CXCL12 chemokine forms with the fully reduced (fr) alarmin HMGB1 a physiologically relevant heterocomplex (frHMGB1•CXCL12) that synergically promotes the inflammatory response elicited by the G-protein coupled receptor CXCR4. The molecular details of complex formation were still elusive. Here we show by an integrated structural approach that frHMGB1•CXCL12 is a fuzzy heterocomplex. Unlike previous assumptions, frHMGB1 and CXCL12 form a dynamic equimolar assembly, with structured and unstructured frHMGB1 regions recognizing the CXCL12 dimerization surface. We uncover an unexpected role of the acidic intrinsically disordered region (IDR) of HMGB1 in heterocomplex formation and its binding to CXCR4 on the cell surface. Our work shows that the interaction of frHMGB1 with CXCL12 diverges from the classical rigid heterophilic chemokines dimerization. Simultaneous interference with multiple interactions within frHMGB1•CXCL12 might offer pharmacological strategies against inflammatory conditions.
Topics: Humans; Chemokine CXCL12; HMGB1 Protein; Receptors, CXCR4; Inflammation; Signal Transduction
PubMed: 38331917
DOI: 10.1038/s41467-024-45505-7 -
Molecular Medicine (Cambridge, Mass.) Feb 2024In sepsis, intestinal barrier dysfunction is often caused by the uncontrolled death of intestinal epithelial cells (IECs). CD4CD8αα intraepithelial lymphocytes (IELs),...
BACKGROUND
In sepsis, intestinal barrier dysfunction is often caused by the uncontrolled death of intestinal epithelial cells (IECs). CD4CD8αα intraepithelial lymphocytes (IELs), a subtype of CD4 T cells residing within the intestinal epithelium, exert cytotoxicity by producing granzyme B (GrB) and perforin (Prf). Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently identified alarmin which stimulates TLR4 on immune cells to induce proinflammatory responses. Here, we hypothesized that eCIRP enhances CD4CD8αα IEL cytotoxicity and induces IEC death in sepsis.
METHODS
We subjected wild-type (WT) and CIRP mice to sepsis by cecal ligation and puncture (CLP) and collected the small intestines to isolate IELs. The expression of GrB and Prf in CD4CD8αα IELs was assessed by flow cytometry. IELs isolated from WT and TLR4 mice were challenged with recombinant mouse CIRP (eCIRP) and assessed the expression of GrB and Prf in CD4CD8αα by flow cytometry. Organoid-derived IECs were co-cultured with eCIRP-treated CD4CD8αα cells in the presence/absence of GrB and Prf inhibitors and assessed IEC death by flow cytometry.
RESULTS
We found a significant increase in the expression of GrB and Prf in CD4CD8αα IELs of septic mice compared to sham mice. We found that GrB and Prf levels in CD4CD8αα IELs were increased in the small intestines of WT septic mice, while CD4CD8αα IELs of CIRP mice did not show an increase in those cytotoxic granules after sepsis. We found that eCIRP upregulated GrB and Prf in CD4CD8αα IELs isolated from WT mice but not from TLR4 mice. Furthermore, we also revealed that eCIRP-treated CD4CD8αα cells induced organoid-derived IEC death, which was mitigated by GrB and Prf inhibitors. Finally, histological analysis of septic mice revealed that CIRP mice were protected from tissue injury and cell death in the small intestines compared to WT mice.
CONCLUSION
In sepsis, the cytotoxicity initiated by the eCIRP/TLR4 axis in CD4CD8αα IELs is associated with intestinal epithelial cell (IEC) death, which could lead to gut injury.
Topics: Animals; Mice; Intestinal Mucosa; Intestines; Intraepithelial Lymphocytes; Mice, Inbred C57BL; Sepsis; Toll-Like Receptor 4
PubMed: 38302880
DOI: 10.1186/s10020-024-00790-2 -
American Journal of Reproductive... Jan 2024In women of reproductive age, endometriosis may contribute to dysmenorrhea, chronic pelvic pain, dyspareunia, infertility, adenomyosis, and endometrial ovarian cyst...
PROBLEM
In women of reproductive age, endometriosis may contribute to dysmenorrhea, chronic pelvic pain, dyspareunia, infertility, adenomyosis, and endometrial ovarian cyst (EOC). Recent studies have shown that chronic inflammation occurs in the pelvis of endometriosis patients and that this inflammation is exacerbated by immunosuppression, leading to survival endometrial debris. However, the detailed immunological mechanisms underlying the aggravation of inflammation and immunosuppression in endometriosis patients remain unclear.
METHOD OF STUDY
We investigate the alarmins (high-mobility group box-1, IL-33, IL-1α, and S100B protein), proinflammatory cytokines (IL-6 and IL-1β), and immune cells (CD8 T cells, CD4 T cells, natural killer cells, natural killer T cells, dendritic cells, and macrophages) in peritoneal fluid of patients with EOC using enzyme-linked immunosorbent assay, electrochemiluminescence, and flow cytometry. Then, we analyzed the correlation between these factors and the aggravating indicators of endometriosis, tumor size and revised American Society for Reproductive Medicine (r-ASRM) score.
RESULTS
Unexpectedly, there was no correlation between each alarmin level and aggravating indicators. However, the expression of pattern recognition receptors, toll-like receptor 4, and receptor of advanced glycation end-products on macrophages was inversely correlated with aggravating indicators.
CONCLUSIONS
The aggravation of endometriosis is associated with a decrease in alarmin receptors but not alarmin levels. Investigation of innate immune systems, such as alarmins and their receptors, may help elucidate new mechanisms of endometriosis.
Topics: Humans; Female; Endometriosis; Alarmins; CD8-Positive T-Lymphocytes; Down-Regulation; Macrophages; Receptors, Pattern Recognition; Inflammation
PubMed: 38282610
DOI: 10.1111/aji.13812 -
Biochimica Et Biophysica Acta.... Mar 2024Asthma is quite heterogenous and can be categorized as eosinophilic, mixed granulocytic (presence of both eosinophils and neutrophils in the airways) and neutrophilic....
Asthma is quite heterogenous and can be categorized as eosinophilic, mixed granulocytic (presence of both eosinophils and neutrophils in the airways) and neutrophilic. Clinically, mixed granulocytic asthma (MGA) often tends to be severe and requires large doses of corticosteroids. High mobility group box 1 (HMGB1) is one of the epithelium-derived alarmins that contributes to type 2 inflammation and asthma. This study was aimed to investigate the role of glucose transporter 1 (GLUT1) in modulation of airway epithelial HMGB1 production in MGA. Induced sputum and bronchial biopsy specimens were obtained from healthy subjects and asthma patients. BALB/c mice, the airway epithelial cell line BEAS-2B, or primary human bronchial epithelial cells (HBECs) were immunized with allergens. Intracellular and extracellular HMGB1 were both detected. The role of GLUT1 was assessed by using a pharmacological antagonist BAY876. MGA patients have a significant higher sputum HMGB1 level than the health and subjects with other inflammatory phenotypes. Nuclear-to-cytoplasmic translocation of HMGB1 was also observed in the bronchial epithelia. Allergen exposure markedly induced GLUT1 expression in murine lungs and cultured epithelial cells. Pharmacological antagonism of GLUT1 with BAY876 dramatically decreased airway hyperresponsiveness, neutrophil and eosinophil accumulation, as well as type 2 inflammation in murine models of MGA. Besides, the allergen-induced up-regulation of HMGB1 was also partly recovered by BAY876, accompanied by inhibited secretion into the airway lumen. In vitro, treatment with BAY876 relieved the allergen-induced over-expression and secretion of HMGB1 in airway epithelia. Taken together, our data indicated that GLUT1 mediates bronchial epithelial HMGB1 release in MGA.
Topics: Humans; Animals; Mice; Glucose Transporter Type 1; HMGB1 Protein; Asthma; Epithelial Cells; Inflammation; Allergens
PubMed: 38281711
DOI: 10.1016/j.bbadis.2024.167040 -
Biomolecules Dec 2023Coronary artery ectasia (CAE) is defined as abnormal dilation of a coronary artery with a diameter exceeding that of adjacent normal arterial segment by >1.5 times. CAE...
Coronary artery ectasia (CAE) is defined as abnormal dilation of a coronary artery with a diameter exceeding that of adjacent normal arterial segment by >1.5 times. CAE is a pathological entity of the coronary arteries and characterized as a variant of coronary atherosclerosis. CAE frequently coexists with coronary artery disease (CAD). While inflammation appears to be involved, the pathophysiology of CAE remains unclear. Damage-associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue, are deemed as alarm signals by the innate immune system. Inflammatory agents can generate DAMPs and DAMPs can create a pro-inflammatory state. In a prospective cross-sectional study, we enrolled 29 patients with CAE and non-obstructive CAD, 19 patients with obstructive CAD without CAE, and 14 control subjects with normal (control) coronary arteries age- and sex-matched with the CAE patients, to investigate the differential expression of plasma DAMPs. Patients with CAE and non-obstructive CAD had increased plasma levels of the DAMPs S100B, S100A12, HMGB1, and HSP70, the DAMPs receptor TLR4, and miR328a-3p compared to CAD and controls. Plasma levels of the mir328a-3p target the protective soluble form of the DAMPs receptor for advanced glycation end products (sRAGE), and the antioxidant DJ-1 was decreased in both CAE and CAD compared to controls. In an in vitro human umbilical vein endothelial cells model, circulating levels of S100B, HMGB1, HSP70 as well as CAE patient plasma induced inflammatory responses. The differential expression of the DAMPs S100B, HSP70, HMGB1, and their receptors TLR4 and sRAGE in CAE versus CAD makes them attractive novel biomarkers as therapeutic targets and therapeutics.
Topics: Humans; HMGB1 Protein; Dilatation, Pathologic; Coronary Angiography; Prospective Studies; Cross-Sectional Studies; Endothelial Cells; Toll-Like Receptor 4; Coronary Artery Disease; Alarmins
PubMed: 38275751
DOI: 10.3390/biom14010010 -
Periodontology 2000 Jan 2024It is nowadays well accepted that chronic inflammation plays a pivotal role in tumor initiation and progression. Under this aspect, the oral cavity is predestined to... (Review)
Review
It is nowadays well accepted that chronic inflammation plays a pivotal role in tumor initiation and progression. Under this aspect, the oral cavity is predestined to examine this connection because periodontitis is a highly prevalent chronic inflammatory disease and oral squamous cell carcinomas are the most common oral malignant lesions. In this review, we describe how particular molecules of the human innate host defense system may participate as molecular links between these two important chronic noncommunicable diseases (NCDs). Specific focus is directed toward antimicrobial polypeptides, such as the cathelicidin LL-37 and human defensins, as well as S100 proteins and alarmins. We report in which way these peptides and proteins are able to initiate and support oral tumorigenesis, showing direct mechanisms by binding to growth-stimulating cell surface receptors and/or indirect effects, for example, inducing tumor-promoting genes. Finally, bacterial challenges with impact on oral cancerogenesis are briefly addressed.
PubMed: 38265172
DOI: 10.1111/prd.12552 -
Journal of Clinical Medicine Jan 2024Periodontitis is a chronic inflammatory disease. We have previously shown that salivary DNA is higher in patients with periodontitis. Neutrophil extracellular traps...
Periodontitis is a chronic inflammatory disease. We have previously shown that salivary DNA is higher in patients with periodontitis. Neutrophil extracellular traps (NETs) are involved in the pathogenesis of chronic inflammatory diseases. The objective of this case-control study was to compare patients with periodontitis and healthy controls regarding the salivary concentrations of extracellular DNA and NET components. Unstimulated saliva samples were collected from 49 patients with periodontitis and 71 controls before an oral examination. Salivary extracellular DNA was isolated and quantified fluorometrically and using PCR. NET-associated markers were assessed using ELISA. We have found significantly higher concentrations of salivary extracellular DNA in samples from periodontitis patients (five-times higher for supernatant and three times for pellet). Our results show that patients also have three-times-higher salivary nucleosomes and NET-associated enzymes-myeloperoxidase and neutrophil elastase (both two-times higher). Neutrophil elastase and salivary DNA in the pellet correlated positively with the pocket depth/clinical attachment level in periodontitis patients (r = 0.31-weak correlation; = 0.03 and r = 0.41-moderate correlation, = 0.004). Correlations between salivary extracellular DNA and NET enzymes were positive and significant. Based on our results, the higher salivary extracellular DNA in periodontitis seems to be related to components of NETs, albeit with weak to moderate correlations indicating that NETs are produced in periodontitis and can play a role in its pathogenesis similarly to other inflammatory diseases. Further studies should prove this assumption with potential diagnostic and therapeutic consequences.
PubMed: 38256602
DOI: 10.3390/jcm13020468