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American Journal of Physiology. Renal... Dec 2023The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been... (Review)
Review
The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of induce a hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of , resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse.
Topics: Mice; Humans; Animals; Nephrosis, Lipoid; Podocytes; Common Cold; Proteinuria; Glomerular Basement Membrane; Recurrence; Nephrotic Syndrome; Transcription Factors; Homeodomain Proteins
PubMed: 37795536
DOI: 10.1152/ajprenal.00219.2023 -
Journal of Clinical Immunology Oct 2023The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4...
The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis.245 words.
Topics: Humans; Interleukin-4; Leukocytes, Mononuclear; Lymphoma, Follicular; STAT6 Transcription Factor; Gain of Function Mutation; HEK293 Cells; Janus Kinases
PubMed: 37316763
DOI: 10.1007/s10875-023-01530-7 -
The Journal of Experimental Medicine Sep 2023Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple...
Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs. However, little is known about the mechanism by which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3-/- mice was shown to depend on Toll-like receptor 7 (TLR7), which senses a combination of nucleosides and oligoribonucleotides (ORNs). TLR7 increased phagocyte numbers by driving the proliferation of Ly6Chi immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3-/- mice. Downstream of TLR7, FcRγ and DAP10 were required for monocyte proliferation. Histiocytosis is accompanied by inflammation in SLC29A3 disorders. However, TLR7 in nucleoside-laden splenic monocytes failed to activate inflammatory responses. Enhanced production of proinflammatory cytokines was observed only after stimulation with ssRNAs, which would increase lysosomal ORNs. Patient-derived monocytes harboring the G208R SLC29A3 mutation showed enhanced survival and proliferation in a TLR8-antagonist-sensitive manner. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders.
Topics: Animals; Mice; Cytokines; Histiocytosis; Mutation; Nucleosides; Toll-Like Receptor 7; Toll-Like Receptor 8
PubMed: 37462944
DOI: 10.1084/jem.20230054 -
Biomedicines Jul 2023Several epidemiological studies have described childhood obesity as a risk factor for atopic disease, particularly asthma. At the same time, this association seems to be... (Review)
Review
Several epidemiological studies have described childhood obesity as a risk factor for atopic disease, particularly asthma. At the same time, this association seems to be more conflicting for allergic rhinitis, atopic dermatitis, and chronic urticaria. This article aims to deepen the possibility of a relationship between childhood obesity and allergic diseases. As regards asthma, the mechanical and inflammatory effects of obesity can lead to its development. In addition, excess adiposity is associated with increased production of inflammatory cytokines and adipokines, leading to low-grade systemic inflammation and an increased risk of asthma exacerbations. Allergic rhinitis, atopic dermatitis, food allergies, and chronic urticaria also seem to be related to this state of chronic low-grade systemic inflammation typical of obese children. Vitamin D deficiency appears to play a role in allergic rhinitis, while dyslipidemia and skin barrier defects could explain the link between obesity and atopic dermatitis. Starting from this evidence, it becomes of fundamental importance to act on body weight control to achieve general and allergic health, disentangling the detrimental link between obesity allergic diseases and childhood obesity. Further studies on the association between adiposity and atopy are needed, confirming the biologically active role of fat tissue in the development of allergic diseases and exploring the possibility of new therapeutic strategies.
PubMed: 37509700
DOI: 10.3390/biomedicines11072061 -
The Journal of Allergy and Clinical... Dec 2023Atopic diseases are characterized by type 2 inflammation, with high levels of allergen-specific T2 cell immune responses and elevated production of IgE. These common... (Review)
Review
Atopic diseases are characterized by type 2 inflammation, with high levels of allergen-specific T2 cell immune responses and elevated production of IgE. These common disorders have increased in incidence around the world, which is partly explained by detrimental disturbances to the early-life intestinal microbiome. Although most studies have focused exclusively on bacterial members of the microbiome, intestinal fungi have started to be recognized for their impact on host immune development and atopy pathogenesis. From this perspective, we review recent findings demonstrating the strong interactions between members of the mycobiome and the host immune system early in life, leading to immune tolerance during eubiosis or inducing sensitization and overt T2 cell responses during dysbiosis. Current evidence places intestinal fungi as central players in the development of allergic diseases and potential targets for atopy prevention and treatments.
Topics: Humans; Mycobiome; Hypersensitivity; Hypersensitivity, Immediate; Allergens; Inflammation; Fungi
PubMed: 37865199
DOI: 10.1016/j.jaci.2023.10.006 -
Pediatric Pulmonology Nov 2023Plastic bronchitis is a term used to describe group of life-threatening disorders characterized by the presence of large obstructing casts in the airways. Eosinophilic... (Review)
Review
Plastic bronchitis is a term used to describe group of life-threatening disorders characterized by the presence of large obstructing casts in the airways. Eosinophilic plastic bronchitis is a subtype of plastic bronchitis that occurs mainly in children and has not been well-described in the literature. Patients may have a history of asthma or atopy, but many do not. They often present with cough and wheezing, and frequently have complete collapse of one lung seen on imaging. The severity of presentation varies depending on the location of the casts, ranging from mild symptoms to severe airway obstruction and death. Bronchoscopy is often required to both diagnose and treat this condition. A variety of medical therapies have been used, although no formal studies have evaluated their efficacy. Symptoms may resolve after initial cast removal, but in some patients, cast formation recurs. Here, we report a case series of nine patients with eosinophilic plastic bronchitis and review the existing literature of this condition.
Topics: Child; Humans; Bronchitis; Asthma; Lung; Airway Obstruction; Bronchoscopy
PubMed: 37606213
DOI: 10.1002/ppul.26650 -
Frontiers in Pediatrics 2023pneumonia (MPP) is common among children, but the impact of atopy on MPP severity in children is unknown. This study investigated whether atopic vs. nonatopic children...
BACKGROUND
pneumonia (MPP) is common among children, but the impact of atopy on MPP severity in children is unknown. This study investigated whether atopic vs. nonatopic children had greater MPP severity.
METHODS
Retrospective analysis was conducted on 539 (ages 3-14 years) patients who were hospitalized in the First Affiliated Hospital of Anhui Medical University for MPP between January 2018 and December 2021, 195 were atopic and 344 were nonatopic. Of them, 204 had refractory MPP, and 335 had general MPP. And of atopic children, 94 had refractory MPP, and 101 had general MPP. Data on demographic and clinical characteristics, laboratory findings, clinical treatments were analyzed.
RESULTS
Significantly more boys with MPP were atopic than nonatopic (< 0.05). More atopic (than nonatopic) children presented with prolonged fever and hospitalization, severe extra-pulmonary complications, asthma attaking, steroid and oxygen treatment, and increased IgE levels (all < 0.05). In atopic (vs. nonatopic) children with MPP, the incidence of sputum plugs under the fiberoptic bronchoscopy and lobar pneumonia was significantly increased and required bronchoscopy-assisted and steroid therapy. Compared with nonatopic children, more atopic children developed refractory MPP (< 0.05). Prolonged fever and hospitalization, severe extra-pulmonary complications, lymphocyte count, procalcitonin and lactate dehydrogenase levels, and percentages of atopy were all significantly higher (< 0.05) among children with refractory MPP vs. general MPP. Moreover, Prolonged fever and hospitalization, lymphocyte count, procalcitonin and lactate dehydrogenase levels, and the treantment of steroid were all significantly higher (< 0.05) among atopic children with refractory MPP vs. general MPP. Spearman correlation analysis showed strong associations between atopy and male sex, length of hospital stay, fever duration, IgE level, wheezing, lobar pneumonia, refractory MPP, and treatment with oxygen, hormones or bronchoscopy (< 0.05).
CONCLUSIONS
Atopy may be a risk factor for and was positively correlated with the severity of MPP in children.
PubMed: 38078330
DOI: 10.3389/fped.2023.1281479 -
Frontiers in Immunology 2024Chronic urticaria (CU) is one of the most common dermatological diseases and has a significant impact on the quality of life of patients. However, the pathogenesis of... (Review)
Review
Chronic urticaria (CU) is one of the most common dermatological diseases and has a significant impact on the quality of life of patients. However, the pathogenesis of this disease remains unclear. Autoimmunity in chronic spontaneous urticaria (CSU) has received considerable attention and has been studied previously. Atopy is an important characteristic of CU; however, it has not been fully recognized. Atopy predisposes individuals to immune responses to allergens, leading to type 2 inflammation and immunoglobulin E (IgE) overproduction. Compared with healthy individuals, patients with CU have a higher proportion of atopy, and an atopic background is correlated with the clinical characteristics of CU. The total IgE levels in patients with CU is significantly higher than those in healthy individuals. Although its level is not higher than that in classic allergic diseases, it is closely related to CU. Exogenous allergens, auto-allergens, and specific IgEs, which are closely related to atopy, have been reported, and their roles in CU pathogenesis are also being studied. Local and systemic atopic inflammation is present in patients with CU. This review summarizes the current knowledge regarding atopy and CU, speculating that there are CU subtypes, such as atopic CSU or atopic chronic inducible urticaria (CIndU) and that atopy may be involved in the pathogenesis of CU. These findings provide a new perspective for a comprehensive understanding of the clinical features of CU and further research regarding its pathogenesis.
Topics: Humans; Urticaria; Quality of Life; Chronic Urticaria; Hypersensitivity, Immediate; Allergens; Immunoglobulin E; Inflammation
PubMed: 38380314
DOI: 10.3389/fimmu.2024.1279976 -
Journal of Investigational Allergology... Dec 2023Sunflower seed is one of the most common edible seeds and its consumption is growing. Case reports of sunflower seed allergy have been described since the 1970s....
BACKGROUND AND OBJECTIVE
Sunflower seed is one of the most common edible seeds and its consumption is growing. Case reports of sunflower seed allergy have been described since the 1970s. However, there are few data on the prevalence and clinical manifestations of sunflower seed allergy. To improve understanding of sunflower seed allergy.
METHODS
We evaluated the clinical and immunological features of patients with sunflower seed allergy diagnosed in the Allergy Department of a tertiary hospital in Madrid over a 5-years period.
RESULTS
Forty-seven patients reported adverse reactions after ingestion of sunflower seed and had specific sensitization to sunflower seed determined by skin prick test (median 8 mm) or specific IgE (median 1.10 kUA/L). Most had an adult-onset reaction to sunflower seed preceded by a history of atopy and other food allergies, predominantly to peach, peanut and nuts. Clinical presentation of sunflower seed allergy ranged from mild to severe, with a high proportion of patients suffering severe reactions, often undertreated. A variability in the severity of symptoms was seen on repeated exposures to sunflower seed on a same patient. Levels of sunflower seed IgE were strongly correlated with levels of IgE to non-specific lipid transfer proteins, while no significant differences were found in the severity of the reactions according to sensitization to those proteins.
CONCLUSION
Our findings reveal a variability of clinical presentations of sunflower seed allergy on repeated exposures and an underuse of epinephrine in anaphylaxis. We highlight the importance of strict avoidance of sunflower seed and accurate prescription and administration of epinephrine in allergic patients.
PubMed: 38085525
DOI: 10.18176/jiaci.0965