Allergen-specific IgA and IgG antibodies as inhibitors of mast cell function in food allergy.

Food allergy, a group of adverse immune responses to normally innocuous food protein antigens, is an increasingly prevalent public health issue. The most common form is IgE-mediated food allergy in which food antigen-induced crosslinking of the high-affinity IgE-receptor, FcεRI, on the surface of mast cells triggers the release of inflammatory mediators that contribute to a wide range of clinical manifestations, including systemic anaphylaxis. Mast cells also play a critical function in adaptive immunity to foods, acting as adjuvants for food-antigen driven Th2 cell responses. While the diagnosis and treatment of food allergy has improved in recent years, no curative treatments are currently available. However, there is emerging evidence to suggest that both allergen-specific IgA and IgG antibodies can counter the activating effects of IgE antibodies on mast cells. Most notably, both antigen-specific IgA and IgG antibodies are induced in the course of oral immunotherapy. In this review, we highlight the role of mast cells in food allergy, both as inducers of immediate hypersensitivity reactions and as adjuvants for type 2 adaptive immune responses. Furthermore, we summarize current understanding of the immunomodulatory effects of antigen-specific IgA and IgG antibodies on IgE-induced mast cell activation and effector function. A more comprehensive understanding of the regulatory role of IgA and IgG in food allergy may provide insights into physiologic regulation of immune responses to ingested antigens and could seed novel strategies to treat allergic disease.

Nested non-covalent interactions expand the functions of supramolecular polymer networks.

Supramolecular polymer networks contain non-covalent cross-links that enable access to broadly tunable mechanical properties and stimuli-responsive behaviors; the incorporation of multiple unique non-covalent cross-links within such materials further expands their mechanical responses and functionality. To date, however, the design of such materials has been accomplished through discrete combinations of distinct interaction types in series, limiting materials design logic. Here we introduce the concept of leveraging "nested" supramolecular crosslinks, wherein two distinct types of non-covalent interactions exist in parallel, to control bulk material functions. To demonstrate this concept, we use polymer-linked Pd2L4 metal-organic cage (polyMOC) gels that form hollow metal-organic cage junctions through metal-ligand coordination and can exhibit well-defined host-guest binding within their cavity. In these "nested" supramolecular network junctions, the thermodynamics of host-guest interactions within the junctions affect the metal-ligand interactions that form those junctions, ultimately translating to substantial guest-dependent changes in bulk material properties that could not be achieved in traditional supramolecular networks with multiple interactions in series.

A Retrospective Analysis of Foreign Body Ingestions Among the Pediatric Age Group in a Tertiary Care Hospital in Jeddah, Saudi Arabia.

BACKGROUND: Foreign body ingestion (FBI) among the pediatric age group is considered a major clinical problem that can cause life-threatening complications, as it can obstruct the airway due to poor/immature airway protection reflexes. OBJECTIVE: In this study, we aimed to retrospectively describe the epidemiology, clinical characteristics, and outcomes of FBI among the pediatric age group in Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia. METHODS: We conducted a retrospective study of pediatric patients (0-14 years) presenting to a tertiary care hospital in Jeddah, Saudi Arabia, from January 2019 to October 2022. The study reviewed records of patients with FBI in the emergency department. Data collection included age, gender, comorbidities, foreign body (FB) type, anatomical location, presenting symptoms, time to emergency room (ER) presentation, need for endoscopy, and complications. We performed a statistical analysis using the Statistical Package for Social Sciences (SPSS) 25 (IBM SPSS Statistics, Armonk, NY), where p<0.05 was considered statistically significant. RESULTS: We identified 244 FBI cases, with most cases being male (62.7%). The most common site of FB impaction was the stomach (38.9%), followed by the upper esophagus (29.1%). Clinical presentation was variable, with 20.5% of cases experiencing vomiting, 13.5% experiencing drooling, and 9.4% experiencing dysphagia. Out of 244 cases, 132 (54.1%) were referred to gastroenterology for urgent FB removal by endoscopy. A total of 186 cases (76.2%) did not have complications, whereas 3.6% had serious sequela. The association between age and FBI was statistically significant (p=0.00), whereas there was no association between gender and FBI. CONCLUSION: Our results showed that FB ingestion was prevalent among children at our tertiary care hospital, with urgent endoscopy being the most common removal procedure. Early detection and immediate presentation to the emergency room are crucial for preventing complications. Common FBI included coins and batteries, with most incidents in 1-3-year-old males. Parents should be aware of the dangers of FBI and implement preventive measures to reduce its incidence.

A Model Ensemble Approach Enables Data-Driven Property Prediction for Chemically Deconstructable Thermosets in the Low-Data Regime.

Thermosets present sustainability challenges that could potentially be addressed through the design of deconstructable variants with tunable properties; however, the combinatorial space of possible thermoset molecular building blocks (e.g., monomers, cross-linkers, and additives) and manufacturing conditions is vast, and predictive knowledge for how combinations of these molecular components translate to bulk thermoset properties is lacking. Data science could overcome these problems, but computational methods are difficult to apply to multicomponent, amorphous, statistical copolymer materials for which little data exist. Here, leveraging a data set with 101 examples, we introduce a closed-loop experimental, machine learning (ML), and virtual screening strategy to enable predictions of the glass transition temperature (Tg) of polydicyclopentadiene (pDCPD) thermosets containing cleavable bifunctional silyl ether (BSE) comonomers and/or cross-linkers with varied compositions and loadings. Molecular features and formulation variables are used as model inputs, and uncertainty is quantified through model ensembling, which together with heavy regularization helps to avoid overfitting and ultimately achieves predictions within <15 °C for thermosets with compositionally diverse BSEs. This work offers a path to predicting the properties of thermosets based on their molecular building blocks, which may accelerate the discovery of promising plastics, rubbers, and composites with improved functionality and controlled deconstructability.

Prevalence and Associated Risk Factors of Dry Eye Disease Among Children and Adults in Saudi Arabia: A Cross-Sectional Study.

BACKGROUND: Dry eye disease (DED) is characterized by loss of homeostasis of the tear film or failure to produce sufficient amounts of tears to moisturize the eyes. The condition has been associated with several preventable risk factors.  Objective: The objective of this study is to calculate the prevalence of dry eye and determine the associated risk factors among adults and children in Saudi Arabia.  Methods: This is a cross-sectional study targeting all Saudi populations, including all the regions of Saudi Arabia. The Ocular Surface Disease Index (OSDI) and the five-item Dry Eye Questionnaire (DEQ-5) were used for data collection. Data were collected using an online form that was distributed through social media.  Results: A total of 541 responses were analyzed. The OSDI scores showed that females represented 70.9%, and the age group of 20-40 years represented 59.7%. The prevalence of DED, including all severity levels, was 74.9%. The distribution across levels was as follows: mild cases at 26.2%, moderate cases at 18.2%, and severe at 30.4%. On the other hand, DEQ-5 has shown a prevalence of 37% among the pediatric age group. Several risk factors have been significantly associated with adults' dry eye, including low humidity (P-value=0.002), reading, driving, or watching electronic screens for extended durations (P-value=0.019), autoimmune diseases (P-value=0.033), and undergoing eye procedures (P-value-0.013).  Conclusion: The current study reports a high prevalence rate of dry eyes among the Saudi population. Reading, driving, and using electronic screens for an extended period were found to be associated with the severity of DED. Prospective studies should focus on the epidemiology of the disease, which will provide evidence for better preventive and therapeutic measures.

IgG:FcγRIIb signals block effector programs of IgE:FcεRI-activated mast cells but spare survival pathways.

BACKGROUND: IgE-induced mast cell (MC) degranulation can be inhibited by IgG antibodies, signaling via FcγRIIb, but the effects of IgG on IgE-induced MC transcription are unknown. OBJECTIVE: We sought to assess inhibitory IgG:FcγRIIb effects on MC responses to IgE using complementary transcriptomic and functional approaches. METHODS: RNA sequencing was performed on bone marrow-derived MCs from wild-type and FcγRIIb-deficient mice to identify genes activated following IgE receptor crosslinking that were further modulated in the presence of antigen-specific IgG in an FcγRIIb-dependent fashion. Parallel analyses of signaling pathways and allergic responses in vivo were performed to assess the impact of these changes in gene expression. RESULTS: Rapid changes in the transcription of 879 genes occurred in MCs activated by IgE, peaking at 1 hour. Surprisingly, only 12% of these were altered by IgG signaling via FcγRIIb, including numerous transcripts involved in orchestrating type 2 responses linked to spleen tyrosine kinase signaling. Consistent with this finding, IgG suppressed IgE-induced phospho-intermediates in the spleen tyrosine kinase signaling pathway. In vivo studies confirmed that the IgG-mediated suppression of both systemic anaphylaxis and MC-driven tissue recruitment of inflammatory cells following allergen challenge was dependent on FcγRIIb. In contrast, genes in the STAT5a cell survival pathway were unaltered by IgG, and STAT5a phosphorylation increased after IgE-induced MC activation but was unaffected by IgG. CONCLUSIONS: Our findings indicate that inhibitory IgG:FcγRIIb signals block an IgE-induced proallergic program but spare a prosurvival program.

The effect of COVID-19 home quarantine on the psychological state of pharmacy students: a cross-sectional study.

BACKGROUND: Psychological morbidity has been documented in medical and pharmaceutical undergraduate students in different countries around the world. In this study, we examined the impact of coronavirus disease 2019 (COVID-19) home quarantine on the depressive psychological aspects of last-grade pharmacy students. METHODS: A cross-sectional study was conducted by the Department of Clinical Pharmacy, Faculty of Pharmacy, Deraya University, Egypt. Two hundred and sixty-eight last-grade pharmacy students were included in this study, and they completed a self-administered, pre-designed, anonymous questionnaire. The main outcome measures were the Hamilton Depression Rating Scale (HRS) and Patient Health Questionnaire-9 (PHQ-9), which were measured to screen for the symptoms of psychological depression and determine the degree of depression severity between the beginning and the end of the COVID-19 home quarantine period. Data entry and analysis were done using the Statistical Package for Social Science (SPSS) software version 26. Descriptive statistics were employed for analyses of the data, and categorical variables were described by frequencies and percentages. Bivariate and multivariable analyses were performed to examine relations between demographic data and psychological scales. The study protocol was approved by the Faculty of Pharmacy, Minia University Ethical Committee. RESULTS: A total of 268 students participated in this study (102 males and 166 females). The mean ± SD score of baseline HRS and HRS at the end of the study was 6.3 ± 4.45, 7.95 ± 5.36, respectively, with the presence of a statistically significant difference between the two scores (p < 0.001). The mean ± SD score of baseline PHQ-9 and PHQ-9 at the end of the study was 4.35 ± 3.45, 5.37 ± 4.14, respectively, with the presence of a statistically significant difference between the two scores (p < 0.001). The results showed that the COVID-19 home quarantine period led to a depressive psychological effect on the students in this study. CONCLUSIONS: Students' psychological depression causes morbidity and, in some cases, mortality. Psychological depressive problems were significantly associated with the COVID-19 home quarantine period, which calls for early intervention to solve it. Student counselling services must be more accessible and affordable to overcome this problem.

Immune dysregulation caused by homozygous mutations in CBLB.

CBL-B is an E3 ubiquitin ligase that ubiquitinates proteins downstream of immune receptors to downregulate positive signaling cascades. Distinct homozygous mutations in CBLB were identified in 3 unrelated children with early-onset autoimmunity, one of whom also had chronic urticaria. Patient T cells exhibited hyperproliferation in response to anti-CD3 cross-linking. One of the mutations, p.R496X, abolished CBL-B expression, and a second mutation, p.C464W, resulted in preserved CBL-B expression. The third mutation, p.H285L in the SH2 domain of CBL-B, was expressed at half the normal level in the patient's cells. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient's p.H285L mutation, had T and B cell hyperproliferation in response to antigen receptor cross-linking. CblbH257L mice had increased percentages of T regulatory cells (Tregs) that had normal in vitro suppressive function. However, T effector cells from the patient with the p.H285L mutation and CblbH257L mice were resistant to suppression by WT Tregs. Bone marrow-derived mast cells from CblbH257L mice were hyperactivated after FcεRI cross-linking, and CblbH257L mice demonstrated exaggerated IgE-mediated passive anaphylaxis. This study establishes CBL-B deficiency as a cause of immune dysregulation.

Allergen-Specific IgA Antibodies Block IgE-Mediated Activation of Mast Cells and Basophils.

Mast cells and basophils have long been implicated in the pathogenesis of IgE-mediated hypersensitivity reactions. They express the high-affinity IgE receptor, FcϵRI, on their surface. Antigen-induced crosslinking of IgE antibodies bound to that receptor triggers a signaling cascade that results in activation, leading to the release of an array of preformed vasoactive mediators and rapidly synthesized lipids, as well as the de novo production of inflammatory cytokines. In addition to bearing activating receptors like FcεRI, these effector cells of allergy express inhibitory ones including FcγR2b, an IgG Fc receptor with a cytosolic inhibitory motif that activates protein tyrosine phosphatases that suppress IgE-mediated activation. We and others have shown that food allergen-specific IgG antibodies strongly induced during the course of oral immunotherapy (OIT), signal via FcγR2b to suppress IgE-mediated mast cell and basophil activation triggered by food allergen challenge. However, the potential inhibitory effects of IgA antibodies, which are also produced in response to OIT and are present at high levels at mucosal sites, including the intestine where food allergens are encountered, have not been well studied. Here we uncover an inhibitory function for IgA. We observe that IgA binds mouse bone marrow-derived mast cells (BMMCs) and peritoneal mast cells. Binding to BMMCs is dependent on calcium and sialic acid. We also found that IgA antibodies inhibit IgE-mediated mast cell degranulation in an allergen-specific fashion. Antigen-specific IgA inhibits IgE-mediated mast cell activation early in the signaling cascade, suppressing the phosphorylation of Syk, the proximal protein kinase mediating FcεRI signaling, and suppresses mast cell production of cytokines. Furthermore, using basophils from a peanut allergic donor we found that IgA binds to basophils and that activation by exposure to peanuts is effectively suppressed by IgA. We conclude that IgA serves as a regulator of mast cell and basophil degranulation, suggesting a physiologic role for IgA in the maintenance of immune homeostasis at mucosal sites.

Endohedrally Functionalized Metal-Organic Cage-Cross-Linked Polymer Gels as Modular Heterogeneous Catalysts.

The immobilization of homogeneous catalysts onto supports to improve recyclability while maintaining catalytic efficiency is often a trial-and-error process limited by poor control of the local catalyst environment and few strategies to append catalysts to support materials. Here, we introduce a modular heterogenous catalysis platform that addresses these challenges. Our approach leverages the well-defined interiors of self-assembled Pd12L24 metal-organic cages/polyhedra (MOCs): simple mixing of a catalyst-ligand of choice with a polymeric ligand, spacer ligands, and a Pd salt induces self-assembly of Pd12L24-cross-linked polymer gels featuring endohedrally catalyst-functionalized junctions. Semi-empirical calculations show that catalyst incorporation into the MOC junctions of these materials has minimal affect on the MOC geometry, giving rise to well-defined nanoconfined catalyst domains as confirmed experimentally using several techniques. Given the unique network topology of these freestanding gels, they are mechanically robust regardless of their endohedral catalyst composition, allowing them to be physically manipulated and transferred from one reaction to another to achieve multiple rounds of catalysis. Moreover, by decoupling the catalyst environment (interior of MOC junctions) from the physical properties of the support (the polymer matrix), this strategy enables catalysis in environments where homogeneous catalyst analogues are not viable, as demonstrated for the Au(I)-catalyzed cyclization of 4-pentynoic acid in aqueous media.

The Anti-Rheumatic Drug, Leflunomide, Induces Nephrotoxicity in Mice via Upregulation of TGFß-Mediated p53/Smad2/3 Signaling.

Recent studies indicated renal toxicity and interstitial nephritis in patients receiving leflunomide (LEFN), but the exact mechanism is still unknown. The transforming growth factor ß (TGFß)/p53/Smad2/3 pathway crucially mediates renal fibrosis. We aimed to assess the nephrotoxic effect of LEFN in mice and the possible role of TGFß-stimulated p53/SMAD2/3 signaling. The study design involved distributing sixty male albino mice into four groups: (i) vehicle-treated mice, (ii) LEFN (2.5 mg/kg), (iii) LEFN (5 mg/kg), and (iv) LEFN (10 mg/kg). The drug was given orally every 48 h and continued for 8 weeks. Blood samples were then taken from mice for the determination of kidney function parameters. Right kidneys were used for histopathologic staining and immunohistochemistry, whereas left kidneys were frozen and used for Western blot analysis of the target proteins, p-p53 and Smad2/3. Results indicated that chronic administration of LEFN in mice resulted in a four- and nine-fold increase in serum urea and creatinine levels, respectively. Kidney specimens stained with hematoxylin and eosin or periodic acid-Schiff showed significant histopathological manifestations, such as cellular irregularity, interstitial congestion, and moderate lymphocytic inflammatory infiltrate in mice treated with LEFN. Western blotting indicated upregulation of the p-p53/Smad2/3 proteins. LEFN, especially in the highest dose (10 mg/kg), produced prominent nephrotoxicity in mice. This toxicity is mediated through stimulating fibrotic changes through TGFß-stimulated p53/Smad2/3 signaling and induction of glomerular and tubular apoptosis. An improved understanding of LEFN-induced nephrotoxicity would have great implications in the prediction, prevention, and management of leflunomide-treated rheumatic patients, and may warrant further clinical studies for following up these toxidromes.

Association between acute kidney injury and brain injury on term-equivalent age brain magnetic resonance imaging in very preterm infants.

BACKGROUND: This study aimed to investigate the relationship between acute kidney injury (AKI) in the first 2 weeks of life and brain injury on term-equivalent age magnetic resonance imaging in very preterm infants. METHODS: We included 116 infants with a birth weight of < 1500 g who were born at the King Saud Medical City at ≤ 32 gestational weeks. They were admitted to the neonatal intensive care unit and underwent term-equivalent age and pre-discharge brain magnetic resonance imaging. A negative binomial with generalized linear models and a robust variance estimator (Huber-White) was applied for univariate relative risk analysis. The Kidokoro score was then used to determine the effect of AKI on brain morphology and growth at term-equivalent age. RESULTS: Sixty-eight (64.2%) infants had developed an AKI in the first 2 weeks of life. AKI was significantly associated with cerebellum signal abnormalities, cerebellar volume reduction, and a high total cerebellum score (P = 0.04, P < 0.001, P < 0.001, respectively). CONCLUSIONS: AKI in the first 2 weeks of life is associated with brain insult, especially in the cerebellum. More well-designed studies are required to investigate the association and impact of AKI on the central nervous system. A higher resolution version of the Graphical abstract is available as Supplementary information.

Association between morphine exposure and impaired brain development on term-equivalent age brain magnetic resonance imaging in very preterm infants.

To investigate the relationship between morphine exposure in the first week of life and brain injury on term-equivalent age magnetic resonance imaging (MRI) in very preterm infants. A retrospective study included 106 infants with a birth weight of < 1500 g who were born at King Saud Medical City at ≤ 32 gestational weeks, were admitted to the neonatal intensive care unit, and underwent term-equivalent age or pre-discharge brain MRI. A univariate analysis in addition to modified log-Poisson regression with a robust variance estimator was applied, and the effect of early morphine exposure and cumulative dose in the first seven days on brain morphology and growth at term-equivalent age was determined using the Kidokoro score. Sixty-eight (64.2%) infants had received morphine in the first week of life (median cumulative dose: 1.68 mg/kg, interquartile range 0.48-2.52 mg/kg). Early initiation of morphine administration was significantly associated with high total white matter (adjusted relative risk [aRR] 1.32, 95% confidence interval [CI] 1.01-1.72) and cerebellum (aRR 1.36, 95% CI 1.03-1.81) scores and a small cerebellar volume (aRR 1.28, 95% CI 1.02-1.61). Morphine exposure in the first week of life was independently associated with white matter and cerebellar injury on term-equivalent age brain MRI in very preterm infants.

In-situ construction of Zr-based metal-organic framework core-shell heterostructure for photocatalytic degradation of organic pollutants.

Photocatalysis is an eco-friendly promising approach to the degradation of textile dyes. The majority of reported studies involved remediation of dyes with an initial concentration ≤50 mg/L, which was away from the existing values in textile wastewater. Herein, a simple solvothermal route was utilized to synthesize CoFe2O4@UiO-66 core-shell heterojunction photocatalyst for the first time. The photocatalytic performance of the as-synthesized catalysts was assessed through the photodegradation of methylene blue (MB) and methyl orange (MO) dyes at an initial concentration (100 mg/L). Under simulated solar irradiation, improved photocatalytic performance was accomplished by as-obtained CoFe2O4@UiO-66 heterojunction compared to bare UiO-66 and CoFe2O4. The overall removal efficiency of dyes (100 mg/L) over CoFe2O4@UiO-66 (50 mg/L) reached >60% within 180 min. The optical and photoelectrochemical measurements showed an enhanced visible light absorption capacity as well as effective interfacial charge separation and transfer over CoFe2O4@UiO-66, emphasizing the successful construction of heterojunction. The degradation mechanism was further explored, which revealed the contribution of holes (h+), superoxide (•O2 -), and hydroxyl (•OH) radicals in the degradation process, however, h+ were the predominant reactive species. This work might open up new insights for designing MOF-based core-shell heterostructured photocatalysts for the remediation of industrial organic pollutants.

Relationship between intraventricular hemorrhage and acute kidney injury in premature infants and its effect on neonatal mortality.

Intraventricular hemorrhage (IVH) and acute kidney injury (AKI) are important neonatal morbidities in premature infants. This study aimed to investigate the relationship between IVH and AKI in premature infants and whether this association affects the incidence of neonatal mortality. Infants [gestational age (GA) ≤ 32 weeks; birth weight (BW) < 1500 g] were retrospectively evaluated in a large tertiary neonatal intensive care unit. Of 710 premature infants, 268 (37.7%) developed AKI. Infants with IVH were more likely to have AKI than those without IVH. Infants with severe IVH had a higher incidence of AKI than infants with mild IVH. Infants younger than 28 weeks with IVH were more likely to have AKI than those without IVH. An association between IVH grades and AKI stages was observed in the overall study population, in infants with GA < 28 weeks, and in infants with GA between 28 and 32 weeks. Mortality was increased 1.5 times in infants with IVH and AKI compared with that in infants with IVH but without AKI. Furthermore, mortality was increased in infants with IVH and AKI compared with infants without IVH or AKI. This study shows a direct relationship between the severity of IVH and the degree of AKI; both IVH and AKI increase the incidence of neonatal mortality.

IgE and IgG Antibodies as Regulators of Mast Cell and Basophil Functions in Food Allergy.

Food allergy is a major health issue, affecting the lives of 8% of U.S. children and their families. There is an urgent need to identify the environmental and endogenous signals that induce and sustain allergic responses to ingested allergens. Acute reactions to foods are triggered by the activation of mast cells and basophils, both of which release inflammatory mediators that lead to a range of clinical manifestations, including gastrointestinal, cutaneous, and respiratory reactions as well as systemic anaphylaxis. Both of these innate effector cell types express the high affinity IgE receptor, FcϵRI, on their surface and are armed for adaptive antigen recognition by very-tightly bound IgE antibodies which, when cross-linked by polyvalent allergen, trigger degranulation. These cells also express inhibitory receptors, including the IgG Fc receptor, FcγRIIb, that suppress their IgE-mediated activation. Recent studies have shown that natural resolution of food allergies is associated with increasing food-specific IgG levels. Furthermore, oral immunotherapy, the sequential administration of incrementally increasing doses of food allergen, is accompanied by the strong induction of allergen-specific IgG antibodies in both human subjects and murine models. These can deliver inhibitory signals via FcγRIIb that block IgE-induced immediate food reactions. In addition to their role in mediating immediate hypersensitivity reactions, mast cells and basophils serve separate but critical functions as adjuvants for type 2 immunity in food allergy. Mast cells and basophils, activated by IgE, are key sources of IL-4 that tilts the immune balance away from tolerance and towards type 2 immunity by promoting the induction of Th2 cells along with the innate effectors of type 2 immunity, ILC2s, while suppressing the development of regulatory T cells and driving their subversion to a pathogenic pro-Th2 phenotype. This adjuvant effect of mast cells and basophils is suppressed when inhibitory signals are delivered by IgG antibodies signaling via FcγRIIb. This review summarizes current understanding of the immunoregulatory effects of mast cells and basophils and how these functions are modulated by IgE and IgG antibodies. Understanding these pathways could provide important insights into innovative strategies for preventing and/or reversing food allergy in patients.

Mast Cells as Regulators of Adaptive Immune Responses in Food Allergy.

Mast cells are a critical first line of defense against endogenous and environmental threats. Their participation in innate immunity is well characterized; activation of toll like receptors as well as receptors for complement, adenosine, and a host of other ligands leads to mast cell release of preformed mediators contained within granules along with newly synthesized arachidonic acid metabolites, cytokines, and chemokines. These confer protective effects including the induction of mucus secretion, smooth muscle contraction, and activation of common itch and pain sensations, all of which act to promote expulsion of noxious agents. While their innate immune role as sentinel cells is well established, recent research has brought into focus their separate but also critical function in adaptive immunity particularly in the setting of IgE mediated food allergies. Crosslinking of FcεR1, the high affinity receptor for IgE, when bound to IgE and antigen, triggers the release of the same factors and elicits the same physiologic responses that occur after activation by innate stimuli. Though IgE-activated mast cells are best known for their role in acute allergic reactions, including the most severe manifestation, anaphylaxis, accumulating evidence has suggested an immunoregulatory effect in T cell-mediated immunity, modulating the balance between type 2 immunity and tolerance. In this review, we outline how mast cells act as adjuvants for food antigen driven Th2 cell responses, while curtailing Treg function.

IgE and mast cells: The endogenous adjuvant.

Mast cells and IgE are most familiar as the effectors of type I hypersensitivity reactions including anaphylaxis. It is becoming clear however that this pair has important immunomodulatory effects on innate and adaptive cells of the immune system. In this purview, they act as endogenous adjuvants to ignite evolving immune responses, promote the transition of allergic disease into chronic illness and disrupt the development of active mechanisms of tolerance to ingested foods. Suppression of IgE-mediated mast cell activation can be exerted by molecules targeting IgE, FcɛRI or signaling kinases including Syk, or by IgG antibodies acting via inhibitory Fcγ receptors. In 2015 we reviewed the evidence for the adjuvant functions of mast cells. This update includes the original text, incorporates some important developments in the field over the past five years and discusses how interventions targeting these pathways might have promise in the development of strategies to treat allergic disease.

Single hepatocytes show persistence and transcriptional inactivity of hepatitis B.

There is no cure for the more than 270 million people chronically infected with HBV. Nucleos(t)ide analogs (NUCs), the mainstay of anti-HBV treatment, block HBV reverse transcription. NUCs do not eliminate the intranuclear covalently closed circular DNA (cccDNA), from which viral RNAs, including pregenomic RNA (pgRNA), are transcribed. A key gap in designing a cure is understanding how NUCs affect HBV replication and transcription because serum markers yield an incomplete view of intrahepatic HBV. We applied single-cell laser capture microdissection and droplet digital PCR to paired liver biopsies collected from 5 HBV/HIV-coinfected persons who took NUCs over 2-4 years. From biopsy 1 to 2, proportions of HBV-infected hepatocytes declined with adherence to NUC treatment (P < 0.05); we extrapolated that eradication of HBV will take over 10 decades with NUCs in these participants. In individual hepatocytes, pgRNA levels diminished 28- to 73-fold during NUC treatment, corresponding with decreased tissue HBV core antigen staining (P < 0.01). In 4 out of 5 participants, hepatocytes with cccDNA but undetectable pgRNA (transcriptionally inactive) were present, and these were enriched in 3 participants during NUC treatment. Further work to unravel mechanisms of cccDNA transcriptional inactivation may lead to therapies that can achieve this in all hepatocytes, resulting in a functional cure.

Omeprazole inhibits IgE-mediated mast cell activation and allergic inflammation induced by ingested allergen in mice.

BACKGROUND: Patients with eosinophilic esophagitis have increased numbers of mucosal mast cells. Administration of the proton pump inhibitor omeprazole can reduce both esophageal mast cell and eosinophil numbers and attenuate type 2 inflammation in these subjects. OBJECTIVE: Given that maintenance of an acidic environment within granules is important for mast cell homeostasis, we sought to evaluate the effects of omeprazole on mast cell functions including development, IgE:FcεRI-mediated activation, and responses to food allergen. METHODS: Mast cell degranulation, cytokine secretion, and early signaling events in the FcεRI pathway, including protein kinase phosphorylation and Ca2+ flux, were measured after IgE crosslinking in murine bone marrow-derived mast cells and human cord blood-derived mast cells. The effects of omeprazole on these responses were investigated as was its impact on mast cell-dependent anaphylaxis and food allergy phenotypes in vivo. RESULTS: Murine and human mast cells treated with omeprazole exhibited diminished degranulation and release of cytokines and histamine in response to allergen. In murine mast cells, phosphorylation of protein kinases, ERK and SYK, was decreased. Differentiation of mast cells from bone marrow progenitors was also inhibited. IgE-mediated passive anaphylaxis was blunted in mice treated with omeprazole as was allergen-induced mast cell expansion and mast cell activation in the intestine in a model of food allergy. CONCLUSIONS: Our findings suggest that omeprazole targets pathways important for the differentiation and activation of murine mast cells and for the manifestations of food allergy and anaphylaxis.