Elizabeth H. Yen

The recycling and transcytotic pathways for IgG transport by FcRn are distinct and display an inherent polarity

The Fc receptor FcRn traffics immunoglobulin G (IgG) in both directions across polarized epithelial cells that line mucosal surfaces, contributing to host defense. We show that FcRn traffics IgG from either apical or basolateral membranes into the recycling endosome (RE), after which the actin motor myosin Vb and the GTPase Rab25 regulate a sorting step that specifies transcytosis without affecting recycling. Another regulatory component of the RE, Rab11a, is dispensable for transcytosis, but regulates recycling to the basolateral membrane only. None of these proteins affect FcRn trafficking away from lysosomes. Thus, FcRn transcytotic and recycling sorting steps are distinct. These results are consistent with a single structurally and functionally heterogeneous RE compartment that traffics FcRn to both cell surfaces while discriminating between recycling and transcytosis pathways polarized in their direction of transport.

First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study

Background Recent data in mice suggest that acid suppression during pregnancy yields offspring with type 2 T helper‐dominant immunity, suggesting a predisposition for allergy.

PEDIATRIC CHRONIC PANCREATITIS IS ASSOCIATED WITH GENETIC RISK FACTORS AND SUBSTANTIAL DISEASE BURDEN

OBJECTIVE To determine the clinical presentation, diagnostic variables, risk factors, and disease burden in children with chronic pancreatitis. STUDY DESIGN We performed a cross-sectional study of data from the International Study Group of Pediatric Pancreatitis: In Search for a Cure, a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. RESULTS Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were white; median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty-nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency department visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed 1 day of school in the past month as the result of chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (P = .002), visit the emergency department (P = .01), and experience hospitalizations (P = .03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic endoscopic retrograde pancreatography; one or more pancreatic surgeries were performed in 30 (39%). CONCLUSIONS Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial.

Relationships between Levels of Serum IgE, Cell-Bound IgE, and IgE-Receptors on Peripheral Blood Cells in a Pediatric Population

Background Elevated serum immunoglobulin (Ig) E is a diagnostic marker of immediate-type allergic reactions. We hypothesize that serum IgE does not necessarily reflect total body IgE because in vivo IgE can be bound to cell surface receptors such as FcεRI and FcεRII (CD23). The aim of this study was to analyze the relationships between levels of serum IgE, cell-bound IgE, and IgE-receptors on peripheral blood cells in a pediatric population. Methodology Whole blood samples from 48 children (26 boys, 22 girls, mean age 10,3±5,4 years) were analyzed by flow cytometry for FcεRI, CD23, and cell-bound IgE on dendritic cells (CD11c+MHC class II+), monocytes (CD14+), basophils (CD123+MHC class II-) and neutrophils (myeloperoxidase+). Total serum IgE was measured by ELISA and converted into z-units to account for age-dependent normal ranges. Correlations were calculated using Spearman rank correlation test. Principal Findings Dendritic cells, monocytes, basophils, and neutrophils expressed the high affinity IgE-receptor FcεRI. Dendritic cells and monocytes also expressed the low affinity receptor CD23. The majority of IgE-receptor positive cells carried IgE on their surface. Expression of both IgE receptors was tightly correlated with cell-bound IgE. In general, cell-bound IgE on FcεRI+ cells correlated well with serum IgE. However, some patients carried high amounts of cell-bound IgE despite low total serum IgE levels. Conclusion/Significance In pediatric patients, levels of age-adjusted serum IgE, cell-bound IgE, and FcεRI correlate. Even in the absence of elevated levels of serum IgE, cell-bound IgE can be detected on peripheral blood cells in a subgroup of patients.

Comparative analysis of FcεRI expression patterns in patients with eosinophilic and reflux esophagitis.

Background and Objective: Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus. The IgE receptors on immune cells that infiltrate the esophagus are poorly defined. The high-affinity receptor for IgE, FcϵRI, may play a role in EoE. The objective of the present study is to identify and compare the IgE receptors in the esophageal epithelium of patients with EoE, reflux esophagitis (RE), and normal controls. Patients and Methods: A retrospective case-control study of 62 patients (19 EoE, 22 RE, 21 normal controls) was conducted. Biopsies were immunostained for FcϵRI, CD23, galectin-3, c-kit, CD1a, and langerin. Results: FcϵRI was the only IgE receptor present in the esophageal epithelium of patients with EoE. The FcϵRI-positive cell count varied by diagnosis (proximal biopsies EoE 32.6 ± 19.0 cells/high-power field, RE 26.7 ± 16.6, controls 15.6 ± 8.3, ANOVA P = 0.005; distal biopsies EoE 24.2 ± 16.2, RE 35.7 ± 27.6, controls 15.3 ± 8.4, P = 0.006). In the proximal esophagus, the FcϵRI count was higher in EoE than in controls (P = 0.006); in the distal esophagus, the FcϵRI count was higher in RE than in controls (P = 0.004). EoE and RE had similar FcϵRI-positive cell counts. A subset of FcϵRI-positive cells was similar in morphology and distribution to Langerhans cells (CD1a and langerin positive). Conclusions: The presence of FcϵRI-positive cells in high numbers in the esophageal epithelium implies this receptor must be critical in the IgE-mediated activation of immune cells in the esophagus. Langerhans cells in the esophageal epithelium appear to express FcϵRI. The role of Langerhans cells in the pathophysiology of EoE needs to be elucidated.

A Soluble Form of the High Affinity IgE Receptor, Fc-Epsilon-RI, Circulates in Human Serum

Soluble IgE receptors are potential in vivo modulators of IgE-mediated immune responses and are thus important for our basic understanding of allergic responses. We here characterize a novel soluble version of the IgE-binding alpha-chain of Fc-epsilon-RI (sFcεRI), the high affinity receptor for IgE. sFcεRI immunoprecipitates as a protein of ∼40 kDa and contains an intact IgE-binding site. In human serum, sFcεRI is found as a soluble free IgE receptor as well as a complex with IgE. Using a newly established ELISA, we show that serum sFcεRI levels correlate with serum IgE in patients with elevated IgE. We also show that serum of individuals with normal IgE levels can be found to contain high levels of sFcεRI. After IgE-antigen-mediated crosslinking of surface FcεRI, we detect sFcεRI in the exosome-depleted, soluble fraction of cell culture supernatants. We further show that sFcεRI can block binding of IgE to FcεRI expressed at the cell surface. In summary, we here describe the alpha-chain of FcεRI as a circulating soluble IgE receptor isoform in human serum.

Design and Implementation of INSPPIRE

Objectives: Acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are rare and poorly understood diseases in children. Better understanding of these disorders can only be accomplished via a multicenter, structured, data collection approach. Methods: The International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE) consortium was created to investigate the epidemiology, etiologies, pathogenesis, natural history, and outcomes of pediatric ARP and CP. Patient and physician questionnaires were developed to capture information on demographics, medical history, family and social history, medications, hospitalizations, risk factors, diagnostic evaluation, treatments, and outcome information. Information collected in paper questionnaires was then transferred into Research Electronic Data Capture (REDCap), tabulated, and analyzed. Results: The administrative structure of the INSPPIRE consortium was established, and National Institutes of Health funding was obtained. A total of 14 sites (10 in the United States, 2 in Canada, and 2 overseas) participated. Questionnaires were amended and updated as necessary, followed by changes made into the REDCap database. Between September 1, 2012 and August 31, 2013, a total of 194 children were enrolled into the study: 54% were girls, 82% were non-Hispanic, and 72% were whites. Conclusions: The INSPPIRE consortium demonstrates the feasibility of building a multicenter patient registry to study the rare pediatric diseases, ARP and CP. Analyses of collected data will provide a greater understanding of pediatric pancreatitis and create opportunities for therapeutic interventional studies that would not otherwise be possible without a multicenter approach.

Topical inhaled ciclesonide for treatment of eosinophilic esophagitis

Reply To the Editor: We were encouraged to read of the experience of Lee et al1 with ciclesonide and would address their concerns as follows. In our series of 4 patients, all 4 had taken topical fluticasone before successful use of ciclesonide, making steroid resistance alone unlikely. We wonder whether some of the differences in response could be from the younger age (mean, 7.75 vs 13.5 years) of our patients. Younger patients could have a shorter esophagus, making for better coverage by the swallowed preparation. In addition, there would be a higher probability that parents, as opposed to the patient himself or herself, would administer the medication, leading to higher compliance. With respect to serum IgE levels, patients reported in our letter had increased IgE levels (172–441 IU/mL) but did not have the same degree of increased serum IgE levels as the 2 nonresponders in the Rubenstein series.1 Finally, our patients were treated for an average of 3 months, whereas the exact duration of treatment in their group was not noted. Longer duration might be necessary to achieve histologic remission because one of their nonresponders had somewhat of a diminished eosinophilia. As with any disease, there might be genetically defined differences with respect to therapeutic responsiveness, and these could be addressed with future biomarker studies, as suggested previously.2,3

Elevated levels of leukotriene C4 synthase mRNA distinguish a subpopulation of eosinophilic oesophagitis patients

Cysteinyl leukotrienes contribute to Th2‐type inflammatory immune responses. Their levels in oesophageal tissue, however, do not distinguish patients with eosinophilic oesophagitis (EoE) from controls.

The Causal Evaluation of Acute Recurrent and Chronic Pancreatitis in Children: Consensus From the INSPPIRE Group

Objectives: Acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) have been diagnosed in children at increasing rates during the past decade. As pediatric ARP and CP are still relatively rare conditions, little quality evidence is available on which to base the diagnosis and determination of etiology. The aim of the study was to review the current state of the literature regarding the etiology of these disorders and to developed a consensus among a panel of clinically active specialists caring for children with these disorders to help guide the diagnostic evaluation and identify areas most in need of future research. Methods: A systematic review of the literature was performed and scored for quality, followed by consensus statements developed and scored by each individual in the group for level of agreement and strength of the supporting data using a modified Delphi method. Scores were analyzed for the level of consensus achieved by the group. Results: The panel reached consensus on 27 statements covering the definitions of pediatric ARP and CP, evaluation for potential etiologies of these disorders, and long-term monitoring. Statements for which the group reached consensus to make no recommendation or could not reach consensus are discussed. Conclusions: This consensus helps define the minimal diagnostic evaluation and monitoring of children with ARP and CP. Even in areas in which we reached consensus, the quality of the evidence is weak, highlighting the need for further research. Improved understanding of the underlying cause will facilitate treatment development and targeting.