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2025

A molecular basis for milk allergen immune recognition in eosinophilic esophagitis
J Allergy Clin Immunol . 2025 Jan 31:S0091-6749(25)00050-8.

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A molecular basis for milk allergen immune recognition in eosinophilic esophagitis
J Allergy Clin Immunol . 2025 Jan 31:S0091-6749(25)00050-8.

Dilollo J, Hu A, Qu H, Canziani KE, Clement RL, McCright SJ, Shreffler WG, Hakonarson H, Spergel JM, Cerosaletti K, Hill DA.

PubMed

Link
IFNg signaling impairs Regulatory B cell function resulting in worse control of esophageal food allergy
Allergy. In Press.

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IFNg signaling impairs Regulatory B cell function resulting in worse control of esophageal food allergy
Allergy. In Press.

Clement RL, Dilollo J, Rodríguez-López EM, Guerrier CM, Hill DA.

PubMed

Link

Abstract

Background: Eosinophilic Esophagitis (EoE) is a chronic food allergy that causes esophageal inflammation and fibrosis; and manifests with symptoms of reflux, chest pain, swallowing difficulty, and food impactions. Though the prevalence of EoE is increasing by ~15% each year, our understanding of EoE immunopathology is limited. A noted feature of EoE is the presence of food-specific IgG4 antibodies in the circulation and esophageal tissue. Production of IgG4 is confined to IL-10⁺ B cells (Bregs) in other allergic diseases, suggesting Bregs may be present in EoE.

Methods: We examined circulating Bregs in patients with EoE milk allergy. In parallel, we performed mechanistic investigations of the role of Bregs in a murine model of food-antigen-dependent EoE. Flow cytometry and histologic analyses were used to assess esophageal and draining lymph node immune cells, and in vitro assays were used to evaluate Breg functional capacity.

Results: Breg frequency was reduced in both EoE milk allergic subjects and an EoE disease model. Murine Breg suppressive capacity was impaired during EoE-like inflammation. Inducible deletion of Breg-derived IL-10 worsened EoE-like inflammation, while adoptive transfer of IL-10 sufficient Bregs suppressed DC activation and improved esophageal eosinophilia. IFNg was sufficient to suppress Breg expansion and IL-10 production in vitro and contributed to Breg dysfunction and esophageal inflammation in vivo.

Conclusion: Bregs play an immunoregulatory role during EoE by controlling esophageal eosinophilia but are functionally impaired due to IFNg-mediated signaling. These findings have important implications for understanding EoE’s etiology and implementing future therapies that target IFNg.

2024

Risk Factors for Hospitalization in Subspecialty Patients with Severe Persistent Asthma
Respir Med . 2024 Dec:235:107867.

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Risk Factors for Hospitalization in Subspecialty Patients with Severe Persistent Asthma
Respir Med . 2024 Dec:235:107867.

Seshadri N, Faig W, Young LR, Hill DA.

PubMed

Link

Abstract

Background and Objectives: Children with severe persistent asthma managed by subspecialists represent a unique patient population. The factors predisposing these children to hospital admission are poorly understood. This study aimed to identify factors associated with future emergency department (ED) visits and hospitalization in this group.

Methods: A chart review was conducted for children with severe persistent asthma evaluated by a pulmonologist between 1/1/2021 and 6/30/2022. Asthma-related ED visits and hospitalizations were recorded from electronic medical records. Chi-square testing, mixed effects modeling, and logistic regression were used to analyze associations between patient characteristics and hospitalization. A secondary analysis evaluated factors contributing to ED visits.

Results: We identified 244 unique patients with 487 pulmonary clinic visits. Of these, 56% were black, 58% had public insurance, and 32% had a history of ICU admission for asthma. In the 12 months following a clinic visit, 84 (34%) patients had an ED visit, and 46 (19%) had at least one hospitalization. Secondhand smoke exposure (OR 2.74, 95% CI 1.16-6.45), public insurance (OR 3.37, 95% CI 1.46-7.82), and prior ICU admission (OR 2.29, 95% CI 1.09-4.79) were positively associated with hospitalization for asthma exacerbation. Among hospitalized patients, bronchopulmonary dysplasia (BPD) and gastroesophageal reflux disease (GERD) were linked to shorter time to admission.

Conclusions: Despite subspecialty care, children with severe persistent asthma exposed to cigarette smoke, with prior ICU admission, or with public insurance are at higher risk of subsequent ED visits and hospitalization. These findings will inform targeted interventions to prevent hospitalization in this patient population.
Eosinophilic gastrointestinal disorders and the role for the epithelium in pathogenesis and treatment
Current Opinion in Pediatrics. 2024 Dec 1;36(6):668-673

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Eosinophilic gastrointestinal disorders and the role for the epithelium in pathogenesis and treatment
Current Opinion in Pediatrics. 2024 Dec 1;36(6):668-673

Rodríguez-López EM, Hill DA.

PubMed

Abstract

Purpose of Review: This review aims to provide an overview of the current understanding of eosinophilic gastrointestinal disorders (EGIDs) and the role of the epithelium in influencing disease pathogenesis to inform and devise future therapeutic strategies.

Recent Findings: Changes in epithelial cell structure, functions, and integrity are observed in EGIDs. In eosinophilic esophagitis (EoE), the esophageal epithelium has been shown to play key roles in perpetuating the inflammatory response in EoE through the expression of pro-inflammatory cytokines and immunological cell-surface proteins. Similar mechanisms appear to exist in the other EGIDs, including eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). Because of the increasing rarity of each non-EoE EGID, research focusing on how the epithelium is modulating disease in each lower gastrointestinal compartment is still in its rudimentary stages.

Summary: While there has been significant progress in understanding the role of the epithelium in EoE, further research is needed to obtain a better understanding of the mechanisms mediating epithelial-immune crosstalk in non-EoE EGIDs. Using EoE-epithelial cell research to inform future EGID investigations could lead to the development of new therapeutic interventions, such as targeted therapies to restore epithelial barrier function and reduce inflammation, to improve rare disease-patient quality of life.
Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity
Nature Communications. 2024 Jun 25;15(1):5394

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Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity
Nature Communications. 2024 Jun 25;15(1):5394

Paneru BD, Chini J, McCright SJ, DeMarco N, Miller J, Joannas LD, Henao-Mejia J, Titchenell PM, Merrick DM, Lim HW, Lazar MA, Hill DA.

PubMed

Link

Abstract

Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.
Advances and ongoing challenges in eosinophilic gastrointestinal disorders
J Allergy Clin Immunol. 2024 Oct;154(4):882-892

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Advances and ongoing challenges in eosinophilic gastrointestinal disorders
J Allergy Clin Immunol. 2024 Oct;154(4):882-892

Wright BL, Abonia JP, Abud EM, Aceves SS, Ackerman SJ, Braskett M, Chang JW, Chehade M, Constantine GM, Davis CM, Dellon ES, Doyle AD, Durban R, Hill DA, Jensen ET, Kewalramani A, Khoury P, Klion AD, Kottyan L, Kuang FL, McGowan EC, Ruffner MA, Spencer LA, Spergel JM, Uchida AM, Wechsler JB, Pesek RD.

PubMed

Abstract

The Consortium of Eosinophilic Gastrointestinal disease Researchers (CEGIR) and The International Gastrointestinal Eosinophil Researchers (TIGERS) organized a day-long symposium at the 2024 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured new discoveries in basic and translational research and debates on the mechanisms and management of eosinophilic gastrointestinal diseases (EGIDs). Updates on recent clinical trials and consensus guidelines were also presented. Herein, we summarize the updates on EGIDs presented at the symposium.
COVID-19 and Asthma Onset in Children
Pediatrics. 2024 May 1;153(5)

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COVID-19 and Asthma Onset in Children
Pediatrics. 2024 May 1;153(5)

Senter JP, Aisenberg LK, Dudley JW, Luan X, Huang J, Kenyon CC, Hill DA.

PubMed

Link

Abstract

Objectives: Respiratory viral infections are risk factors for the onset of asthma in infants and children. Infection with the SARS-CoV-2 virus can cause severe lung inflammation and prolonged respiratory symptoms in some individuals. We sought to determine whether SARS-CoV-2 infection modified pediatric incident asthma risk.

Methods: This retrospective cohort study examined children ages 1-16 within the Children’s Hospital of Philadelphia Care Network who received PCR testing for SARS-CoV-2 between March 1, 2020 and February 28, 2021. Multivariable Cox regression models assessed the hazard ratio of new asthma diagnosis between SARS-CoV-2 PCR positive and SARS-CoV-2 PCR negative groups within an 18-month window of observation. Models were adjusted for demographic characteristics, socioeconomic variables, and atopic comorbidities.

Results: There were 27,423 subjects included in the study. In adjusted analyses, SARS-CoV-2 PCR positivity had no significant effect on the hazard of new asthma diagnosis (HR: 0.96; p = 0.79). Black race (HR: 1.49; p = 0.004), food allergies (HR: 1.26; p = 0.025), and allergic rhinitis (HR: 2.30; p < 0.001) significantly increased the hazard of new asthma diagnosis. Pre-term birth (HR: 1.48; p = 0.005) and body mass index (HR: 1.13; p < 0.001) significantly increased the hazard of new asthma diagnosis for children <5 years old.

Conclusions: SARS-CoV-2 PCR positivity was not associated with new asthma diagnosis in children within the observation period, while known risk factors for pediatric asthma were confirmed. This study informs the prognosis and care of children with a history of SARS-CoV-2 infection.

2023

The immune-epithelial interface in eosinophilic esophagitis: a conversation
Frontiers in Allergy. 2023 Oct 3:4:1270581

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The immune-epithelial interface in eosinophilic esophagitis: a conversation
Frontiers in Allergy. 2023 Oct 3:4:1270581

Hill DA, Muir AB.

PubMed
Breakthroughs in understanding and treating eosinophilic gastrointestinal diseases...
J Allergy Clin Immunol. 2023 Dec;152(6):1382-1393

Read More about Breakthroughs in understanding and treating eosinophilic gastrointestinal diseases...

Breakthroughs in understanding and treating eosinophilic gastrointestinal diseases...
J Allergy Clin Immunol. 2023 Dec;152(6):1382-1393

Chehade M, Wright BL, Atkins D, Aceves SS, Ackerman SJ, Assa'ad AH, Bauer M, Collins MH, Commins SP, Davis CM, Dellon ES, Doerfler B, Gleich GJ, Gupta SK, Hill DA, Jensen ET, Katzka D, Kliewer K, Kodroff E, Kottyan LC, Kyle S, Muir AB, Pesek RD, Peterson K, Shreffler WG, Spergel JM, Strobel MJ, Wechsler J, Zimmermann N, Furuta GT, Rothenberg ME.

PubMed

Abstract

The Consortium of Eosinophilic Gastrointestinal Diseases (CEGIR) and The International Gastrointestinal Eosinophil Researchers (TIGERs) organized a day-long symposium at the 2022 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured a review of recent discoveries in the basic biology and pathogenesis of eosinophilic gastrointestinal diseases (EGIDs) in addition to advances in our understanding of the clinical features of EGIDs. Diagnostic and management approaches were reviewed and debated, and clinical trials of emerging therapies were highlighted. Herein, we briefly summarize the breakthrough discoveries in EGIDs.
The role of extracellular vesicle-derived miRNAs in adipose tissue function and metabolic health
Immunometabolism. 2023 Jul 26;5(3):e00027

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The role of extracellular vesicle-derived miRNAs in adipose tissue function and metabolic health
Immunometabolism. 2023 Jul 26;5(3):e00027

Paneru B, Hill DA.

PubMed

Abstract

Extracellular vesicles (EVs) are nanometer size lipid particles that are released from virtually every cell type. Recent studies have shown that miRNAs carried by EVs play important roles in inter-cellular and inter-organ communication. In the context of obesity and insulin resistance, EV derived miRNAs functionally bridge major metabolic organs including the adipose tissue, skeletal muscle, liver, and pancreas, to regulate insulin secretion and signaling. As a result, many of these EV derived miRNAs have been proposed as potential disease biomarkers and/or therapeutic agents. However, the field’s knowledge of EV miRNA-mediated regulation of mammalian metabolism is still in its infancy. Here, we review the evidence indicating that EV-derived miRNAs provide cell-to-cell and organ-to-organ communication to support metabolic health, highlight the potential medical relevance of these discoveries, and discuss the most important knowledge gaps and future directions for this field.
Patterns in the Development of Pediatric Allergy
Pediatrics. 2023 Aug 1;152(2)

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Patterns in the Development of Pediatric Allergy
Pediatrics. 2023 Aug 1;152(2)

Gabryszewski S, Dudley J, Shu D, Faerber JA, Grundmeier RW, Fiks AG, Hill DA.

PubMed

Link

Abstract

Objectives: Describe clinical and epidemiologic patterns of pediatric allergy using longitudinal electronic health records (EHRs) from a multistate consortium of US practices.

Methods: Using the multistate Comparative Effectiveness Research through Collaborative Electronic Reporting EHR database, we defined a cohort of 218 485 children (0–18 years) who were observed for $5 years between 1999 and 2020. Children with atopic dermatitis (AD), immunoglobulin E–mediated food allergy (IgE-FA), asthma, allergic rhinitis (AR), and eosinophilic esophagitis (EoE) were identified using a combination of diagnosis codes and medication prescriptions. We determined age at diagnosis, cumulative incidence, and allergic comorbidity.

Results: Allergic disease cumulative (and peak age of) incidence was 10.3% (4 months) for AD, 4.0% (13 months) for IgE-FA, 20.1% (13 months) for asthma, 19.7% (26 months) for AR, and 0.11% (35 months) for EoE. The most diagnosed IgE-FAs were peanut (1.9%), egg (0.8%), and shellfish (0.6%). A total of 13.4% of children had $2 allergic conditions, and respiratory allergies (ie, asthma, AR) were commonly comorbid with each other, and with other allergic conditions.

Conclusions: We detail pediatric allergy patterns using longitudinal, health care provider-based data from EHR systems across multiple US states and varied pediatric practice types. Our results support the population-level allergic march progression and indicate high rates of comorbidity among children with food and respiratory allergies.
Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis
Sci Transl Med. 2023 Feb 8;15(682):eadc9653

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Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis
Sci Transl Med. 2023 Feb 8;15(682):eadc9653

Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MA.

PubMed

Abstract

Current therapeutic strategies for treating nonalcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mice and humans. At the nonalcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which were mainly demarcated by receptor tyrosine kinase ephrin type B receptor 2 (EphB2). EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomous inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in a mouse model of NASH. Thus, EphB2-expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.

2022

Effects of oral immunotherapy on immune tolerance
Ann Allergy Asthma Immunol. 2022 Dec;129(6):659-660

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Effects of oral immunotherapy on immune tolerance
Ann Allergy Asthma Immunol. 2022 Dec;129(6):659-660

Capucilli P, Hill DA

PubMed
Altered adipose tissue macrophage populations in people with HIV on integrase inhibitor-containing ART
AIDS. 2022 Sep 1;36(11):1493-1500

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Altered adipose tissue macrophage populations in people with HIV on integrase inhibitor-containing ART
AIDS. 2022 Sep 1;36(11):1493-1500

Vakili S, Paneru B, Guerrier CM, Miller J, Baumrin E, Forrestel A, Lynn K, Frank I, Lo Re V, Collman RG, Hill DA

PubMed

Link

Abstract

Objective: Antiretroviral therapy (ART) extends the life of people living with HIV (PWH), but these individuals are at increased risk for obesity, dyslipidemia, diabetes, and cardiovascular disease. These comorbidities may be a consequence of HIV-related chronic inflammation and/or adverse effects of ART on tissue regulatory adipose tissue macrophages (ATM). We sought to determine the effects of HIV/ART on metabolically beneficial ATM populations and functions.

Design: We examined subcutaneous ATMs from PWH on integrase inhibitor-containing ART (n=5) and uninfected persons (n=9). We complemented these studies with ex vivo and in vitro analyses of peripheral blood mononuclear cell (PBMC) and murine macrophage lipid metabolism and fatty acid oxidation gene expression.

Methods: ATM populations were examined by flow cytometry. Macrophage lipid metabolism and fatty acid oxidation gene expression were examined by Seahorse assay and quantitative PCR.

Results: Adipose tissue from PWH had reduced populations of metabolically activated CD9⁺ ATMs compared to that of uninfected controls (P<0.001). PBMCs of PWH had lower fatty acid metabolism compared to those of uninfected controls (P<0.01). Analysis of murine macrophages revealed that dolutegravir reduced lipid metabolism (P<0.001) and increased expression of the fatty acid beta-oxidation enzyme Enoyl-CoA Hydratase, Short Chain 1 (P<0.05).

Conclusions: We report the loss of metabolically beneficial ATM populations in PWH on ART, altered fatty acid metabolism of blood immune cells, and evidence that dolutegravir alters macrophage fatty acid metabolism. Future studies should examine direct or indirect effects and mechanisms of dolutegravir, and other integrase inhibitors and ART classes, on fatty acid beta-oxidation.
Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction
Cell Rep. 2022 Jun 14;39(11):110942

Read More about Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction

Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction
Cell Rep. 2022 Jun 14;39(11):110942

Sterling JK, Baumann B, Foshe S, Voigt A, Guttha S, Alnemri A, McCright SJ, Li M, Zauhar RJ, Montezuma SR, Kapphahn RJ, Chavali VRM, Hill DA, Ferrington DA, Stambolian D, Mullins RF, Merrick D, Dunaief JL.

PubMed

Abstract

Age-related macular degeneration (AMD), the leading cause of irreversible blindness among Americans over 50, is characterized by dysfunction and death of retinal pigment epithelial (RPE) cells. The RPE accumulates iron in AMD, and iron overload triggers RPE cell death in vitro and in vivo. However, the mechanism of RPE iron accumulation in AMD is unknown. We show that high-fat-diet-induced obesity, a risk factor for AMD, drives systemic and local inflammatory circuits upregulating interleukin-1β (IL-1β). IL-1β upregulates RPE iron importers and downregulates iron exporters, causing iron accumulation, oxidative stress, and dysfunction. We term this maladaptive, chronic activation of a nutritional immunity pathway the cellular iron sequestration response (CISR). RNA sequencing (RNA-seq) analysis of choroid and retina from human donors revealed that hallmarks of this pathway are present in AMD microglia and macrophages. Together, these data suggest that inflamed adipose tissue, through the CISR, can lead to RPE pathology in AMD.
Improvement in Eosinophilic Esophagitis when using Dupilumab for other Indications or Compassionate Use
Ann Allergy Asthma Immunol. 2022 May;128(5):589-593

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Improvement in Eosinophilic Esophagitis when using Dupilumab for other Indications or Compassionate Use
Ann Allergy Asthma Immunol. 2022 May;128(5):589-593

Spergel BS, Ruffner MA, Godwin B, Liacouras CA, Cianferoni A, Gober L, Hill DA, Brown-Whitehorn TA, Chaiboonma K, Aceves SA, Muir AM, Spergel JM

PubMed

Abstract

Background: Dupilumab has been approved to treat atopic dermatitis, asthma, and nasal polyps and is in active clinical trials for treatment of Eosinophilic Esophagitis (EoE). Given shared immunopathology, we hypothesized that EoE symptoms and inflammation would improve when dupilumab therapy was used for other allergic indications.

Objective: To measure the clinical and histologic response in EoE to dupilumab when treating other atopic diseases.

Methods: We completed a retrospective chart review of all patients at Children's Hospital of Philadelphia and Rady Children Hospital who were prescribed dupilumab for atopic dermatitis, asthma, or nasal polyps and had a concomitant clinical diagnosis of EoE. Demographic information along with histology, symptom scores, medications, and diet information were collected. Response to dupilumab was evaluated.

Results: 45 patients were identified. 11 patients were prescribed dupilumab for asthma, 27 for atopic dermatitis, 3 for nasal polyps, and 4 for compassionate use for EoE. There was no follow-up data for 8 patients. Follow-up histology was available for 26 patients: 22 of 26 had less than 6 eosinophils/high power field (eos/hpf) after initiation of dupilumab with significant improvement (pre: 52.9 + 35.1 to post: 4.5 + 10.9 eos/hpf, p<0.005). 28 patients had improvement of symptoms with 24 patients reporting complete resolution of symptoms after dupilumab initiation. Reductions in EoE treatment medications (swallowed steroids, PPIs), or expansion of diet, occurred in 29 patients treated with dupilumab.

Conclusion: Dupilumab therapy initiated for atopic disease effectively induces symptomatic and histologic remission of esophageal disease and reduces the need for EoE-directed therapy in patients with concomitant EoE.
The importance of using core outcome measures during therapeutic studies of eosinophilic esophagitis
J Allergy Clin Immunol. 2022 Feb;149(2):541-542

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The importance of using core outcome measures during therapeutic studies of eosinophilic esophagitis
J Allergy Clin Immunol. 2022 Feb;149(2):541-542

Hill DA

PubMed
COVID-19 Pandemic-Related Reductions in Pediatric Asthma Exacerbations Corresponded with an Overall Decrease in Respiratory Viral Infections
J Allergy Clin Immunol Pract. 2022 Jan;10(1):91-99

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COVID-19 Pandemic-Related Reductions in Pediatric Asthma Exacerbations Corresponded with an Overall Decrease in Respiratory Viral Infections
J Allergy Clin Immunol Pract. 2022 Jan;10(1):91-99

Sayed S, Diwadkar AR, Dudley JW, O’Brien J, Dvorin D, Kenyon CK, Himes BE, Hill DA, Henrickson SE

PubMed

Link

Abstract

Background: Respiratory viruses, air pollutants, and aeroallergens are all implicated in worsening pediatric asthma symptoms, but their relative contributions to asthma exacerbations are poorly understood. A significant decrease in asthma exacerbations has been observed during the COVID-19 pandemic, providing a unique opportunity to study how major asthma triggers correlate with asthma activity.

Objective: To determine whether changes in respiratory viruses, air pollutants, and/or aeroallergens during the COVID-19 pandemic were concomitant with decreased asthma exacerbations.

Methods: Health care utilization and respiratory viral testing data between January 1st, 2015 and December 31st, 2020 were extracted from the Children’s Hospital of Philadelphia (CHOP) Care Network’s electronic health record. Air pollution and allergen data were extracted from U.S. Environmental Protection Agency public databases and a National Allergy Bureau-certified station, respectively. Pandemic data (2020) were compared to historical data.

Results: Recovery of in-person asthma encounters during phased re-opening (June 6^th – November 15^th, 2020) was uneven: primary care well and specialty encounters reached 94% and 74% of pre-pandemic levels, respectively, while primary care sick and hospital encounters reached 21% and 40% of pre-pandemic levels, respectively. During the pandemic, Influenza A and Influenza B decreased to <1% of pre-pandemic case frequency, while RSV and rhinovirus infections decreased to 3.4% and 26% of pre-pandemic levels, respectively. No changes in air pollution or aeroallergen levels relative to historical observations were noted.

Conclusion: Our results suggest that viral respiratory infections are a primary driver of pediatric asthma exacerbations. These findings have broad relevance to both clinical practice and the development of health policies aimed at reducing asthma morbidity.

2021

Peripheral markers of allergen-specific immune activation predict clinical allergy in eosinophilic esophagitis
Allergy. 2021 Nov;76(11):3470-3478

Read More about Peripheral markers of allergen-specific immune activation predict clinical allergy in eosinophilic esophagitis

Peripheral markers of allergen-specific immune activation predict clinical allergy in eosinophilic esophagitis
Allergy. 2021 Nov;76(11):3470-3478

Dilollo J, Rodríguez-López EM, Wilkey L, Martin EK, Spergel JM, Hill DA

PubMed

Link

Abstract

Background: Eosinophilic esophagitis (EoE) is a T cell-mediated disease that is caused by specific foods and results in esophageal dysfunction. Existing allergy testing modalities are not helpful when attempting to identify EoE-causal foods necessitating empiric food elimination and recurrent endoscopy. The goal of this study was to identify and compare allergen-specific immune features that can be assayed in a minimally-invasive manner to predict clinical food allergy in EoE.

Methods: We obtained blood samples from control subjects (n=17), subjects with clinical EoE milk allergy (n=17), and subjects with IgE-mediated milk allergy (n=9). We measured total and milk-specific plasma IgG4 levels and peripheral memory CD4⁺ T helper (T_H) cell proliferation and cytokine production after stimulation with endotoxin-depleted milk proteins. Sensitivity and specificity for predicting clinical EoE milk allergy was calculated and compared between approaches.

Results: Total and milk-specific IgG4 levels were not significantly different between control subjects and subjects with clinical EoE milk allergy. Stimulation with milk proteins caused T_H lymphocytes from subjects with clinical EoE milk allergy to proliferate more (%P1 of 38.3±4.6 vs 12.7±2.8, P<0.0001), and produce more type 2 cytokines (%IL-4⁺ of 33.7±2.8 vs 6.9±1.6, P<0.0001), than cells from control subjects. Milk-dependent memory T_H cell proliferation (sensitivity and specificity of 88 and 82%, respectively) and IL-4 production (sensitivity and specificity of 100%) most strongly predicted clinical EoE milk allergy.

Conclusions: Peripheral markers of allergen-specific immune activation may be useful in identifying EoE-causal foods. Assaying milk-dependent IL-4 production by circulating memory T_H lymphocytes most accurately predicts clinical EoE milk allergy.
One march, many paths: Insights into allergic march trajectories
Ann Allergy Asthma Immunol. 2021 Sep;127(3):293-300

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One march, many paths: Insights into allergic march trajectories
Ann Allergy Asthma Immunol. 2021 Sep;127(3):293-300

Gabryszewski SJ, Hill DA

PubMed

Abstract

Objective: The classical allergic march model posits that atopy begins in infancy with atopic dermatitis and progresses to asthma and allergic rhinitis in a subset of individuals. The growing prevalence and severity of allergic diseases has prompted renewed interest in refining this model. This review outlines epidemiologic evidence for the existence of allergic march trajectories (distinct paths of atopy development in individuals), reviews the roles that genetics, environment, and disease endotypes play in determining trajectory outcomes, and discusses the clinical utility of the trajectory model.

Data Sources: PubMed search of English-language articles and reviews without date limits pertaining to the epidemiology, genetics, and immunologic mechanisms of allergic march trajectories and disease endotypes.

Study Selections: Studies and reviews were selected based on their high quality and direct relevance to the review topic.

Results: Recent work in the field has shown that IgE-mediated food allergy and eosinophilic esophagitis are components of the allergic march. Further, the field is acknowledging that variability exists in the number and sequence of allergic manifestations that individuals develop. These allergic march pathways, or trajectories, are influenced by genetic, environmental, and psychosocial factors that are incompletely understood.

Conclusion: Continued elucidation of the landscape and origins of allergic march trajectories will inform efforts to personalize allergic disease prevention, diagnosis, and treatment.
Early-life environmental exposures associate with individual and cumulative allergic morbidity
Pediatr Allergy Immunol. 2021 Jul;32(5):1089-1093

Read More about Early-life environmental exposures associate with individual and cumulative allergic morbidity

Early-life environmental exposures associate with individual and cumulative allergic morbidity
Pediatr Allergy Immunol. 2021 Jul;32(5):1089-1093

Gabryszewski SJ, Dudley JW, Grundmeier RW, Hill DA

PubMed

Link

Abstract

Several early-life environmental factors have been associated with altered risk for the development and/or severity of individual allergic conditions. These include exposures implicated in the modulation of the microbiome, such as infant delivery mode, diet, and exposure to antibiotics and antacids. The impact of these early-life factors on allergic multimorbidity remains unknown. To address this knowledge gap, we used electronic medical records for a birth cohort of 158,510 children to track development of atopic dermatitis (AD), IgE-mediated food allergy (IgE-FA), asthma, and allergic rhinitis (AR) in individual children over time. We measured hazard ratios (HRs), adjusted for birth year, race, ethnicity, sex, and insurance payer type, to assess how development of both individual and multiple allergic conditions is influenced by birth mode, feeding practice during the first year of life, or exposure to antibiotics and/or antacids during the first six months of life. We found that vaginal delivery (VD; HR 0.89, 0.83, 0.84, 0.79 for at least 1, 2, 3, 4 conditions, respectively; p≤0.001) and exclusive breastmilk (BM) feeding (HR 0.74, 0.75, 0.89, for at least 1, 2, 3 conditions, respectively; p≤0.001) are associated with reduced cumulative allergic burden, while antibiotic exposure (HR 1.40, 1.44, 1.48, 1.63 for at least 1, 2, 3, 4 conditions, respectively; p≤0.001) and antacid exposure (HR 1.26, 1.35, 1.32 for at least 1, 2, 3 conditions, respectively; p≤0.001) are associated with increased cumulative allergic burden during childhood. This work expands our understanding of how a child’s early-life environment may influence their risk of allergy development and progression.
Prevalence of Asthma in Hospitalized and Non-Hospitalized Children with COVID-19
J Allergy Clin Immunol Pract. 2021 May;9(5):2077-2079.e2

Read More about Prevalence of Asthma in Hospitalized and Non-Hospitalized Children with COVID-19

Prevalence of Asthma in Hospitalized and Non-Hospitalized Children with COVID-19
J Allergy Clin Immunol Pract. 2021 May;9(5):2077-2079.e2

Floyd GC, Dudley JW, Xiao R, Feudtner C, Taquechel K, Miller K, Henrickson SE, Hill DA, Kenyon CK

PubMed

Abstract

Background: Several underlying medical conditions are associated with severe presentations of coronavirus disease 2019 (COVID-19) in children, but the association between existing asthma and COVID-19 severity is unclear.

Objective: Our primary objective was to determine whether an existing asthma diagnosis was associated with hospitalization in a cohort of children testing positive for COVID-19.

Methods: We extracted 979 electronic medical records for children ≤21 years of age with a positive polymerase chain reaction (PCR) test for severe acute respiratory coronavirus 2 (March 17^th – August 26^th 2020) in a large pediatric health system spanning outpatient, emergency department (ED), and inpatient settings. We used multivariable logistic regression models to determine the association between current asthma diagnosis and COVID-19-related hospitalization risk, adjusting for demographic and clinical characteristics including age, sex, race, ethnicity, payer, concurrent obesity diagnosis, and number of complex chronic conditions (CCC).

Results: Of the 979 children testing positive for COVID-19 across all care settings, 205 (21%) had a current asthma diagnosis. Of the 121 (12%) children hospitalized within 14 days of positive COVID-19 PCR, 11 (9%) had asthma. After adjusting for the above demographic and clinical characteristics, asthma diagnosis was associated with a lower odds of hospitalization for COVID-19 (OR: 0.28; 95%CI: 0.14-0.55; P <.001).

Conclusion: In a large cohort of children testing positive for COVID-19, current asthma diagnosis was associated with lower odds of subsequent hospitalization. Further work using multi-center data is needed to confirm this inverse association and explore potential explanations for this phenomenon.
Conserved IFN Signature between Adult and Pediatric Eosinophilic Esophagitis
J Immunol. 2021 Mar 15;206(6):1361-1371

Read More about Conserved IFN Signature between Adult and Pediatric Eosinophilic Esophagitis

Conserved IFN Signature between Adult and Pediatric Eosinophilic Esophagitis
J Immunol. 2021 Mar 15;206(6):1361-1371

Ruffner MA, Hu A, Dilollo J, Benocek K, Shows D, Gluck M, Spergel JM, Ziegler SF, Hill DA, Cerosaletti K.

PubMed

Link

Abstract

Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus that occurs in both children and adults. Previous studies of affected tissue from pediatric cohorts have identified prominent signatures of eosinophilia and type 2 inflammation. However, the details of the immune response in adults with EoE are still being elucidated. To determine whether EoE in adults shares inflammatory profiles with those observed in children, we performed RNA sequencing of paired human esophageal biopsies and blood samples from adults with EoE or gastroesophageal reflux disease. Unbiased analysis of differentially expressed genes in tissue revealed a strong IFN signature that was significantly enriched in EoE patients as compared with patients with gastroesophageal reflux disease. Both type I and type II IFN–responsive genes were upregulated in adult biopsies, but not in blood. A similar increase in expression of IFN gene sets was observed in pediatric EoE biopsies as compared with non-EoE samples, and in public pediatric and adult RNA-sequencing data. Finally, we found that human peripheral CD4+ T cells from children with EoE produce IFN-g upon activation with EoE-causal allergens. Together, this work identifies a conserved IFN signature in pediatric and adult EoE, highlighting a role for non–type 2 inflammatory networks in the disease process in humans.
Unsupervised Modeling and Genome-Wide Association Identify Novel Features of Allergic March Trajectories
J Allergy Clin Immunol. 2021 Feb;147(2):677-685.e10

Read More about Unsupervised Modeling and Genome-Wide Association Identify Novel Features of Allergic March Trajectories

Unsupervised Modeling and Genome-Wide Association Identify Novel Features of Allergic March Trajectories
J Allergy Clin Immunol. 2021 Feb;147(2):677-685.e10

Gabryszewski SJ, Chang X, Dudley JW, Mentch F, March M, Holmes JH, Moore J, Grundmeier RW, Hakonarson H, Hill DA.

PubMed

Link

Abstract

Background: The allergic march refers to the natural history of allergic conditions during infancy and childhood. However, population-level disease incidence patterns do not necessarily reflect the development of allergic disease in individuals. A better understanding of the factors that predispose to different allergic trajectories is needed.

Objective: Determine the demographic and genetic features that associate with the major allergic march trajectories.

Methods: Presence or absence of common allergic conditions (atopic dermatitis, AD; IgE-mediated food allergy, IgE-FA; asthma; and allergic rhinitis, AR) was ascertained in a pediatric primary care birth cohort of 158,510 subjects. Hierarchical clustering and decision tree modeling was used to associate demographic features with allergic outcomes. Genome-wide association study (GWAS) tested for risk loci associated with specific allergic trajectories.

Results: We found an association between self-identified “Black” race and progression from AD to asthma. Conversely, “Asian or Pacific Islander” race associated with AD to IgE-FA, and “White” race associated with AD to AR. GWAS of trajectory groups identified risk loci associated with progression from AD to Asthma (rs60242841), and AD to AR (rs9565267, rs151041509, rs78171803). Consistent with our epidemiologic associations, rs60242841 is more common in individuals of African ancestry (AA) than European ancestry (EA), while rs9565267 and rs151041509 are more common in EA than AA individuals.

Conclusion: We identify novel associations between race and progression along distinct allergic trajectories. Ancestral genetic differences may contribute to these associations. These results uncover important health disparities, refine the concept of the allergic march, and represent a step towards developing individualized medical approaches for these conditions.

2020

Pediatric Asthma Healthcare Utilization, Viral Testing, and Air Pollution Changes during the COVID-19 Pandemic
J Allergy Clin Immunol Pract. Nov-Dec 2020;8(10):3378-3387

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Pediatric Asthma Healthcare Utilization, Viral Testing, and Air Pollution Changes during the COVID-19 Pandemic
J Allergy Clin Immunol Pract. Nov-Dec 2020;8(10):3378-3387

Taquechel K, Diwadkar AR, Sayed S, Dudley JW, Grundmeier RW, Kenyon CC, Henrickson SE, Himes BE, Hill DA

PubMed

Link

Abstract

Background: The COVID-19 pandemic caused dramatic changes in daily routines and healthcare utilization and delivery patterns in the United States. Understanding the influence of these changes and associated public health interventions on asthma care is important to determine effects on patient outcomes and identify measures that will ensure optimal future healthcare delivery.

Objective: We sought to identify changes in pediatric asthma-related healthcare utilization, respiratory viral testing, and air pollution during the COVID-19 pandemic.

Methods: For the time period Jan 17-May 17, 2015-2020, asthma-related encounters and weekly summaries of respiratory viral testing data were extracted from Children's Hospital of Philadelphia (CHOP) electronic health records, and pollution data for four criteria air pollutants were extracted from AirNow. Changes in encounter characteristics, viral testing patterns, and air pollution before and after Mar 17, 2020, the date public health interventions to limit viral transmission were enacted in Philadelphia, were assessed and compared to data from 2015-2019 as a historical reference.

Results: After Mar 17, 2020, in-person asthma encounters decreased by 87% (outpatient) and 84% (emergency + inpatient). Video telemedicine, which was not previously available, became the most highly utilized asthma encounter modality (61% of all visits), and telephone encounters increased by 19%. Concurrently, asthma-related systemic steroid prescriptions and frequency of rhinovirus test positivity decreased, while air pollution levels did not substantially change, compared to historical trends.

Conclusion: The COVID-19 pandemic in Philadelphia was accompanied by changes in pediatric asthma healthcare delivery patterns, including reduced admissions and systemic steroid prescriptions. Reduced rhinovirus infections may have contributed to these patterns.
Initial Effects of the COVID-19 Pandemic on Pediatric Asthma Emergency Department Utilization
J Allergy Clin Immunol Pract. 2020 Sep;8(8):2774-2776.e1

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Initial Effects of the COVID-19 Pandemic on Pediatric Asthma Emergency Department Utilization
J Allergy Clin Immunol Pract. 2020 Sep;8(8):2774-2776.e1

Kenyon CC, Hill DA, Henrickson SE, Bryant-Stephens TC, Zorc JJ.

PubMed
Elevated Atopic Comorbidity in Patients with Food Protein-Induced Enterocolitis
J Allergy Clin Immunol Pract. 2020 Mar;8(3):1039-1046

Read More about Elevated Atopic Comorbidity in Patients with Food Protein-Induced Enterocolitis

Elevated Atopic Comorbidity in Patients with Food Protein-Induced Enterocolitis
J Allergy Clin Immunol Pract. 2020 Mar;8(3):1039-1046

Ruffner MA, Wang KY, Dudley JW, Cianferoni A, Grundmeier RW, Spergel JM, Brown-Whitehorn TF, Hill DA.

PubMed

Link

Abstract

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. Its relationship to the major atopic manifestations (atopic dermatitis [AD], IgE-mediated food allergy [IgE-FA], allergic rhinitis [AR], asthma) is not understood.

Objective: To determine the clinical characteristics, epidemiologic features, and natural history of FPIES in relation to the major atopic manifestations.

Methods: We examined our primary care birth cohort of 158,510 pediatric patients, of whom 214 patients met 2017 FPIES diagnostic criteria. We measured the influence of FPIES on developing subsequent atopic disease.

Results: Pediatric FPIES incidence was between 0.17% and 0.42% depending on birth year. As in prior reports, most patients had an acute presentation (78%), and milk, soy, oat, rice, potato, and egg were common triggers. The mean age of diagnosis was 6.8 months. Atopic comorbidity was higher in patients with FPIES compared with healthy children (AD, 20.6% vs 11.7%; IgE-FA, 23.8% vs 4.0%; asthma, 26.6% vs 18.4%; AR, 28.0% vs 16.7%; P < .001 χ²). However, longitudinal analyses indicated that prior FPIES did not influence the rate of atopy development.

Conclusions: The incidence of FPIES in our cohort was initially low, but is increasing. Food allergen distribution, presentation, and age of onset are similar to prior reports. Patients with FPIES have high rates of atopic comorbidity. However, longitudinal analysis does not support direct causation as the etiology of these associations. Rather it suggests a shared predisposition to both types of allergy, or associative bias effects. This work refines our understanding of the natural history of FPIES by elucidating associations between FPIES and atopy.

2019

Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis
Am J Hum Genet. 2019 Sep 5;105(3):549-561

Read More about Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis

Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis
Am J Hum Genet. 2019 Sep 5;105(3):549-561

Bosticardo M, Yamazaki Y, Cowan J, Giardino G, Corsino C, Scalia G, Prencipe R, Ruffner M, Hill DA, Sakovich I, Yemialyanava I, Tam JS, Padem N, Elder ME, Sleasman JW, Perez E, Niebur H, Seroogy CM, Sharapova S, Gebbia J, Kleiner GI, Peake J, Abbott JK, Gelfand EW, Crestani E, Biggs C, Butte MJ, Hartog N, Hayward A, Chen K, Heimall J, Seeborg F, Bartnikas LM, Cooper MA, Pignata C, Bhandoola A, Notarangelo LD.

PubMed

Abstract

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4⁺ but lower than normal CD8⁺ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1^nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.
Allergic Comorbidity in Eosinophilic Esophagitis: Mechanistic Relevance and Clinical Implications
Clin Rev Allergy Immunol. 2019 Aug;57(1):111-127

Read More about Allergic Comorbidity in Eosinophilic Esophagitis: Mechanistic Relevance and Clinical Implications

Allergic Comorbidity in Eosinophilic Esophagitis: Mechanistic Relevance and Clinical Implications
Clin Rev Allergy Immunol. 2019 Aug;57(1):111-127

Capucilli P, Hill DA.

PubMed

Abstract

Allergic eosinophilic esophagitis (EoE) is a chronic, allergen-mediated inflammatory disease of the esophagus, and the most common cause of prolonged dysphagia in children and young adults in the developed world. While initially undistinguished from gastroesophageal reflux disease-associated esophageal eosinophilia, EoE is now recognized as a clinically distinct entity that shares fundamental inflammatory features of other allergic conditions and is similarly increasing in incidence and prevalence. The clinical and epidemiologic associations between EoE and other allergic manifestations are well established. In addition to exaggerated rates of atopic dermatitis, IgE-mediated food allergy, asthma, and allergic rhinitis in EoE patients, each of these allergic manifestations imparts individual and cumulative risk for subsequent EoE diagnosis. As such, EoE may be a member of the "allergic march"-the natural history of allergic manifestations during childhood. Several determinants likely contribute to the relationship between these conditions, including shared genetic, environmental, and immunologic factors. Herein, we present a comprehensive review of allergic comorbidity in EoE. We discuss areas of the genome associated with both EoE and other allergic diseases, including the well-studied variants encoding thymic stromal lymphopoietin and calpain 14, among other "atopic" regions. We summarize ways that environmental factors (such as microbiome-altering pressures and aeroallergen exposure) may predispose to multiple allergic conditions including EoE. Finally, we touch on some fundamental features of type 2 inflammation, and the resulting implications for the development of multiple allergic manifestations. We conclude with an analysis of the "type 2" biologics, and how mechanistic similarities between EoE and the other allergic manifestations have important implications for screening and treatment of the allergic patient.
Eosinophilic esophagitis during sublingual and oral allergen immunotherapy
Curr Opin Allergy Clin Immunol. 2019 Aug;19(4):350-357

Read More about Eosinophilic esophagitis during sublingual and oral allergen immunotherapy

Eosinophilic esophagitis during sublingual and oral allergen immunotherapy
Curr Opin Allergy Clin Immunol. 2019 Aug;19(4):350-357

Cafone J, Capucilli P, Hill DA, Spergel JM.

PubMed

Abstract

Purpose of review: The aim of this review is to discuss the current evidence regarding the development of eosinophilic esophagitis (EoE) in individuals undergoing oral and sublingual immunotherapy (SLIT) for both food and environmental allergens. Cumulative incidence of EoE in patients on allergen immunotherapy for peanut, milk, and egg is estimated.

Recent findings: De novo development of EoE in patients undergoing oral and SLIT has been demonstrated on the scale of case reports and prospective randomized trials. However, few individuals with EoE-like symptoms during immunotherapy undergo endoscopy, and the long-term outcomes of immunotherapy-associated EoE are unknown.

Summary: Evidence exists to suggest that allergen immunotherapy could place individuals at risk for the development of EoE, the true incidence of which may vary depending on antigen exposure and methods used to define the condition.
Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner
Cell. 2019 Jul 25;178(3):686-698.e14

Read More about Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner

Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner
Cell. 2019 Jul 25;178(3):686-698.e14

Jaitin DA, Adlung L, Thaiss CA, Weiner A, Li B, Descamps H, Lundgren P, Bleriot C, Liu Z, Deczkowska A, Keren-Shaul H, David E, Zmora N, Eldar SM, Lubezky N, Shibolet O, Hill DA, Lazar MA, Colonna M, Ginhoux F, Shapiro H, Elinav E, Amit I.

PubMed

Link

Abstract

Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2⁺ lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.
Screening children for eosinophilic esophagitis: allergic and other risk factors
Expert Rev Clin Immunol. 2019 Apr;15(4):315-318

Read More about Screening children for eosinophilic esophagitis: allergic and other risk factors

Screening children for eosinophilic esophagitis: allergic and other risk factors
Expert Rev Clin Immunol. 2019 Apr;15(4):315-318

Ruffner MA, Capucilli P, Hill DA, Spergel JM.

PubMed

2018

Epithelial acid imbalance in patients with eosinophilic esophagitis
J Allergy Clin Immunol. 2018 Dec;142(6):1757-1758

Read More about Epithelial acid imbalance in patients with eosinophilic esophagitis

Epithelial acid imbalance in patients with eosinophilic esophagitis
J Allergy Clin Immunol. 2018 Dec;142(6):1757-1758

Hill DA, Spergel JM.

PubMed
Eosinophilic Esophagitis Is a Late Manifestation of the Allergic March
J Allergy Clin Immunol Pract. 2018 Sep - Oct;6(5):1528-1533

Read More about Eosinophilic Esophagitis Is a Late Manifestation of the Allergic March

Eosinophilic Esophagitis Is a Late Manifestation of the Allergic March
J Allergy Clin Immunol Pract. 2018 Sep - Oct;6(5):1528-1533

Hill DA, Grundmeier RW, Ramos M, Spergel JM.

PubMed

Link

Abstract

Background: The allergic march describes the natural history of allergic conditions as they develop during childhood. Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease that can be triggered by specific foods. Despite its allergic pathophysiology, the epidemiologic relationship between EoE and established members of the allergic march is unknown.

Objective: We sought to determine whether EoE meets epidemiologic criteria for being considered a member of the allergic march.

Methods: Using a primary care birth cohort of 130,435 children, we determined the natural histories of atopic dermatitis (AD), IgE-mediated food allergy (IgE-FA), asthma, EoE, and allergic rhinitis (AR) in individual patients. We then performed case-control analyses to establish the extent that existing allergic conditions influence the rate of subsequent EoE diagnosis.

Results: A total of 139 children developed EoE during the observation period (prevalence of 0.11%). The peak age of EoE diagnosis was 2.6 years, as compared with 0.3 years, 1 year, 1.1 years, and 2.1 years for AD, IgE-FA, asthma, and AR, respectively. The presence of AD (hazard ratio [HR] 3.2, 95% confidence interval [CI] 2.2-4.6), IgE-FA (HR 9.1, 95% CI 6.5-12.6), and asthma (HR 1.9, 95% CI 1.3-2.7) was independently and cumulatively associated with subsequent EoE diagnosis. The presence of AR was associated with subsequent EoE diagnosis (HR 2.8, 95% CI 2.0-3.9), and the presence of EoE was associated with subsequent AR diagnosis (HR 2.5, 95% CI 1.7-3.5).

Conclusions: Allergic comorbidities are positively associated with EoE diagnosis. Together, our findings suggest that EoE is a late manifestation of the allergic march.
A march by any other name
Ann Allergy Asthma Immunol. 2018 Jul;121(1):137-138

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A march by any other name
Ann Allergy Asthma Immunol. 2018 Jul;121(1):137-138

Hill DA, Camargo CA Jr, Paller AS, Spergel JM.

PubMed
Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue
Proc Natl Acad Sci U S A. 2018 May 29;115(22):E5096-E5105

Read More about Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue

Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue
Proc Natl Acad Sci U S A. 2018 May 29;115(22):E5096-E5105

Hill DA, Lim HW, Kim YH, Ho WY, Foong YH, Nelson VL, Nguyen HCB, Chegireddy K, Kim J, Habertheuer A, Vallabhajosyula P, Kambayashi T, Won KJ, Lazar MA.

PubMed

Link

Abstract

Obesity is characterized by an accumulation of macrophages in adipose, some of which form distinct crown-like structures (CLS) around fat cells. While multiple discrete adipose tissue macrophage (ATM) subsets are thought to exist, their respective effects on adipose tissue, and the transcriptional mechanisms that underlie the functional differences between ATM subsets, are not well understood. We report that obese fat tissue of mice and humans contain multiple distinct populations of ATMs with unique tissue distributions, transcriptomes, chromatin landscapes, and functions. Mouse Ly6c ATMs reside outside of CLS and are adipogenic, while CD9 ATMs reside within CLS, are lipid-laden, and are proinflammatory. Adoptive transfer of Ly6c ATMs into lean mice activates gene programs typical of normal adipocyte physiology. By contrast, adoptive transfer of CD9 ATMs drives gene expression that is characteristic of obesity. Importantly, human adipose tissue contains similar ATM populations, including lipid-laden CD9 ATMs that increase with body mass. These results provide a higher resolution of the cellular and functional heterogeneity within ATMs and provide a framework within which to develop new immune-directed therapies for the treatment of obesity and related sequela.
Severe immunodeficiency associated with acute lymphoblastic leukemia and its treatment
Ann Allergy Asthma Immunol. 2018 May;120(5):537-538.e1

Read More about Severe immunodeficiency associated with acute lymphoblastic leukemia and its treatment

Severe immunodeficiency associated with acute lymphoblastic leukemia and its treatment
Ann Allergy Asthma Immunol. 2018 May;120(5):537-538.e1

Raje N, Snyder BL, Hill DA, Streicher JL, Sullivan KE.

PubMed
PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism
Genes Dev. 2018 Aug 1;32(15-16):1035-1044

Read More about PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism
Genes Dev. 2018 Aug 1;32(15-16):1035-1044

Nelson VL, Nguyen HCB, Garcìa-Cañaveras JC, Briggs ER, Ho WY, DiSpirito JR, Marinis JM, Hill DA, Lazar MA.

PubMed

Abstract

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARγ contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARγ functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARγ expression is itself markedly increased by IL4. This suggests that PPARγ functions at the center of a feed-forward loop that is central to AA of macrophages.
Reply to: Medication contaminants as a potential cause of anaphylaxis to vincristine: What about drug specific antigens?
Pediatr Blood Cancer. 2018 Feb;65(2)

Read More about Reply to: Medication contaminants as a potential cause of anaphylaxis to vincristine: What about drug specific antigens?

Reply to: Medication contaminants as a potential cause of anaphylaxis to vincristine: What about drug specific antigens?
Pediatr Blood Cancer. 2018 Feb;65(2)

Hill DA, Leahy AB, Sciasci J, O'Neill SP, Reilly A, Balamuth N, Seeholzer SH, Spergel JM, Brown-Whitehorn TF.

PubMed
Is eosinophilic esophagitis a member of the atopic march?
Ann Allergy Asthma Immunol. 2018 Feb;120(2):113-114

Read More about Is eosinophilic esophagitis a member of the atopic march?

Is eosinophilic esophagitis a member of the atopic march?
Ann Allergy Asthma Immunol. 2018 Feb;120(2):113-114

Hill DA, Spergel JM.

PubMed
The atopic march: Critical evidence and clinical relevance
Ann Allergy Asthma Immunol. 2018 Feb;120(2):131-137

Read More about The atopic march: Critical evidence and clinical relevance

The atopic march: Critical evidence and clinical relevance
Ann Allergy Asthma Immunol. 2018 Feb;120(2):131-137

Hill DA, Spergel JM.

PubMed
Medication contaminants as a potential cause of anaphylaxis to vincristine
Pediatr Blood Cancer. 2018 Jan;65(1)

Read More about Medication contaminants as a potential cause of anaphylaxis to vincristine

Medication contaminants as a potential cause of anaphylaxis to vincristine
Pediatr Blood Cancer. 2018 Jan;65(1)

Hill DA, Leahy AB, Sciasci J, O'Neill SP, Reilly A, Balamuth N, Seeholzer SH, Spergel JM, Brown-Whitehorn TF.

Link

Abstract

Vincristine (VCR) is a vinca alkaloid and common chemotherapeutic that is used to treat multiple pediatric and adult malignancies. Despite its common use, cases of anaphylaxis to VCR are rare and typically isolated to a single individual. We report a series of eight patients with adverse reactions to VCR over the course of 11 months at a single institution, four of which progressed to anaphylaxis and one of which resulted in cardiac arrest. Mass spectrometry analysis of medication lots was performed to test for possible contaminant(s). Our findings highlight the risk of anaphylaxis during therapy with VCR.

2017

The Prevalence of Eosinophilic Esophagitis in Pediatric Patients with IgE-Mediated Food Allergy
J Allergy Clin Immunol Pract. 2017 Mar - Apr;5(2):369-375

Read More about The Prevalence of Eosinophilic Esophagitis in Pediatric Patients with IgE-Mediated Food Allergy

The Prevalence of Eosinophilic Esophagitis in Pediatric Patients with IgE-Mediated Food Allergy
J Allergy Clin Immunol Pract. 2017 Mar - Apr;5(2):369-375

Hill DA, Dudley JW, Spergel JM.

PubMed

Link

Abstract

Background: Eosinophilic esophagitis (EoE) is an allergic inflammatory disease that is triggered by food allergens and characterized by progressive esophageal dysfunction. Recently, EoE has been identified in patients who underwent oral immunotherapy (OIT) for IgE-mediated food allergy, suggesting an association.

Objective: We sought to ascertain whether significant associations exist between IgE-mediated food allergies and EoE.

Methods: Using the analysis of electronic medical record data and manual chart review, we examined our subspecialty care network of 35,528 children and adolescents to identify and characterize patients with IgE-mediated and EoE food allergy. The most common food allergens were defined, and the prevalence of EoE in patients with IgE-mediated food allergy was determined. Logistic regression was used to measure the extent to which IgE-mediated food allergy to specific foods is associated with EoE.

Results: The most common causes of EoE were milk, soy, egg, grains, and meats, an allergen pattern that is distinct from that of IgE-mediated food allergy. The prevalence of EoE in patients with IgE-mediated food allergy was higher than that reported in the general population (4.7% vs 0.04%). The distribution of IgE-mediated food allergens in patients with EoE was similar to that of the general population, and IgE-mediated allergy to egg (2.27; 1.91-2.64), milk (4.19; 3.52-4.97), or shellfish (1.55; 1.24-1.92) was significantly associated with an EoE diagnosis.

Conclusions: Our findings support a clinical association between these conditions that has implications for the management of children with food allergy, and particular relevance to patients undergoing OIT.
Physiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP
Cell Metab. 2016 Dec 13;24(6):863-874

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Physiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP
Cell Metab. 2016 Dec 13;24(6):863-874

Papazyan R, Sun Z, Kim YH, Titchenell PM, Hill DA, Lu W, Damle M, Wan M, Zhang Y, Briggs ER, Rabinowitz JD, Lazar MA.

PubMed

Abstract

Liver fat accumulation precedes non-alcoholic steatohepatitis, an increasing cause of end-stage liver disease. Histone deacetylase 3 (HDAC3) is required for hepatic triglyceride homeostasis, and sterol regulatory element binding protein (SREBP) regulates the lipogenic response to feeding, but the crosstalk between these pathways is unknown. Here we show that inactivation of SREBP by hepatic deletion of SREBP cleavage activating protein (SCAP) abrogates the increase in lipogenesis caused by loss of HDAC3, but fatty acid oxidation remains defective. This combination leads to accumulation of lipid intermediates and to an energy drain that collectively cause oxidative stress, inflammation, liver damage, and, ultimately, synthetic lethality. Remarkably, this phenotype is prevented by ectopic expression of nuclear SREBP1c, revealing a surprising benefit of de novo lipogenesis and triglyceride synthesis in preventing lipotoxicity. These results demonstrate that HDAC3 and SCAP control symbiotic pathways of liver lipid metabolism that are critical for suppression of lipotoxicity.

2016

The epidemiologic characteristics of healthcare provider-diagnosed eczema, asthma, allergic rhinitis, and food allergy in children: a retrospective cohort study
BMC Pediatr. 2016 Aug 20;16:133

Read More about The epidemiologic characteristics of healthcare provider-diagnosed eczema, asthma, allergic rhinitis, and food allergy in children: a retrospective cohort study

The epidemiologic characteristics of healthcare provider-diagnosed eczema, asthma, allergic rhinitis, and food allergy in children: a retrospective cohort study
BMC Pediatr. 2016 Aug 20;16:133

Hill DA, Grundmeier RW, Ram G, Spergel JM.

PubMed

Link

Abstract

Background: The rates of childhood allergic conditions are changing, prompting the need for continued surveillance. Examination of healthcare provider-based diagnosis data is an important and lacking methodology needed to complement existing studies that rely on participant reporting.

Methods: Utilizing our care network of 1,050,061 urban and sub-urban children, we defined two retrospective cohorts: (1) a closed birth cohort of 29,662 children and (2) a cross-sectional cohort of 333,200 children. These cohorts were utilized to determine the epidemiologic characteristics of the conditions studied. Logistic regression was utilized to determine the extent to which food allergy was associated with respiratory allergy.

Results: In our birth cohort, the peak age at diagnosis of eczema, asthma, rhinitis, and food allergy was between 0 and 5 months (7.3 %), 12 and 17 months (8.7 %), 24 and 29 months (2.5 %), and 12 and 17 months (1.9 %), respectively. In our cross-sectional cohort, eczema and rhinitis prevalence rates were 6.7 % and 19.9 %, respectively. Asthma prevalence was 21.8 %, a rate higher than previously reported. Food allergy prevalence was 6.7 %, with the most common allergenic foods being peanut (2.6 %), milk (2.2 %), egg (1.8 %), shellfish (1.5 %), and soy (0.7 %). Food allergy was associated with development of asthma (OR 2.16, 95 % CI 1.94-2.40), and rhinitis (OR 2.72, 95 % CI 2.45-3.03).

Conclusions: Compared with previous reports, we measure lower rates of eczema and higher rates of asthma. The distribution of the major allergenic foods diverged from prior figures, and food allergy was associated with the development of respiratory allergy. The utilization of provider-based diagnosis data contributes an important and lacking methodology that complements existing studies.
The Immunologic Mechanisms of Eosinophilic Esophagitis
Curr Allergy Asthma Rep. 2016 Feb;16(2):9

Read More about The Immunologic Mechanisms of Eosinophilic Esophagitis

The Immunologic Mechanisms of Eosinophilic Esophagitis
Curr Allergy Asthma Rep. 2016 Feb;16(2):9

Hill DA, Spergel JM.

PubMed

Abstract

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease that is triggered by food and/or environmental allergens and is characterized by a clinical and pathologic phenotype of progressive esophageal dysfunction due to tissue inflammation and fibrosis. EoE is suspected in patients with painful swallowing, among other symptoms, and is diagnosed by the presence of 15 or more eosinophils per high-power field in one or more of at least four esophageal biopsy specimens. The prevalence of EoE is increasing and has now reached rates similar to those of other chronic gastrointestinal disorders such as Crohn's disease. In recent years, our understanding of the immunologic mechanisms underlying this condition has grown considerably. Thanks to new genetic, molecular, cellular, animal, and translational studies, we can now postulate a detailed pathway by which exposure to allergens results in a complex and coordinated type 2 inflammatory cascade that, if not intervened upon, can result in pain on swallowing, esophageal strictures, and food impaction. Here, we review the most recent research in this field to synthesize and summarize our current understanding of this complex and important disease.

2015 and before

The development of IgE-mediated immediate hypersensitivity after the diagnosis of eosinophilic esophagitis to the same food
J Allergy Clin Immunol Pract. 2015 Jan-Feb;3(1):123-4

Read More about The development of IgE-mediated immediate hypersensitivity after the diagnosis of eosinophilic esophagitis to the same food

The development of IgE-mediated immediate hypersensitivity after the diagnosis of eosinophilic esophagitis to the same food
J Allergy Clin Immunol Pract. 2015 Jan-Feb;3(1):123-4

Hill DA, Shuker M, Cianferoni A, Wong T, Ruchelli E, Spergel JM, Brown-Whitehorn TF.

PubMed

Link
Resolution of acute IgE-mediated allergy with development of eosinophilic esophagitis triggered by the same food
J Allergy Clin Immunol. 2014 May;133(5):1487-9, 1489.e1

Read More about Resolution of acute IgE-mediated allergy with development of eosinophilic esophagitis triggered by the same food

Resolution of acute IgE-mediated allergy with development of eosinophilic esophagitis triggered by the same food
J Allergy Clin Immunol. 2014 May;133(5):1487-9, 1489.e1

Maggadottir SM, Hill DA, Ruymann K, Brown-Whitehorn TF, Cianferoni A, Shuker M, Wang ML, Chikwava K, Verma R, Liacouras CA, Spergel JM.

Link
Omalizumab therapy is associated with reduced circulating basophil populations in asthmatic children
Allergy. 2014 May;69(5):674-7

Read More about Omalizumab therapy is associated with reduced circulating basophil populations in asthmatic children

Omalizumab therapy is associated with reduced circulating basophil populations in asthmatic children
Allergy. 2014 May;69(5):674-7

Hill DA, Siracusa MC, Ruymann KR, Tait Wojno ED, Artis D, Spergel JM.

Link

Abstract

Basophils have been implicated in promoting the early development of TH 2 cell responses in some murine models of TH 2 cytokine-associated inflammation. However, the specific role of basophils in allergic asthma remains an active area of research. Recent studies in animal models and human subjects suggest that IgE may regulate the homeostasis of human basophil populations. Here, we examine basophil populations in children with severe asthma before and during therapy with the IgE-directed monoclonal antibody omalizumab. Omalizumab therapy was associated with a significant reduction in circulating basophil numbers, a finding that was concurrent with improved clinical outcomes. The observation that circulating basophils are reduced following omalizumab therapy supports a mechanistic link between IgE levels and circulating basophil populations, and may provide new insights into one mechanism by which omalizumab improves asthma symptoms.
Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis
Nat Med. 2013 Aug;19(8):1005-13

Read More about Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis

Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis
Nat Med. 2013 Aug;19(8):1005-13

Noti M, Wojno ED, Kim BS, Siracusa MC, Giacomin PR, Nair MG, Benitez AJ, Ruymann KR, Muir AB, Hill DA, Chikwava KR, Moghaddam AE, Sattentau QJ, Alex A, Zhou C, Yearley JH, Menard-Katcher P, Kubo M, Obata-Ninomiya K, Karasuyama H, Comeau MR, Brown-Whitehorn T, de Waal Malefyt R, Sleiman PM, Hakonarson H, Cianferoni A, Falk GW, Wang ML, Spergel JM, Artis D.

Link

Abstract

Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.
The influence of commensal bacteria-derived signals on basophil-associated allergic inflammation
Gut Microbes. 2013 Jan-Feb;4(1):76-83

Read More about The influence of commensal bacteria-derived signals on basophil-associated allergic inflammation

The influence of commensal bacteria-derived signals on basophil-associated allergic inflammation
Gut Microbes. 2013 Jan-Feb;4(1):76-83

Hill DA, Artis D.

Link

Abstract

Commensal bacteria that colonize mammalian mucosal surfaces are reported to influence T helper type 2 (TH 2) cytokine-dependent inflammation and susceptibility to allergic disease. However, the mechanisms that underlie these observations are only beginning to be understood. We recently utilized studies of murine model systems and atopic patient populations to elucidate a mechanism by which commensal bacteria-derived signals limit serum immunoglobulin E levels, influence basophil development and steady-state circulating basophil populations and regulate basophil-associated TH 2 cell responses and allergic inflammation. In this addendum, we summarize the findings of our recent work and other developments in the field, discuss the broader implications of these findings and generate new hypotheses regarding our understanding of host-commensal relationships. These areas of investigation may be applicable to the development of new preventative or therapeutic approaches to reduce the burden of allergic disease.
A tool kit for quantifying eukaryotic rRNA gene sequences from human microbiome samples
Genome Biol. 2012 Jul 3;13(7):R60

Read More about A tool kit for quantifying eukaryotic rRNA gene sequences from human microbiome samples

A tool kit for quantifying eukaryotic rRNA gene sequences from human microbiome samples
Genome Biol. 2012 Jul 3;13(7):R60

Dollive S, Peterfreund GL, Sherrill-Mix S, Bittinger K, Sinha R, Hoffmann C, Nabel CS, Hill DA, Artis D, Bachman MA, Custers-Allen R, Grunberg S, Wu GD, Lewis JD, Bushman FD.

Link

Abstract

Eukaryotic microorganisms are important but understudied components of the human microbiome. Here we present a pipeline for analysis of deep sequencing data on single cell eukaryotes. We designed a new 18S rRNA gene-specific PCR primer set and compared a published rRNA gene internal transcribed spacer (ITS) gene primer set. Amplicons were tested against 24 specimens from defined eukaryotes and eight well-characterized human stool samples. A software pipeline https://sourceforge.net/projects/brocc/ was developed for taxonomic attribution, validated against simulated data, and tested on pyrosequence data. This study provides a well-characterized tool kit for sequence-based enumeration of eukaryotic organisms in human microbiome samples.
Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation
Nat Med. 2012 Mar 25;18(4):538-46

Read More about Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation

Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation
Nat Med. 2012 Mar 25;18(4):538-46

Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, Kambayashi T, Larosa DF, Renner ED, Orange JS, Bushman FD, Artis D.

Link

Abstract

Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (T(H)2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated T(H)2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell-intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow-resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to T(H)2 cytokine-dependent inflammation and allergic disease.
Lymph node hypertrophy following Leishmania major infection is dependent on TLR9
J Immunol. 2012 Feb 1;188(3):1394-401

Read More about Lymph node hypertrophy following Leishmania major infection is dependent on TLR9

Lymph node hypertrophy following Leishmania major infection is dependent on TLR9
J Immunol. 2012 Feb 1;188(3):1394-401

Carvalho LP, Petritus PM, Trochtenberg AL, Zaph C, Hill DA, Artis D, Scott P.

Link

Abstract

Control of the protozoan parasite Leishmania major is dependent on establishing a robust T cell response. An early event in the development of an effective T cell response is the expansion (or hypertrophy) of the lymph node draining the site of infection, although the mechanisms involved in this response are not completely understood. In this study, we show that lymph node hypertrophy following L. major infection in mice is associated with increased recruitment of lymphocytes to the lymph node from the blood, and that CD62L-deficient mice, which are unable to recruit cells to the lymph node, develop a chronic infection with L. major. Injection of L. major-activated dendritic cells promoted lymph node hypertrophy, and this correlated with an increase in the expression of CCR7 on dendritic cells, although the upregulation of CCR7 occurred on the bystander (uninfected) dendritic cells rather than those containing parasites. We found that increased CCR7 expression was TLR9-dependent, that TLR9(-/-) dendritic cells migrated less efficiently to the draining lymph node, and that TLR9(-/-) mice exhibited a deficit in lymph node expansion following L. major infection, as well as increased susceptibility. Taken together, to our knowledge, these results are the first to demonstrate that activation of dendritic cells via TLR9 is essential for the induction of lymph node hypertrophy in leishmaniasis.
TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation
Nature. 2011 Aug 14;477(7363):229-33

Read More about TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation

TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation
Nature. 2011 Aug 14;477(7363):229-33

Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA, Wherry EJ, Jessup HK, Siegel LA, Kambayashi T, Dudek EC, Kubo M, Cianferoni A, Spergel JM, Ziegler SF, Comeau MR, Artis D.

Link

Abstract

CD4(+) T-helper type 2 (T(H)2) cells, characterized by their expression of interleukin (IL)-4, IL-5, IL-9 and IL-13, are required for immunity to helminth parasites and promote the pathological inflammation associated with asthma and allergic diseases. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, indicating that TSLP is a critical regulator of T(H)2 cytokine-associated inflammatory diseases. In support of genetic analyses, exaggerated TSLP production is associated with asthma, atopic dermatitis and food allergies in patients, and studies in murine systems demonstrated that TSLP promotes T(H)2 cytokine-mediated immunity and inflammation. However, the mechanisms through which TSLP induces T(H)2 cytokine responses remain poorly defined. Here we demonstrate that TSLP promotes systemic basophilia, that disruption of TSLP-TSLPR interactions results in defective basophil responses, and that TSLPR-sufficient basophils can restore T(H)2-cell-dependent immunity in vivo. TSLP acted directly on bone-marrow-resident progenitors to promote basophil responses selectively. Critically, TSLP could elicit basophil responses in both IL-3-IL-3R-sufficient and -deficient environments, and genome-wide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited basophils. Furthermore, activated human basophils expressed TSLPR, and basophils isolated from eosinophilic oesophagitis patients were distinct from classical basophils. Collectively, these studies identify previously unrecognized heterogeneity within the basophil cell lineage and indicate that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating basophil haematopoiesis and eliciting a population of functionally distinct basophils that promote T(H)2 cytokine-mediated inflammation.
Intestinal bacteria and the regulation of immune cell homeostasis
Annu Rev Immunol. 2010;28:623-67

Read More about Intestinal bacteria and the regulation of immune cell homeostasis

Intestinal bacteria and the regulation of immune cell homeostasis
Annu Rev Immunol. 2010;28:623-67

Hill DA, Artis D.

Link

Abstract

The human intestine is colonized by an estimated 100 trillion bacteria. Some of these bacteria are essential for normal physiology, whereas others have been implicated in the pathogenesis of multiple inflammatory diseases including IBD and asthma. This review examines the influence of signals from intestinal bacteria on the homeostasis of the mammalian immune system in the context of health and disease. We review the bacterial composition of the mammalian intestine, known bacterial-derived immunoregulatory molecules, and the mammalian innate immune receptors that recognize them. We discuss the influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory disease. We conclude with an examination of successes and future challenges in using bacterial communities or their products in the prevention or treatment of human disease.
Malaria parasite mutants with altered erythrocyte permeability: a new drug resistance mechanism and important molecular tool
Future Microbiol. 2010 Jan;5(1):81-97

Read More about Malaria parasite mutants with altered erythrocyte permeability: a new drug resistance mechanism and important molecular tool

Malaria parasite mutants with altered erythrocyte permeability: a new drug resistance mechanism and important molecular tool
Future Microbiol. 2010 Jan;5(1):81-97

Hill DA, Desai SA.

Link

Abstract

Erythrocytes infected with plasmodia, including those that cause human malaria, have increased permeability to a diverse collection of organic and inorganic solutes. While these increases have been known for decades, their mechanistic basis was unclear until electrophysiological studies revealed flux through one or more ion channels on the infected erythrocyte membrane. Current debates have centered on the number of distinct ion channels, which channels mediate the transport of each solute and whether the channels represent parasite-encoded proteins or human channels activated after infection. This article reviews the identification of the plasmodial surface anion channel and other proposed channels with an emphasis on two distinct channel mutants generated through in vitro selection. These mutants implicate parasite genetic elements in the parasite-induced permeability, reveal an important new antimalarial drug resistance mechanism and provide tools for molecular studies. We also critically examine the technical issues relevant to the detection of ion channels by electrophysiological methods; these technical considerations have general applicability for interpreting studies of various ion channels proposed for the infected erythrocyte membrane.
Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis
Mucosal Immunol. 2010 Mar;3(2):148-58

Read More about Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis

Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis
Mucosal Immunol. 2010 Mar;3(2):148-58

Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ, Bushman FD, Artis D.

Link

Abstract

Despite widespread use of antibiotics, few studies have measured their effects on the burden or diversity of bacteria in the mammalian intestine. We developed an oral antibiotic treatment protocol and characterized its effects on murine intestinal bacterial communities and immune cell homeostasis. Antibiotic administration resulted in a 10-fold reduction in the amount of intestinal bacteria present and sequencing of 16S rDNA segments revealed significant temporal and spatial effects on luminal and mucosal-associated communities including reductions in luminal Firmicutes and mucosal-associated Lactobacillus species, and persistence of bacteria belonging to the Bacteroidetes and Proteobacteria phyla. Concurrently, antibiotic administration resulted in reduced RELM beta production, and reduced production of interferon-gamma and interleukin-17A by mucosal CD4(+) T lymphocytes. This comprehensive temporal and spatial metagenomic analyses will provide a resource and framework to test the influence of bacterial communities in murine models of human disease.
Maintaining diplomatic relations between mammals and beneficial microbial communities
Sci Signal. 2009 Nov 24;2(98):pe77

Read More about Maintaining diplomatic relations between mammals and beneficial microbial communities

Maintaining diplomatic relations between mammals and beneficial microbial communities
Sci Signal. 2009 Nov 24;2(98):pe77

Hill DA, Artis D.

Link

Abstract

The first reports of diplomatic relations between human communities date back to the 14th century B.C.E. and the age of the Egyptian pharaohs. However, the evolution of analogous relations between mammals and mutualistic microbial communities is as old as multicellular organisms themselves. A fundamental issue surrounding the biology of these mutualistic relationships is how the immune system recognizes beneficial microbes and tolerates their colonization of barrier surfaces while simultaneously preventing their outgrowth and potentially lethal dissemination throughout the host. New evidence provides insight into the molecular mechanisms that orchestrate diplomacy between the mammalian immune system and bacterial communities in the gut.
Community-wide response of the gut microbiota to enteropathogenic Citrobacter rodentium infection revealed by deep sequencing
Infect Immun. 2009 Oct;77(10):4668-78

Read More about Community-wide response of the gut microbiota to enteropathogenic Citrobacter rodentium infection revealed by deep sequencing

Community-wide response of the gut microbiota to enteropathogenic Citrobacter rodentium infection revealed by deep sequencing
Infect Immun. 2009 Oct;77(10):4668-78

Hoffmann C, Hill DA, Minkah N, Kirn T, Troy A, Artis D, Bushman F.

Link

Abstract

We investigated the spatial and temporal response of the murine gut microbiome to infection with Citrobacter rodentium, an attaching-and-effacing bacterium that provokes innate and adaptive immune responses, resulting in transient bacterial colitis. Previous studies have suggested that C. rodentium-induced inflammation is associated with an increased abundance of Enterobacteriaceae. We report here a deeper analysis of this model using DNA bar coding and 454 pyrosequencing to characterize 101,894 partial 16S rRNA gene sequences from 85 microbial samples from tissue-adhered and luminal bacteria of the cecum, proximal colon, and distal colon, which allowed us to identify previously unappreciated spatial and kinetic changes in multiple bacterial lineages. The deep sequencing data revealed that C. rodentium was most abundantly associated with the cecal mucosa at day 9 postinfection and then diminished in abundance, providing the first reported use of deep sequencing to track a pathogen in vivo through the course of infection. Notable changes were associated with both the mucosally adhered and luminal microbiota at both day 9 and day 14 postinfection. Alterations in abundance were seen for Proteobacteria, Deferribacteres, Clostridia, and others; however, changes in Enterobacteriaceae could be accounted for by the presence of C. rodentium itself, which is a member of this family. The Lactobacillus group decreased in abundance during infection, which may be important for pathogenesis because members of this lineage modulate the composition of the gut microbiota and are used as probiotics. Thus, deep sequencing provides previously inaccessible information on how Citrobacter infection and clearance reshapes the gut microbial community in space and time.
Electrophysiological studies of malaria parasite-infected erythrocytes: current status
Int J Parasitol. 2007 Apr;37(5):475-82

Read More about Electrophysiological studies of malaria parasite-infected erythrocytes: current status

Electrophysiological studies of malaria parasite-infected erythrocytes: current status
Int J Parasitol. 2007 Apr;37(5):475-82

Staines HM, Alkhalil A, Allen RJ, De Jonge HR, Derbyshire E, Egée S, Ginsburg H, Hill DA, Huber SM, Kirk K, Lang F, Lisk G, Oteng E, Pillai AD, Rayavara K, Rouhani S, Saliba KJ, Shen C, Solomon T, Thomas SL, Verloo P, Desai SA.

Link

Abstract

The altered permeability characteristics of erythrocytes infected with malaria parasites have been a source of interest for over 30 years. Recent electrophysiological studies have provided strong evidence that these changes reflect transmembrane transport through ion channels in the host erythrocyte plasma membrane. However, conflicting results and differing interpretations of the data have led to confusion in this field. In an effort to unravel these issues, the groups involved recently came together for a week of discussion and experimentation. In this article, the various models for altered transport are reviewed, together with the areas of consensus in the field and those that require a better understanding.
A blasticidin S-resistant Plasmodium falciparum mutant with a defective plasmodial surface anion channel
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):1063-8

Read More about A blasticidin S-resistant Plasmodium falciparum mutant with a defective plasmodial surface anion channel

A blasticidin S-resistant Plasmodium falciparum mutant with a defective plasmodial surface anion channel
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):1063-8

Hill DA, Pillai AD, Nawaz F, Hayton K, Doan L, Lisk G, Desai SA.

Link

Abstract

Erythrocytes infected with malaria parasites exhibit marked increases in permeability to organic and inorganic solutes. The plasmodial surface anion channel (PSAC), an unusual voltage-dependent ion channel induced on the host membrane after infection, may play a central role in these permeability changes. Here, we identified a functional PSAC mutant through in vitro selection with blasticidin S. Resistance to blasticidin S was generated during culture and correlated with significant reductions in permeability to multiple solutes, consistent with uptake via a common pathway. Single channel recordings revealed marked changes in PSAC gating with the addition of a subconductance state not present in wild-type channels. The channel's selectivity profile and pharmacology also were significantly altered. Eventual loss of the mutant phenotype upon removal of selective pressure and slower growth of mutant parasites suggest that PSAC serves an important role in intracellular parasite survival. These findings provide solid evidence for the uptake of diverse solutes via PSAC and implicate one or more parasite genes in expression of this channel.
Babesia and plasmodia increase host erythrocyte permeability through distinct mechanisms
Cell Microbiol. 2007 Apr;9(4):851-60

Read More about Babesia and plasmodia increase host erythrocyte permeability through distinct mechanisms

Babesia and plasmodia increase host erythrocyte permeability through distinct mechanisms
Cell Microbiol. 2007 Apr;9(4):851-60

Alkhalil A, Hill DA, Desai SA.

Link

Abstract

Human erythrocytes infected with Plasmodium falciparum have markedly increased permeability to diverse solutes, many of which may be mediated by an unusual small conductance ion channel, the plasmodial surface anion channel (PSAC). Because these increases may be essential for parasite survival in the bloodstream, an important question is whether other intraerythrocytic parasites induce similar ion channels. Here, we examined this question using human erythrocytes infected with Babesia divergens, a distantly related apicomplexan parasite that can cause severe disease in immunocompromised humans. Osmotic lysis experiments after enrichment of infected erythrocytes with a new method revealed that these parasites also increase host permeability to various organic solutes. These permeability changes differed significantly from those induced by P. falciparum in transport rates, selectivity profiles and temperature dependence. Cell-attached and whole-cell patch-clamp experiments confirmed and extended these differences because neither PSAC-like channels nor significant increases in whole-cell anion conductance were seen after B. divergens infection. While both babesia and plasmodia increase host erythrocyte permeability to a diverse collection of organic solutes, they utilize fundamentally different mechanisms.

Our Publications

2025

A molecular basis for milk allergen immune recognition in eosinophilic esophagitis

IFNg signaling impairs Regulatory B cell function resulting in worse control of esophageal food allergy

2024

Risk Factors for Hospitalization in Subspecialty Patients with Severe Persistent Asthma

Eosinophilic gastrointestinal disorders and the role for the epithelium in pathogenesis and treatment

Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity

Advances and ongoing challenges in eosinophilic gastrointestinal disorders

COVID-19 and Asthma Onset in Children

2023

The immune-epithelial interface in eosinophilic esophagitis: a conversation

Breakthroughs in understanding and treating eosinophilic gastrointestinal diseases...

The role of extracellular vesicle-derived miRNAs in adipose tissue function and metabolic health

Patterns in the Development of Pediatric Allergy

Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis

2022

Effects of oral immunotherapy on immune tolerance

Altered adipose tissue macrophage populations in people with HIV on integrase inhibitor-containing ART

Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction

Improvement in Eosinophilic Esophagitis when using Dupilumab for other Indications or Compassionate Use

The importance of using core outcome measures during therapeutic studies of eosinophilic esophagitis

COVID-19 Pandemic-Related Reductions in Pediatric Asthma Exacerbations Corresponded with an Overall Decrease in Respiratory Viral Infections

2021

Peripheral markers of allergen-specific immune activation predict clinical allergy in eosinophilic esophagitis

One march, many paths: Insights into allergic march trajectories

Early-life environmental exposures associate with individual and cumulative allergic morbidity

Prevalence of Asthma in Hospitalized and Non-Hospitalized Children with COVID-19

Conserved IFN Signature between Adult and Pediatric Eosinophilic Esophagitis

Unsupervised Modeling and Genome-Wide Association Identify Novel Features of Allergic March Trajectories

2020

Pediatric Asthma Healthcare Utilization, Viral Testing, and Air Pollution Changes during the COVID-19 Pandemic

Initial Effects of the COVID-19 Pandemic on Pediatric Asthma Emergency Department Utilization

Elevated Atopic Comorbidity in Patients with Food Protein-Induced Enterocolitis

2019

Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis

Allergic Comorbidity in Eosinophilic Esophagitis: Mechanistic Relevance and Clinical Implications

Eosinophilic esophagitis during sublingual and oral allergen immunotherapy

Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner

Screening children for eosinophilic esophagitis: allergic and other risk factors

2018

Epithelial acid imbalance in patients with eosinophilic esophagitis

Eosinophilic Esophagitis Is a Late Manifestation of the Allergic March