Publications by authors named "Simon P Hogan"

92 Publications

IL-4 Receptor Alpha Signaling alters oral food challenge and Immunotherapy outcomes in mice.

J Allergy Clin Immunol 2022 Aug 4. Epub 2022 Aug 4.

Mary H Weiser Food Allergy Center, Department of Pathology, Michigan Medicine, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200; Department of Pathology, Michigan Medicine, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. Electronic address:

Background: Food allergy diagnosis and management causes a number of social an emotional challenge for individuals with food allergies and caregivers. This has led to increasing interest in the development and usage of approaches to accurately predict food allergy diagnosis, severity of food allergic reactions and treatment outcomes. However, the utility of these approaches is somewhat conflicting.

Objective: Develop and utilize a murine model that mimics the disease course of food allergy diagnosis and treatment in humans and to identify biomarkers that predict reactivity during food challenge and responsiveness during oral immunotherapy and how these outcomes are modified by genetics.

Methods: Skin sensitized Intestinal IL-9Tg (IL9Tg) and IL9Tg mice backcrossed onto the IL4Rα background received single intragastric exposure of egg antigen (OVA), underwent oral food challenge (OFC) and oral immunotherapy (OIT) and food allergy severity, mast cell activation and OVA-specific IgE levels were examined to determine the predictability of these outcomes in determining reactivity and treatment outcomes.

Results: We show that s.c. sensitization and a single intragastric allergen-challenge of egg antigen to BALB/c IL-9Tg mice and IL4Rα IL9Tg induced a food allergic reaction. We show that enhanced IL-4Rα-signaling altered the symptoms induced by the first oral exposure, decreased the cumulative antigen dose and increased severity of reaction during OFC and altered side effect frequency and OIT outcomes. Analysis of the biomarkers following the first oral exposure revealed that only the severity of the initial reaction significantly correlated with the cumulative dose of the OFC.

Conclusion: Collectively, these data indicate that SNPs in IL-4Rα can alter clinical symptoms of food allergic reactions, severity and reactive dose during food challenge and OIT and that severity of first reaction can predict the likelihood of reaction during a food challenge in mice with IL-4Rα gain of function.
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http://dx.doi.org/10.1016/j.jaci.2022.07.011DOI Listing
August 2022

Eosinophilic esophagitis: Immune mechanisms and therapeutic targets.

Clin Exp Allergy 2022 Jul 1. Epub 2022 Jul 1.

Mary H Weiser Food Allergy Center, University of Michigan, Ann Arbor, Michigan, USA.

Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease of the oesophagus and is clinically characterized by upper gastrointestinal (GI) symptoms including dysphagia and esophageal food impaction. Histopathologic manifestations, which include intraepithelial eosinophilic inflammation and alterations of the esophageal squamous epithelium, such as basal zone hyperplasia (BZH) and dilated intercellular spaces (DIS), are thought to contribute to esophageal dysfunction and disease symptoms. Corroborative clinical and discovery science-based studies have established that EoE is characterized by an underlying allergic inflammatory response, in part, related to the IL-13/CCL26/eosinophil axis driving dysregulation of several key epithelial barrier and proliferative regulatory genes including kallikrein (KLK) serine proteases, calpain 14 (CAPN14) and anoctamin 1 (ANO1). The contribution of these inflammatory and proliferative processes to the clinical and histological manifestations of disease are not fully elucidated. Herein, we discuss the immune molecules and cells that are thought to underlie the clinical and pathologic manifestations of EoE and the emerging therapeutics targeting these processes for the treatment of EoE.
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http://dx.doi.org/10.1111/cea.14196DOI Listing
July 2022

Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis.

Elife 2021 10 22;10. Epub 2021 Oct 22.

Department of Internal Medicine, Washington University School of Medicine, St Louis, United States.

Intestinal goblet cells maintain the protective epithelial barrier through mucus secretion and yet sample lumenal substances for immune processing through formation of goblet cell associated antigen passages (GAPs). The cellular biology of GAPs and how these divergent processes are balanced and regulated by goblet cells remains unknown. Using high-resolution light and electron microscopy, we found that in mice, GAPs were formed by an acetylcholine (ACh)-dependent endocytic event remarkable for delivery of fluid-phase cargo retrograde into the trans-golgi network and across the cell by transcytosis - in addition to the expected transport of fluid-phase cargo by endosomes to multi-vesicular bodies and lysosomes. While ACh also induced goblet cells to secrete mucins, ACh-induced GAP formation and mucin secretion were functionally independent and mediated by different receptors and signaling pathways, enabling goblet cells to differentially regulate these processes to accommodate the dynamically changing demands of the mucosal environment for barrier maintenance and sampling of lumenal substances.
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http://dx.doi.org/10.7554/eLife.67292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594945PMC
October 2021

PIR-B Regulates CD4 IL17a T-Cell Survival and Restricts T-Cell-Dependent Intestinal Inflammatory Responses.

Cell Mol Gastroenterol Hepatol 2021 6;12(4):1479-1502. Epub 2021 Jul 6.

Division of Experimental Pathology, Department of Pathology, Ann Arbor, Michigan; Mary H Weiser Food Allergy Center, Michigan Medicine, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background & Aims: CD4 T cells are regulated by activating and inhibitory cues, and dysregulation of these proper regulatory inputs predisposes these cells to aberrant inflammation and exacerbation of disease. We investigated the role of the inhibitory receptor paired immunoglobulin-like receptor B (PIR-B) in the regulation of the CD4 T-cell inflammatory response and exacerbation of the colitic phenotype.

Methods: We used Il10 spontaneous and CD4CD45RB T-cell transfer models of colitis with PIR-B-deficient (Pirb) mice. Flow cytometry, Western blot, and RNA sequencing analysis was performed on wild-type and Pirb CD4 T cells. In silico analyses were performed on RNA sequencing data set of ileal biopsy samples from pediatric CD and non-inflammatory bowel disease patients and sorted human memory CD4 T cells.

Results: We identified PIR-B expression on memory CD4 interleukin (IL)17a cells. We show that PIR-B regulates CD4 T-helper 17 cell (Th17)-dependent chronic intestinal inflammatory responses and the development of colitis. Mechanistically, we show that the PIR-B- Src-homology region 2 domain-containing phosphatase-1/2 axis tempers mammalian target of rapamycin complex 1 signaling and mammalian target of rapamycin complex 1-dependent caspase-3/7 apoptosis, resulting in CD4 IL17a cell survival. In silico analyses showed enrichment of transcriptional signatures for Th17 cells (RORC, RORA, and IL17A) and tissue resident memory (HOBIT, IL7R, and BLIMP1) networks in PIR-B murine CD4 T cells and human CD4 T cells that express the human homologue leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3). High levels of LILRB3 expression were associated strongly with mucosal injury and a proinflammatory Th17 signature, and this signature was restricted to a treatment-naïve, severe pediatric CD population.

Conclusions: Our findings show an intrinsic role for PIR-B/LILRB3 in the regulation of CD4 IL17a T-cell pathogenic memory responses.
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http://dx.doi.org/10.1016/j.jcmgh.2021.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531983PMC
March 2022

Severity grading system for acute allergic reactions-time for validation and assessment of best practices.

Authors:
Simon P Hogan

J Allergy Clin Immunol 2021 07 6;148(1):86-88. Epub 2021 May 6.

Mary H. Weiser Food Allergy Center, Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Mich. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2021.04.031DOI Listing
July 2021

Thermoneutrality Alters Gastrointestinal Antigen Passage Patterning and Predisposes to Oral Antigen Sensitization in Mice.

Front Immunol 2021 25;12:636198. Epub 2021 Mar 25.

Department of Pathology, University of Michigan, Ann Arbor, MI, United States.

Food allergy is an emerging epidemic, and the underlying mechanisms are not well defined partly due to the lack of robust adjuvant free experimental models of dietary antigen sensitization. As housing mice at thermoneutrality (Tn) - the temperature of metabolic homeostasis (26-30°C) - has been shown to improve modeling various human diseases involved in inflammation, we tested the impact of Tn housing on an experimental model of food sensitization. Here we demonstrate that WT BALB/c mice housed under standard temperature (18-20°C, Ts) conditions translocated the luminal antigens in the small intestine (SI) across the epithelium goblet cell antigen passages (GAPs). In contrast, food allergy sensitive mice housed under standard temperature conditions translocated the luminal antigens in the SI across the epithelium secretory antigen passages (SAPs). Activation of SI antigen passages and oral challenge of mice with egg allergens at standard temperature predisposed mice to develop an anaphylactic reaction. Housing mice at Tn altered systemic type 2 cytokine, IL-4, and the landscape of SI antigen passage patterning (villus and crypt involvement). Activation of SI antigen passages and oral challenge of mice with egg antigen under Tn conditions led to the robust induction of egg-specific IgE and development of food-induced mast cell activation and hypovolemic shock. Similarly, Tn housing of WT BALB/c mice altered the cellular patterning of SI antigen passage (GAPs to SAPs). Activation of SI antigen passages and the oral challenge of WT BALB/c mice with egg antigen led to systemic reactivity to egg and mast cell activation. Together these data demonstrate that Tn housing alters antigen passage cellular patterning and landscape, and concurrent oral exposure of egg antigens and SAP activation is sufficient to induce oral antigen sensitization.
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http://dx.doi.org/10.3389/fimmu.2021.636198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034294PMC
September 2021

Uridine diphosphate-glucose/P2Y14R axis is a nonchemokine pathway that selectively promotes eosinophil accumulation.

J Clin Invest 2021 04;131(7)

Mary H. Weiser Food Allergy Center, Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Allergic asthma is a chronic inflammatory airway disease characterized by dysregulated type 2 immune responses, including degranulating airway eosinophils that induce tissue damage and airway hyperresponsiveness (AHR). The type 2 cytokines interleukin 5 (IL-5) and IL-13 and the eosinophil-specific chemokine CCL11/CCL24/CCL26 axis recruit, activate, and regulate eosinophils in the airways. In this issue of the JCI, Karcz et al. identified a mechanism involving the nucleotide sugar UDP-glucose (UDP-G) and the purinergic receptor P2Y14R in amplifying eosinophil accumulation in the lung. During type 2 inflammation, UDP-G activates P2Y14R on eosinophils, inducing the cells to move and migrate into the lung. Pharmacologically or genetically inhibiting P2Y14R on eosinophils attenuated eosinophil infiltration and AHR. Future experiments, including identifying additional type 2 factors regulating P2Y14R expression on lung eosinophils, are necessary to ascertain the impact of targeting P2Y14R as an alternative or adjunctive therapy to current type 2 biologics for the treatment of asthma.
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http://dx.doi.org/10.1172/JCI147735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011882PMC
April 2021

Intestinal epithelial cells in tolerance and allergy to dietary antigens.

J Allergy Clin Immunol 2021 01 1;147(1):45-48. Epub 2020 Nov 1.

Mary H. Weiser Food Allergy Center, Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Mich. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.10.030DOI Listing
January 2021

IL-4-BATF signaling directly modulates IL-9 producing mucosal mast cell (MMC9) function in experimental food allergy.

J Allergy Clin Immunol 2021 01 15;147(1):280-295. Epub 2020 Oct 15.

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Mary H Weiser Food Allergy Center, Michigan Medicine, University of Michigan, Ann Arbor, Mich; Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Mich. Electronic address:

Background: This study group has previously identified IL-9-producing mucosal mast cell (MMC9) as the primary source of IL-9 to drive intestinal mastocytosis and experimental IgE-mediated food allergy. However, the molecular mechanisms that regulate the expansion of MMC9s remain unknown.

Objectives: This study hypothesized that IL-4 regulates MMC9 development and MMC9-dependent experimental IgE-mediated food allergy.

Methods: An epicutaneous sensitization model was used and bone marrow reconstitution experiments were performed to test the requirement of IL-4 receptor α (IL-4Rα) signaling on MMC9s in experimental IgE-mediated food allergy. Flow cytometric, bulk, and single-cell RNA-sequencing analyses on small intestine (SI) MMC9s were performed to illuminate MMC9 transcriptional signature and the effect of IL-4Rα signaling on MMC9 function. A bone marrow-derived MMC9 culture system was used to define IL-4-BATF signaling in MMC9 development.

Results: Epicutaneous sensitization- and bone marrow reconstitution-based models of IgE-mediated food allergy revealed an IL-4 signaling-dependent cell-intrinsic effect on SI MMC9 accumulation and food allergy severity. RNA-sequencing analysis of SI-MMC9s identified 410 gene transcripts reciprocally regulated by IL-4 signaling, including Il9 and Batf. Insilico analyses identified a 3491-gene MMC9 transcriptional signature and identified 2 transcriptionally distinct SI MMC9 populations enriched for metabolic or inflammatory programs. Employing an in vitro MMC9-culture model system showed that generation of MMC9-like cells was induced by IL-4 and this was in part dependent on BATF.

Conclusions: IL-4Rα signaling directly modulates MMC9 function and exacerbation of experimental IgE-mediated food allergic reactions. IL-4Rα regulation of MMC9s is in part BATF-dependent and occurs via modulation of metabolic transcriptional programs.
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http://dx.doi.org/10.1016/j.jaci.2020.08.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856198PMC
January 2021

Recent advances in mechanisms of food allergy and anaphylaxis.

F1000Res 2020 31;9. Epub 2020 Jul 31.

1. Mary H. Weiser Food Allergy Center, Department of Pathology, University of Michigan 4051-BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA.

Food allergens are innocuous proteins that promote tolerogenic adaptive immune responses in healthy individuals yet in other individuals induce an allergic adaptive immune response characterized by the presence of antigen-specific immunoglobulin E and type-2 immune cells. The cellular and molecular processes that determine a tolerogenic versus non-tolerogenic immune response to dietary antigens are not fully elucidated. Recently, there have been advances in the identification of roles for microbial communities and anatomical sites of dietary antigen exposure and presentation that have provided new insights into the key regulatory steps in the tolerogenic versus non-tolerogenic decision-making processes. Herein, we will review and discuss recent findings in cellular and molecular processes underlying food sensitization and tolerance, immunological processes underlying severity of food-induced anaphylaxis, and insights obtained from immunotherapy trials.
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http://dx.doi.org/10.12688/f1000research.25638.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401090PMC
October 2020

Synchronization of mothers and offspring promotes tolerance and limits allergy.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Department of Internal Medicine and.

Allergic disorders, characterized by Th2 immune responses to environmental substances, are increasingly common in children in Western societies. Multiple studies indicate that breastfeeding, early complementary introduction of food allergens, and antibiotic avoidance in the first year of life reduces allergic outcomes in at-risk children. Why the benefit of these practices is restricted to early life is largely unknown. We identified a preweaning interval during which dietary antigens are assimilated by the colonic immune system. This interval is under maternal control via temporal changes in breast milk, coincides with an influx of naive T cells into the colon, and is followed by the development of a long-lived population of colonic peripherally derived Tregs (pTregs) that can be specific for dietary antigens encountered during this interval. Desynchronization of mothers and offspring produced durable deficits in these pTregs, impaired tolerance to dietary antigens introduced during and after this preweaning interval, and resulted in spontaneous Th2 responses. These effects could be rescued by pTregs from the periweaning colon or by Tregs generated in vitro using periweaning colonic antigen-presenting cells. These findings demonstrate that mothers and their offspring are synchronized for the development of a balanced immune system.
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http://dx.doi.org/10.1172/jci.insight.137943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455068PMC
August 2020

Dysregulation of intestinal epithelial CFTR-dependent Cl ion transport and paracellular barrier function drives gastrointestinal symptoms of food-induced anaphylaxis in mice.

Mucosal Immunol 2021 01 23;14(1):135-143. Epub 2020 Jun 23.

Mary H Weiser Food Allergy Center, Department of Pathology, Michigan Medicine, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA.

Food-triggered anaphylaxis can encompass a variety of systemic and intestinal symptoms. Murine-based and clinical studies have revealed a role for histamine and H1R and H2R-pathway in the systemic response; however, the molecular processes that regulate the gastrointestinal (GI) response are not as well defined. In the present study, by utilizing an IgE-mast cell (MC)-dependent experimental model of oral antigen-induced anaphylaxis, we define the intestinal epithelial response during a food-induced anaphylactic reaction. We show that oral allergen-challenge stimulates a rapid dysregulation of intestinal epithelial transcellular and paracellular transport that was associated with the development of secretory diarrhea. Allergen-challenge induced (1) a rapid intestinal epithelial Cftr-dependent Cl secretory response and (2) paracellular macromolecular leak that was associated with modification in epithelial intercellular junction proteins claudin-1, 2, 3 and 5, E-cadherin and desmosomal cadherins. OVA-induced Cftr-dependent Cl secretion and junctional protein degradation was rapid occurring and was sustained for 72 h following allergen-challenge. Blockade of both the proteolytic activity and Cl secretory response was required to alleviate intestinal symptoms of food-induced anaphylaxis. Collectively, these data suggest that the GI symptom of food-induced anaphylactic reaction, secretory diarrhea, is a consequence of CFTR-dependent Cl secretion and proteolytic activity.
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http://dx.doi.org/10.1038/s41385-020-0306-6DOI Listing
January 2021

Developments in the mechanisms of allergy in 2018 through the eyes of Clinical and Experimental Allergy, Part I.

Clin Exp Allergy 2019 12;49(12):1541-1549

Division of Asthma, Allergy and Immunology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.

In the first of two linked articles, we describe the development in the mechanisms underlying allergy as described by Clinical & Experimental Allergy and other journals in 2018. Experimental models of allergic disease, basic mechanisms and clinical mechanisms are all covered.
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http://dx.doi.org/10.1111/cea.13532DOI Listing
December 2019

Goblet cell associated antigen passages support the induction and maintenance of oral tolerance.

Mucosal Immunol 2020 03 9;13(2):271-282. Epub 2019 Dec 9.

Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, 63110, USA.

Tolerance to innocuous antigens from the diet and the commensal microbiota is a fundamental process essential to health. Why tolerance is efficiently induced to substances arising from the hostile environment of the gut lumen is incompletely understood but may be related to how these antigens are encountered by the immune system. We observed that goblet cell associated antigen passages (GAPs), but not other pathways of luminal antigen capture, correlated with the acquisition of luminal substances by lamina propria (LP) antigen presenting cells (APCs) and with the sites of tolerance induction to luminal antigens. Strikingly this role extended beyond antigen delivery. The GAP function of goblet cells facilitated maintenance of pre-existing LP T regulatory cells (Tregs), imprinting LP-dendritic cells with tolerogenic properties, and facilitating LP macrophages to produce the immunomodulatory cytokine IL-10. Moreover, tolerance to dietary antigen was impaired in the absence of GAPs. Thus, by delivering luminal antigens, maintaining pre-existing LP Tregs, and imprinting tolerogenic properties on LP-APCs GAPs support tolerance to substances encountered in the hostile environment of the gut lumen.
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http://dx.doi.org/10.1038/s41385-019-0240-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044050PMC
March 2020

Identification of anoctamin 1 (ANO1) as a key driver of esophageal epithelial proliferation in eosinophilic esophagitis.

J Allergy Clin Immunol 2020 01 21;145(1):239-254.e2. Epub 2019 Oct 21.

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Mary H Weiser Food Allergy Center and Department of Pathology, Ann Arbor, Mich. Electronic address:

Background: The pathology of eosinophilic esophagitis (EoE) is characterized by eosinophil-rich inflammation, basal zone hyperplasia (BZH), and dilated intercellular spaces, and the underlying processes that drive the pathologic manifestations of the disease remain largely unexplored.

Objective: We sought to investigate the involvement of the calcium-activated chloride channel anoctamin 1 (ANO1) in esophageal proliferation and the histopathologic features of EoE.

Methods: We examined mRNA and protein expression of ANO1 in esophageal biopsy samples from patients with EoE and in mice with EoE. We performed molecular and cellular analyses and ion transport assays on an in vitro esophageal epithelial 3-dimensional model system (EPC2-ALI) and murine models of EoE to define the relationship between expression and function of ANO1 and esophageal epithelial proliferation in patients with EoE.

Results: We observed increased ANO1 expression in esophageal biopsy samples from patients with EoE and in mice with EoE. ANO1 was expressed within the esophageal basal zone, and expression correlated positively with disease severity (eosinophils/high-power field) and BZH. Using an in vitro esophageal epithelial 3-dimensional model system revealed that ANO1 undergoes chromatin modification and rapid upregulation of expression after IL-13 stimulation, that ANO1 is the primary apical IL-13-induced Cl transport mechanism within the esophageal epithelium, and that loss of ANO1-dependent Cl transport abrogated esophageal epithelial proliferation. Mechanistically, ANO1-dependent regulation of basal cell proliferation was associated with modulation of TP63 expression and phosphorylated cyclin-dependent kinase 2 levels.

Conclusions: These data identify a functional role for ANO1 in esophageal cell proliferation and BZH in patients with EoE and provide a rationale for pharmacologic intervention of ANO1 function in patients with EoE.
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http://dx.doi.org/10.1016/j.jaci.2019.07.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366251PMC
January 2020

Deletion of ΔdblGata motif leads to increased predisposition and severity of IgE-mediated food-induced anaphylaxis response.

PLoS One 2019 1;14(8):e0219375. Epub 2019 Aug 1.

Division of Allergy and Immunology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.

Background: Previous studies have revealed an important role for the transcription factor GATA-1 in mast cell maturation and degranulation. However, there have been conflicting reports with respect to the requirement of GATA-1 function in mast cell dependent inflammatory processes. Herein, we examine the requirement of GATA-1 signaling in mast cell effector function and IgE-mast cell-dependent anaphylaxis.

Objective: To study the requirement of GATA-1 dependent signaling in the development and severity of IgE-mast cell-dependent anaphylaxis in mice.

Methods: Wild type (Balb/c) and mutant ΔdblGata (Balb/c) mice were employed to study the role of GATA-1 signaling in in vitro IgE-mediated activation of bone marrow derived mast cells (BMMCs). Murine models of passive IgE-mediated and oral antigen-induced IgE-mediated anaphylaxis were employed in mice. Frequency of steady state mast cells in various tissues (duodenum, ear, and tongue), peritoneal cavity, and clinical symptoms (diarrhea, shock, and mast cell activation) and intestinal Type 2 immune cell analysis including CD4+ Th2 cells, type 2 innate lymphoid cells (ILC2), and IL-9 secreting mucosal mast cells (MMC9) were assessed.

Results: In vitro analysis revealed that ΔdblGata BMMCs exhibit a reduced maturation rate, decreased expression of FcεRIα, and degranulation capacity when compared to their wildtype (WT) counterparts. These in vitro differences did not impact tissue resident mast cell numbers, total IgE, and susceptibility to or severity of IgE-mediated passive anaphylaxis. Surprisingly, ΔdblGata mice were more susceptible to IgE-mast cell-mediated oral antigen induced anaphylaxis. The increased allergic response was associated with increased Type 2 immunity (antigen-specific IgE, and CD4+ TH2 cells), MMC9 cells and small intestine (SI) mast cell load.

Conclusion: Diminished GATA-1 activity results in reduced in vitro mast cell FcεRIα expression, proliferation, and degranulation activity. However, in vivo, diminished GATA-1 activity results in normal homeostatic tissue mast cell levels and increased antigen-induced CD4+ Th2 and iMMC9 cell levels and heightened IgE-mast cell mediated reactions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219375PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675080PMC
March 2020

IL-13-induced intestinal secretory epithelial cell antigen passages are required for IgE-mediated food-induced anaphylaxis.

J Allergy Clin Immunol 2019 10 5;144(4):1058-1073.e3. Epub 2019 Jun 5.

Mary H. Weiser Food Allergy Center, Department of Pathology, University of Michigan, Ann Arbor, Mich; Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

Background: Food-induced anaphylaxis (FIA) is an IgE-dependent immune response that can affect multiple organs and lead to life-threatening complications. The processes by which food allergens cross the mucosal surface and are delivered to the subepithelial immune compartment to promote the clinical manifestations associated with food-triggered anaphylaxis are largely unexplored.

Objective: We sought to define the processes involved in the translocation of food allergens across the mucosal epithelial surface to the subepithelial immune compartment in FIA.

Methods: Two-photon confocal and immunofluorescence microscopy was used to visualize and trace food allergen passage in a murine model of FIA. A human colon cancer cell line, RNA silencing, and pharmacologic approaches were used to identify the molecular regulation of intestinal epithelial allergen uptake and translocation. Human intestinal organoid transplants were used to demonstrate the conservation of these molecular processes in human tissues.

Results: Food allergens are sampled by using small intestine (SI) epithelial secretory cells (termed secretory antigen passages [SAPs]) that are localized to the SI villous and crypt region. SAPs channel food allergens to lamina propria mucosal mast cells through an IL-13-CD38-cyclic adenosine diphosphate ribose (cADPR)-dependent process. Blockade of IL-13-induced CD38/cADPR-dependent SAP antigen passaging in mice inhibited induction of clinical manifestations of FIA. IL-13-CD38-cADPR-dependent SAP sampling of food allergens was conserved in human intestinal organoids.

Conclusion: We identify that SAPs are a mechanism by which food allergens are channeled across the SI epithelium mediated by the IL-13/CD38/cADPR pathway, regulate the onset of FIA reactions, and are conserved in human intestine.
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http://dx.doi.org/10.1016/j.jaci.2019.04.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779525PMC
October 2019

What's old is new again: Batf transcription factors and Th9 cells.

Mucosal Immunol 2019 05 4;12(3):583-585. Epub 2019 Mar 4.

Mary H Weiser Food Allergy Center, Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109-2200, USA.

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http://dx.doi.org/10.1038/s41385-019-0155-3DOI Listing
May 2019

Loss of GTPase of immunity-associated protein 5 (Gimap5) promotes pathogenic CD4 T-cell development and allergic airway disease.

J Allergy Clin Immunol 2019 01 25;143(1):245-257.e6. Epub 2018 Oct 25.

Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address:

Background: GTPase of immunity-associated protein 5 (GIMAP5) is essential for lymphocyte homeostasis and survival. Recently, human GIMAP5 single nucleotide polymorphisms have been linked to an increased risk for asthma, whereas loss of Gimap5 in mice has been associated with severe CD4 T cell-driven immune pathology.

Objective: We sought to identify the molecular and cellular mechanisms by which Gimap5 deficiency predisposes to allergic airway disease.

Methods: CD4 T-cell polarization and development of pathogenic CD4 T cells were assessed in Gimap5-deficient mice and a human patient with a GIMAP5 loss-of-function (LOF) mutation. House dust mite-induced airway inflammation was assessed by using a complete Gimap5 LOF (Gimap5) and conditional Gimap5Cd4 mice.

Results: GIMAP5 LOF mutations in both mice and human subjects are associated with spontaneous polarization toward pathogenic T17 and T2 cells in vivo. Mechanistic studies in vitro reveal that impairment of Gimap5-deficient T cell differentiation is associated with increased DNA damage, particularly during T1-polarizing conditions. DNA damage in Gimap5-deficient CD4 T cells could be controlled by TGF-β, thereby promoting T17 polarization. When challenged with house dust mite in vivo, Gimap5-deficient mice displayed an exacerbated asthma phenotype (inflammation and airway hyperresponsiveness), with increased development of T2, T17, and pathogenic T17/T2 cells.

Conclusion: Activation of Gimap5-deficient CD4 T cells is associated with increased DNA damage and reduced survival that can be overcome by TGF-β. This leads to selective survival of pathogenic T17 cells but also T2 cells in human subjects and mice, ultimately promoting allergic airway disease.
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http://dx.doi.org/10.1016/j.jaci.2018.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327968PMC
January 2019

17β-Estradiol protects the esophageal epithelium from IL-13-induced barrier dysfunction and remodeling.

J Allergy Clin Immunol 2019 06 20;143(6):2131-2146. Epub 2018 Dec 20.

Division of Allergy and Immunology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Mary H Weiser Food Allergy Center, Department of Pathology, University of Michigan, Ann Arbor, Mich. Electronic address:

Background: The incidence of eosinophilic esophagitis (EoE) is greater in male than female subjects, and the underlying molecular basis for this sex bias remains unclear.

Objective: We sought to delineate the contribution of the sex hormone estrogen to the EoE phenotype and esophageal epithelial barrier function and remodeling.

Methods: We performed demographic and incidence analyses of EoE in male and female subjects from a single-center pediatric cohort. Estrogen-responsive gene expression analyses and estrogen receptor (ESR) immunofluorescence staining of esophageal biopsy specimens from patients with EoE and control subjects were performed. The effect of 17β-estradiol (E2) on IL-13-induced signaling pathways, gene expression, and esophageal epithelial architecture and barrier function in a primary human esophageal keratinocyte cell (EPC2) culture system (EPC2-air-liquid interface) was examined.

Results: We observed a male predominance in patients with EoE. Analyses of RNA sequencing data sets revealed a significant dysregulation of the estrogen-responsive gene network and expression of ESR1 and ESR2 in esophageal biopsy specimens from patients with EoE compared with control subjects. IL-13 stimulation of EPC2-air-liquid interface cells led to altered cellular architecture with induced dilation of intercellular spaces and barrier dysfunction. Pretreatment of EPC2s with E2 prior to IL-13 exposure abrogated IL-13-induced architectural changes and esophageal barrier dysfunction. Mechanistically, E2-protective effects were dependent on ESR2 and associated with diminishing of IL-13-induced tyrosine kinase 2 and signal transducer and activator of transcription 6 phosphorylation and EoE-dysregulated gene expression.

Conclusions: Estrogen-responsive genes are modified in patients with EoE compared with control subjects. E2 attenuated IL-13-induced architectural changes and esophageal epithelial barrier dysfunction through inhibition of the IL-13/tyrosine kinase 2/signal transducer and activator of transcription 6 pathway via ESR2-dependent process. Estrogen hormone signaling may protect against development of EoE in female subjects.
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http://dx.doi.org/10.1016/j.jaci.2018.10.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556402PMC
June 2019

C5a receptor 1 mice are protected from the development of IgE-mediated experimental food allergy.

Allergy 2019 04 12;74(4):767-779. Epub 2018 Nov 12.

Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.

Background: Food-induced anaphylaxis is a serious allergic reaction caused by Fcε-receptor activation on mast cells (MCs). The exact mechanisms breaking oral tolerance and the effector pathways driving food allergy remain elusive. As complement is activated in food-induced anaphylaxis, we aimed to assess the role of C5a in disease pathogenesis.

Methods: Oral antigen-induced food-induced anaphylaxis was induced in BALB/c wild-type (wt) and C5ar1 mice. Readouts included diarrhea development, changes in rectal temperature, hematocrit, antigen-specific serum IgE, MCPT-1, and intestinal MC numbers, as well as FcεR1-mediated MC functions including C5a receptor 1 (C5aR1) regulation. Further, histamine-mediated hypothermia and regulation of endothelial tight junctions were determined.

Results: Repeated oral OVA challenge resulted in diarrhea, hypothermia, increased hematocrit, high OVA-specific serum IgE, and MCPT-1 levels in wt mice. Male C5ar1 mice were completely whereas female C5ar1 mice were partially protected from anaphylaxis development. Serum MCPT-1 levels were reduced gender-independent, whereas IgE levels were reduced in male but not in female C5ar1 mice. Mechanistically, IgE-mediated degranulation and IL-6 production from C5ar1 BMMCs of both sexes were significantly reduced. Importantly, FcεR1 cross-linking strongly upregulated C5aR1 MC expression in vitro and in vivo. Finally, C5ar1 male mice were largely protected from histamine-induced hypovolemic shock, which was associated with protection from histamine-induced barrier dysfunction in vitro following C5aR targeting.

Conclusions: Our findings identify C5aR1 activation as an important driver of IgE-mediated food allergy through regulation of allergen-specific IgE production, FcεR1-mediated MC degranulation, and histamine-driven effector functions preferentially in male mice.
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http://dx.doi.org/10.1111/all.13637DOI Listing
April 2019

Mechanically induced development and maturation of human intestinal organoids in vivo.

Nat Biomed Eng 2018 Jun 4;2(6):429-442. Epub 2018 Jun 4.

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

The natural ability of stem cells to self-organize into functional tissue has been harnessed for the production of functional human intestinal organoids. Although dynamic mechanical forces play a central role in intestinal development and morphogenesis, conventional methods for the generation of intestinal organoids have relied solely on biological factors. Here, we show that the incorporation of uniaxial strain, by using compressed nitinol springs, in human intestinal organoids transplanted into the mesentery of mice induces growth and maturation of the organoids. Assessment of morphometric parameters, transcriptome profiling, and functional assays of the strain-exposed tissue revealed higher similarities to native human intestine, with regards to tissue size and complexity, and muscle tone. Our findings suggest that the incorporation of physiologically relevant mechanical cues during the development of human intestinal tissue enhances its maturation and enterogenesis.
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http://dx.doi.org/10.1038/s41551-018-0243-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108544PMC
June 2018

Investigating innate immune mechanisms in early-life development and outcomes of food allergy.

J Allergy Clin Immunol 2018 09 7;142(3):790-792. Epub 2018 Aug 7.

Mary H Weiser Food Allergy Center, Department of Pathology, University of Michigan, Ann Arbor, Mich. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215521PMC
September 2018

Enhanced survival following oral and systemic Salmonella enterica serovar Typhimurium infection in polymeric immunoglobulin receptor knockout mice.

PLoS One 2018 1;13(6):e0198434. Epub 2018 Jun 1.

Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.

Background: Polymeric immunoglobulin receptor (pIgR) transport of secretory immunoglobulin A (SIgA) to mucosal surfaces is thought to promote gut integrity and immunity to Salmonella enterica serovar Typhimurium (S. Typhimurium), an invasive pathogen in mice. To elucidate potential mechanisms, we assessed intestinal barrier function and both oral and systemic S. Typhimurium virulence in pIgR knockout (KO) and wildtype (WT) mice.

Methods: In uninfected animals, we harvested jejunal segments for Ussing chamber analyses of transepithelial resistance (TER); mesenteric lymph nodes (mLN) for bacterial culture; and serum and stool for IgA. Separately, we infected mice either orally or intravenously (IV) with S. Typhimurium to compare colonization, tissue dynamics, and inflammation between KOs and WTs.

Results: Uninfected KOs displayed decreased TER and dramatically increased serum IgA and decreased fecal IgA vs. WT; however, KO mLNs yielded fewer bacterial counts. Remarkably, WTs challenged orally with S. Typhimurium exhibited increased splenomegaly, tissue colonization, and pro-inflammatory cytokines vs. pIgR KOs, which showed increased survival following either oral or IV infection.

Conclusions: Absence of pIgR compromises gut integrity but does not exacerbate bacterial translocation nor S. Typhimurium infection. These findings raise the possibility that immune adaptation to increased gut permeability and elevated serum IgA in the setting of SIgA deficiency provides compensatory protection against invasive gut pathogens.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198434PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983570PMC
December 2018

Solute carrier family 9, subfamily A, member 3 (SLC9A3)/sodium-hydrogen exchanger member 3 (NHE3) dysregulation and dilated intercellular spaces in patients with eosinophilic esophagitis.

J Allergy Clin Immunol 2018 12 4;142(6):1843-1855. Epub 2018 May 4.

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pathology, Mary H Weiser Food Allergy Center, Michigan Medicine, University of Michigan, Ann Arbor, Mich. Electronic address:

Background: Eosinophilic esophagitis (EoE) is characterized by histopathologic modifications of esophageal tissue, including eosinophil-rich inflammation, basal zone hyperplasia, and dilated intercellular spaces (DIS). The underlying molecular processes that drive the histopathologic features of EoE remain largely unexplored.

Objective: We sought to investigate the involvement of solute carrier family 9, subfamily A, member 3 (SLC9A3) in esophageal epithelial intracellular pH (pH) and DIS formation and the histopathologic features of EoE.

Methods: We examined expression of esophageal epithelial gene networks associated with regulation of pH in the EoE transcriptome of primary esophageal epithelial cells and an in vitro esophageal epithelial 3-dimensional model system (EPC2-ALI). Molecular and cellular analyses and ion transport assays were used to evaluate the expression and function of SLC9A3.

Results: We identified altered expression of gene networks associated with regulation of pH and acid-protective mechanisms in esophageal biopsy specimens from pediatric patients with EoE (healthy subjects, n = 6; patients with EoE, n = 10). The most dysregulated gene central to regulating pH was SLC9A3. SLC9A3 expression was increased within the basal layer of esophageal biopsy specimens from patients with EoE, and expression positively correlated with disease severity (eosinophils/high-power field) and DIS (healthy subjects, n = 10; patients with EoE, n = 10). Analyses of esophageal epithelial cells revealed IL-13-induced, signal transducer and activator of transcription 6-dependent SLC9A3 expression and Na-dependent proton secretion and that SLC9A3 activity correlated positively with DIS formation. Finally, we showed that IL-13-mediated, Na-dependent proton secretion was the primary intracellular acid-protective mechanism within the esophageal epithelium and that blockade of SLC9A3 transport abrogated IL-13-induced DIS formation.

Conclusions: SLC9A3 plays a functional role in DIS formation, and pharmacologic interventions targeting SLC9A3 function may suppress the histopathologic manifestations in patients with EoE.
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http://dx.doi.org/10.1016/j.jaci.2018.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448407PMC
December 2018

Peroxisomal β-oxidation regulates whole body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease.

JCI Insight 2018 03 22;3(6). Epub 2018 Mar 22.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Nonalcoholic fatty liver disease (NAFLD), a metabolic predisposition for development of hepatocellular carcinoma (HCC), represents a disease spectrum ranging from steatosis to steatohepatitis to cirrhosis. Acox1, a rate-limiting enzyme in peroxisomal fatty acid β-oxidation, regulates metabolism, spontaneous hepatic steatosis, and hepatocellular damage over time. However, it is unknown whether Acox1 modulates inflammation relevant to NAFLD pathogenesis or if Acox1-associated metabolic and inflammatory derangements uncover and accelerate potential for NAFLD progression. Here, we show that mice with a point mutation in Acox1 (Acox1Lampe1) exhibited altered cellular metabolism, modified T cell polarization, and exacerbated immune cell inflammatory potential. Further, in context of a brief obesogenic diet stress, NAFLD progression associated with Acox1 mutation resulted in significantly accelerated and exacerbated hepatocellular damage via induction of profound histological changes in hepatocytes, hepatic inflammation, and robust upregulation of gene expression associated with HCC development. Collectively, these data demonstrate that β-oxidation links metabolism and immune responsiveness and that a better understanding of peroxisomal β-oxidation may allow for discovery of mechanisms central for NAFLD progression.
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http://dx.doi.org/10.1172/jci.insight.93626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926941PMC
March 2018

Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria.

Sci Immunol 2017 12;2(18)

Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

We have a mutually beneficial relationship with the trillions of microorganisms inhabiting our gastrointestinal tract. However, maintaining this relationship requires recognizing these organisms as affable and restraining inflammatory responses to these organisms when encountered in hostile settings. How and when the immune system develops tolerance to our gut microbial members is not well understood. We identify a specific preweaning interval in which gut microbial antigens are encountered by the immune system to induce antigen-specific tolerance to gut bacteria. For some bacterial taxa, physiologic encounters with the immune system are restricted to this interval, despite abundance of these taxa in the gut lumen at later times outside this interval. Antigen-specific tolerance to gut bacteria induced during this preweaning interval is stable and maintained even if these taxa are encountered later in life in an inflammatory setting. However, inhibiting microbial antigen encounter during this interval or extending these encounters beyond the normal interval results in a failure to induce tolerance and robust antigen-specific effector responses to gut bacteria upon reencounter in an inflammatory setting. Thus, we have identified a defined preweaning interval critical for developing tolerance to gut bacteria and maintaining the mutually beneficial relationship with our gut microbiota.
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http://dx.doi.org/10.1126/sciimmunol.aao1314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759965PMC
December 2017

The vascular endothelial specific IL-4 receptor alpha-ABL1 kinase signaling axis regulates the severity of IgE-mediated anaphylactic reactions.

J Allergy Clin Immunol 2018 10 17;142(4):1159-1172.e5. Epub 2017 Nov 17.

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address:

Background: Severe IgE-mediated, food-induced anaphylactic reactions are characterized by pulmonary venous vasodilatation and fluid extravasation, which are thought to lead to the life-threatening anaphylactic phenotype. The underlying immunologic and cellular processes involved in driving fluid extravasation and the severe anaphylactic phenotype are not fully elucidated.

Objective: We sought to define the interaction and requirement of IL-4 and vascular endothelial (VE) IL-4 receptor α chain (IL-4Rα) signaling in histamine-abelson murine leukemia viral oncogene homology 1 (ABL1)-mediated VE dysfunction and fluid extravasation in the severity of IgE-mediated anaphylactic reactions in mice.

Methods: Mice deficient in VE IL-4Rα and models of passive and active oral antigen- and IgE-induced anaphylaxis were used to define the requirements of the VE IL-4Rα and ABL1 pathway in severe anaphylactic reactions. The human VE cell line (EA.hy926 cells) and pharmacologic (imatinib) and genetic (short hairpin RNA knockdown of IL4RA and ABL1) approaches were used to define the requirement of this pathway in VE barrier dysfunction.

Results: IL-4 exacerbation of histamine-induced hypovolemic shock in mice was dependent on VE expression of IL-4Rα. IL-4- and histamine-induced ABL1 activation in human VE cells and VE barrier dysfunction was ABL1-dependent. Development of severe IgE-mediated hypovolemia and shock required VE-restricted ABL1 expression. Treatment of mice with a history of food-induced anaphylaxis with the ABL kinase inhibitor imatinib protected the mice from severe IgE-mediated anaphylaxis.

Conclusion: IL-4 amplifies IgE- and histamine-induced VE dysfunction, fluid extravasation, and the severity of anaphylaxis through a VE IL-4Rα/ABL1-dependent mechanism. These studies implicate an important contribution by the VE compartment in the severity of anaphylaxis and identify a new pathway for therapeutic intervention of IgE-mediated reactions.
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http://dx.doi.org/10.1016/j.jaci.2017.08.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957775PMC
October 2018

Modeling T 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma.

Immunol Rev 2017 07;278(1):20-40

Paediatric Respiratory and Sleep Medicine Unit, Priority Research Centre for Healthy Lungs and GrowUpWell, University of Newcastle and Hunter Medical Research Institute, John Hunter Children's Hospital, Newcastle, NSW, Australia.

In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4 T-helper type-2 lymphocytes (T 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical T 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of T 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote T 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of T 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches.
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http://dx.doi.org/10.1111/imr.12549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492958PMC
July 2017
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