Division Highlights
Genetic Region Identified for a Children’s Food Allergy
Division director Marc Rothenberg, MD, PhD, post-doctorate Joseph Sherill, PhD, and colleagues have identified the first major gene location responsible for eosinophilic esophagitis (EE), a severe, often painful type of food allergy that leaves its victims unable to eat a wide variety of foods (Rothenberg ME, et al. Nature Genetics. 2010;42(4):289-91). The genome-wide analysis studies implicated the 5q22 chromosomal locus in the pathogenesis of EE and identified thymic stromal lymphopoietin (TSLP) as the most likely candidate gene in the region with specific genetic variants in TSLP and its receptor specifically linking with EE compared with other allergic diseases (Sherrill JD, et al. Journal of Allergy and Clinical Immunology. 126(1):160-165. 2010.).
National Registry to Track Eosinophilic Disorders
A $1.6 million federal economic stimulus grant awarded by the National Institute of Diabetes and Digestive and Kidney Diseases has helped to launch the Registry for Eosinophilic Gastrointestinal Disorders (REGID), developed by division director Marc Rothenberg, MD, PhD, along with division faculty Pablo Abonia, MD, and CCHMC co-investigators James Franciosi, MD, and Keith Marsolo, PhD; see www.regid.org. The registry is the first of its kind for eosinophilic disorders and will allow participating centers around the nation to build a database of research-accessible clinical information for thousands of patients coping with eosinophilic disorders.
Interleukin 15 Involved in Eosinophilic Esophagitis
A recent study by associate professor Anil Mishra, PhD, research associate Xiang Zhu, PhD, and colleagues has reported the significance of the induced expression and protein levels of interleukin 15 (IL-15) in human and experimental eosinophilic esophagitis (EE). Notably, transcript levels of IL-15 strongly correlated with esophageal eosinophils in patients with active EE and significantly decreased in patients with improved treated EE, and mouse models of allergen-induced EE demonstrated that the IL-15 receptor, IL-15Rα, was necessary for the development of EE (Zhu X, et al. Gastroenterology. 139(1):182-193.e7. 2010.).
Division Co-director Supports CCHMC’s National and Global Mission
During this past year, co-director Amal Assa’ad, MD, has exemplified the national and global mission of Cincinnati Children’s Hospital Medical Center (CCHMC) through her far-reaching dedication and valued efforts to improve child health. She has represented CCHMC as an invited speaker at plenary sessions and international symposia at three national meetings in the USA and five international meetings in South America, Europe, Asia, and the Middle East. In addition, she has contributed as a reviewer of the first evidence-based guidelines for food allergy by the World Allergy Organization (WAO), the WAO Diagnosis and Rationale Against Cow Milk Allergy (DRACMA) Guidelines, and as a writer and writing section chair for the NIH Expert Panel on Food Allergy Guidelines.
Mast Cells Regulate Homeostatic Intestinal Epithelial Migration and Barrier Function
A recent study by associate professor Simon Hogan, PhD, graduate student Katherine Groschwitz, and colleagues has identified a chymase / mast cell protease 4 -dependent mechanism by which mast cells regulate homeostatic intestinal epithelial migration and barrier function (Groschwitz, et al. Proceedings of the National Academy of Science of the United States of America. okok106(52):22381-6. 2009.).
Eosinophil Viability Increased in Acidic Microenvironment
A recent study by associate professor Nives Zimmermann, MD, graduate student Leah Kottyan, and colleagues has demonstrated that acidity inhibits eosinophil apoptosis and increases cellular viability in a dose-dependent manner between pH 7.5 and 6.0, mainly via the G protein-coupled receptor 65 (GPR65). Notably, GPR65-deficient mice had attenuated airway eosinophilia and increased apoptosis in two distinct models of allergic airway disease (Kottyan, et al. Blood. 114(13):2774-82. 2009.).
Allergic Reaction to Mecasermin
A recent case report by division co-director Amal Assa’ad, MD, clinical fellow Kelly Metz, MD, and colleagues details the second case of cutaneous and systemic allergic reaction to mecasermin, a recombinant human insulin-like growth factor 1 (IGF-1) approved by the Food and Drug Administration for treatment of growth failure in children with severe primary IGF-1 deficiency (Metz, et al. Annals of Allergy, Asthma & Immunology. 103(1):82-3. 2009.)
C-C chemokine receptor type 3 Promising Target for Age-related Macular Degeneration
A recent collaborative research study by division director Marc Rothenberg, MD, PhD, and adjunct assistant professor Ariel Munitz, PhD, has shown promising results for age-related macular degeneration (AMD). Choroidal neovascularsation, the major cause of blindness from AMD, was more effectively reduced by blockade of C-C chemokine receptor type 3 than by blockade of vascular endothelial growth factor A blockade, which is in present clinical use. Additionally, blockade of C-C chemokine receptor type 3 was also less toxic to the retina (Takeda, et al. Nature. 460(7252);225-30. 2009.).
T cell Subsets in Experimental Eosinophilic Esophagitis
A recent study by associate professor Anil Mishra, PhD, research associate Xiang Zhu, PhD, and colleagues has demonstrated an imbalance of esophageal effector and regulatory T cell subsets in a mouse model of eosinophilic esophagitis. Esophageal effector T cells increased whereas regulatory T cells decreased in allergen-challenged mice, suggesting that interaction of these T cell subsets may be required for protective and pathogenic immunity in eosinophilic esophagitis (Zhu, et al. American Journal of Physiology – Gastrointestinal and Liver Physiology. 297(3):G550-8. 2009.).
Involvement of Mast Cells in Eosinophilic Esophagitis
Whereas prior studies have primarily focused on the role of eosinophils in disease diagnosis and pathogenesis of eosinophilic esophagitis, the involvement of mast cells was investigated in a recent study by division director Marc Rothenberg, MD, PhD, assistant professor J. Pablo Abonia, MD, and colleagues. The investigators identified local mastocytosis and mast cell degranulation in the esophagi of patients with eosinophilic esophagitis, defined an esophageal mast cell-associated transcriptome that is significantly divergent from the eosinophil-associated transcriptome, and provided evidence for the involvement of KIT ligand in the pathogenesis of eosinophilic esophagitis (Abonia, et al. Journal of Allergy and Clinical Immunology. 126(1):112-119. 2010.).
Coordinate Interaction Between IL-13 and Epithelial Differentiation Cluster Genes in Eosinophilic Esophagitis
Aiming to uncover molecular explanations for eosinophilic esophagitis pathogenesis, a recent study by division director Marc Rothenberg, MD, PhD, instructor Carine Blanchard, PhD, and colleagues compared epithelial responses between healthy patients and those with eosinophilic esophagitis. Their findings establish that the epithelial response in eosinophilic esophagitis involves a cooperative interaction between IL-13 and expression of epithelial differentiation complex genes (Blanchard, et al. Journal of Immunology. 184(7):4033-41. 2010.).
Glucocorticoid-regulated Genes in Eosinophilic Esophagitis
A recent study by division director Marc Rothenberg, MD, PhD, post-doctorate Julie Caldwell, PhD, and colleagues provides evidence that swallowed glucocorticoid treatment directly affects esophageal gene expression in patients with EE. In particular, increased esophageal FK506-binding protein 5 (FKBP51) transcript levels identify glucocorticoid exposure in vivo and distinguish patients with EE who responded to fluticasone propionate treatment from untreated patients with active EE and patients without EE, suggesting that esophageal FKBP51 levels may have diagnostic and prognostic significance in patients with EE (Caldwell, et al. Journal of Allergy and Clinical Immunology. 125(4):879-88 e8. 2010.).
Polymorphisms in Sialic Acid-binding Immunoglobulin-like Lectin-8 Associated with Asthma Susceptibility
A recent collaborative research study by division director Marc Rothenberg, MD, PhD, and associate professor Nives Zimmermann, MD, has identified a significant association of polymorphisms in the sialic acid-binding immunoglobulin-like lectin-8 gene with susceptibility to asthma in diverse populations (Gao, et al. European Journal of Human Genetics. 18(6):713-9. 2010.).
Arginase I Suppresses Intestinal Inflammation During Acute Schistosomiasis
A recent collaborative research study by division director Marc Rothenberg, MD, PhD, and associate professor Nives Zimmermann, MD, has identified that macrophage-derived arginase I protects hosts from excessive tissue injury caused by worm eggs during acute schistosomiasis by suppressing interleukin 12 / interleukin 23 p40-driven intestinal inflammation (Herbert, et al. Journal of Immunology. 184(11):6438-46. 2010.).
Cationic Amino Acid Transporter 2 Regulates Lung Fibrosis in Allergic Airway Inflammation
Using mouse models of allergic airway inflammation and pulmonary fibrosis, a recent study by associate professor Nives Zimmermann, MD, research assistant Kathryn Niese, and colleagues has identified cationic amino acid transporter 2 as a regulator of fibrotic response in the lung (Niese KA, et al. Respiratory Research. 11(1):87. 2010.).
Differential Involvement of Interleukin 9/Interleukin 9 Receptor Pathway in Systemic and Oral Antigen-induced Anaphylaxis
Using mouse models of parenteral and oral antigen-induced anaphylaxis, a recent study by associate professor Simon Hogan, PhD, research assistant Heather Osterfeld, and colleagues has identified that parenteral antigen-induced systemic anaphylaxis is mediated by immunoglobulin G and immunoglobulin E -dependent pathways that can occur independently of interleukin 9 / interleukin 9 receptor signaling, whereas oral antigen-induced anaphylaxis is strictly immunoglobulin E-mediated and requires the interleukin 9 / interleukin 9 receptor signaling pathway (Osterfeld H, et al. Journal of Allergy and Clinical Immunology. 125(2):469-476.e2. 2010.).
Persistent Rotavirus Vaccine Shedding in Severe Combined Immunodeficiency: A Reason to Screen
A recent case report by division director Marc Rothenberg, MD, PhD, clinical fellow Burcin Uygungil, MD, and colleagues details a case of persistent rotavirus vaccine shedding in a child with previously undiagnosed severe combined immunodeficiency and highlights the need for neonatal screening measures for severe combined immunodeficiency as this case is not an isolated incident (Uygungil, et al. Journal of Allergy and Clinical Immunology. 125(1):270-1. 2010.).
Local B Cells and Immunoglobulin E Production in the Esophageal Mucosa in Eosinophilic Esophagitis
A recent study by division director Marc Rothenberg, MD, PhD, post doctorate Maria Vicario-Perez, PhD, and colleagues has demonstrated the heretofore unproven occurrence of both local immunoglobulin class switching to immunoglobulin E and immunoglobulin E production in the esophageal mucosa of patients with eosinophilic esophagitis. Sensitization and activation of mast cells involving local immunoglobulin E may therefore critically contribute to disease pathogenesis (Vicario, et al. Gut. 59(1):12-20. 2010.).
