S Prakash Babu1, Y-Y K Chen1, S Bonne-Annee1, J Yang2, I Maric3, T G Myers4, T B Nutman1, A D Klion1. 1. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 2. Laboratory of Human Retrovirology and Immunoinformatics, Applied and Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA. 3. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA. 4. Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Abstract
BACKGROUND: Familial eosinophilia (FE) is a rare autosomal dominant inherited disorder characterized by the presence of lifelong peripheral eosinophilia (>1500/μL). Mapped to chromosome 5q31-q33, the genetic cause of FE is unknown, and prior studies have failed to demonstrate a primary abnormality in the eosinophil lineage. OBJECTIVE: The aim of this study was to identify the cells driving the eosinophilia in FE. METHODS: Microarray analysis and real-time PCR were used to examine transcriptional differences in peripheral blood mononuclear cells (PBMC), and in purified cell subsets from affected and unaffected family members belonging to a single large kindred. Cytokine levels in serum and PBMC culture supernatants were assessed by suspension array multiplexed immunoassays. RESULTS: Whereas IL-5 mRNA expression was significantly increased in freshly isolated PBMC from affected family members, this was not accompanied by increased mRNA expression of other Th2 cytokines (IL-4 or IL-13). Serum levels of IL-5 and IL-5 receptor α, but not IgE, were similarly increased in affected family members. Of note, IL-5 mRNA expression was significantly increased in purified CD3+ CD4+, CD14+, CD19+, and ILC2 cells from affected family members, as were IL-5 protein levels in supernatants from both stimulated PBMC and ILC2 cultures. CONCLUSIONS: These data are consistent with the hypothesis that the eosinophilia in FE is secondary to dysregulation of IL-5 production in PBMC (and their component subsets). Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
BACKGROUND:Familial eosinophilia (FE) is a rare autosomal dominant inherited disorder characterized by the presence of lifelong peripheral eosinophilia (>1500/μL). Mapped to chromosome 5q31-q33, the genetic cause of FE is unknown, and prior studies have failed to demonstrate a primary abnormality in the eosinophil lineage. OBJECTIVE: The aim of this study was to identify the cells driving the eosinophilia in FE. METHODS: Microarray analysis and real-time PCR were used to examine transcriptional differences in peripheral blood mononuclear cells (PBMC), and in purified cell subsets from affected and unaffected family members belonging to a single large kindred. Cytokine levels in serum and PBMC culture supernatants were assessed by suspension array multiplexed immunoassays. RESULTS: Whereas IL-5 mRNA expression was significantly increased in freshly isolated PBMC from affected family members, this was not accompanied by increased mRNA expression of other Th2 cytokines (IL-4 or IL-13). Serum levels of IL-5 and IL-5 receptor α, but not IgE, were similarly increased in affected family members. Of note, IL-5 mRNA expression was significantly increased in purified CD3+ CD4+, CD14+, CD19+, and ILC2 cells from affected family members, as were IL-5 protein levels in supernatants from both stimulated PBMC and ILC2 cultures. CONCLUSIONS: These data are consistent with the hypothesis that the eosinophilia in FE is secondary to dysregulation of IL-5 production in PBMC (and their component subsets). Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
Authors: Ronaldo Paolo L Panganiban; Mark H Pinkerton; Saumya Y Maru; Sarah J Jefferson; Alanna N Roff; Faoud T Ishmael Journal: Am J Clin Exp Immunol Date: 2012-11-15
Authors: Byung Hee Koh; Soo Seok Hwang; Joo Young Kim; Wonyong Lee; Min-Jong Kang; Chun Geun Lee; Jung-Won Park; Richard A Flavell; Gap Ryol Lee Journal: Proc Natl Acad Sci U S A Date: 2010-05-18 Impact factor: 11.205
Authors: Todd M Wilson; Irina Maric; Juhi Shukla; Margaret Brown; Carlo Santos; Olga Simakova; Paneez Khoury; Michael P Fay; Alexander Kozhich; Roland Kolbeck; Dean D Metcalfe; Amy D Klion Journal: J Allergy Clin Immunol Date: 2011-07-16 Impact factor: 10.793
Authors: A Y Lin; T B Nutman; D Kaslow; J J Mulvihill; L Fontaine; B J White; T Knutsen; K S Theil; P K Raghuprasad; A M Goldstein; M A Tucker Journal: Am J Med Genet Date: 1998-03-19
Authors: F D Martinez; S Solomon; C J Holberg; P E Graves; M Baldini; R P Erickson Journal: Am J Respir Crit Care Med Date: 1998-12 Impact factor: 21.405
Authors: J D Rioux; V A Stone; M J Daly; M Cargill; T Green; H Nguyen; T Nutman; P A Zimmerman; M A Tucker; T Hudson; A M Goldstein; E Lander; A Y Lin Journal: Am J Hum Genet Date: 1998-10 Impact factor: 11.025
Authors: Heimo Breiteneder; Zuzana Diamant; Thomas Eiwegger; Wytske J Fokkens; Claudia Traidl-Hoffmann; Kari Nadeau; Robyn E O'Hehir; Liam O'Mahony; Oliver Pfaar; Maria J Torres; De Yun Wang; Luo Zhang; Cezmi A Akdis Journal: Allergy Date: 2019-06-04 Impact factor: 13.146