Genetically-Determined Hyperfunction of the S100B/RAGE Axis Is a Risk Factor for Aspergillosis in Stem Cell Transplant Recipients
Open Access
- 17 November 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (11), e27962
- https://doi.org/10.1371/journal.pone.0027962
Abstract
Invasive aspergillosis (IA) is a major threat to the successful outcome of hematopoietic stem cell transplantation (HSCT), although individual risk varies considerably. Recent evidence has established a pivotal role for a danger sensing mechanism implicating the S100B/receptor for advanced glycation end products (RAGE) axis in antifungal immunity. The association of selected genetic variants in the S100B/RAGE axis with susceptibility to IA was investigated in 223 consecutive patients undergoing HSCT. Furthermore, studies addressing the functional consequences of these variants were performed. Susceptibility to IA was significantly associated with two distinct polymorphisms in RAGE (-374T/A) and S100B (+427C/T) genes, the relative contribution of each depended on their presence in both transplantation counterparts [patient SNPRAGE, adjusted hazard ratio (HR), 1.97; P = 0.042 and donor SNPRAGE, HR, 2.03; P = 0.047] or in donors (SNPS100B, HR, 3.15; P = 7.8e-4) only, respectively. Functional assays demonstrated a gain-of-function phenotype of both variants, as shown by the enhanced expression of inflammatory cytokines in RAGE polymorphic cells and increased S100B secretion in vitro and in vivo in the presence of the S100B polymorphism. These findings point to a relevant role of the danger sensing signaling in human antifungal immunity and highlight a possible contribution of a genetically-determined hyperfunction of the S100B/RAGE axis to susceptibility to IA in the HSCT setting.Keywords
This publication has 46 references indexed in Scilit:
- The G82S Polymorphism Promotes Glycosylation of the Receptor for Advanced Glycation End Products (RAGE) at Asparagine 81Online Journal of Public Health Informatics, 2011
- The Danger Signal S100B Integrates Pathogen– and Danger–Sensing Pathways to Restrain InflammationPLoS Pathogens, 2011
- Polo‐like kinase 1 regulates cell proliferation and is targeted by miR‐593* in esophageal cancerInternational Journal of Cancer, 2010
- Association of the RAGE G82S polymorphism with Alzheimer’s diseaseJournal of Neural Transmission, 2010
- Soluble RAGE: Therapy and biomarker in unraveling the RAGE axis in chronic disease and agingBiochemical Pharmacology, 2010
- Anti‐Aspergillus human host defence relies on type 1 T helper (Th1), rather than type 17 T helper (Th17), cellular immunityImmunology, 2010
- RAGE (Receptor for Advanced Glycation Endproducts), RAGE Ligands, and their role in Cancer and InflammationJournal of Translational Medicine, 2009
- Toll-like Receptor 4 Polymorphisms and Aspergillosis in Stem-Cell TransplantationThe New England Journal of Medicine, 2008
- Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus GroupClinical Infectious Diseases, 2008
- Pathogen Recognition and Innate ImmunityCell, 2006