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.
Highlights
Invasive aspergillosis (IA) is a disease typically affecting high-risk patients such as that undergoing allogeneic hematopoietic stem cell transplantation (HSCT)
The G82S polymorphism in receptor for advanced glycation end products (RAGE) was eventually excluded from the analyses given it displayed a minor allele frequency lower than 5% in our patient cohort
Several polymorphisms in genes involved in the damage-associated molecular patterns (DAMPs)/RAGE axis have been described to influence susceptibility to a number of inflammatory conditions [21,32,33,34,35,36]
Summary
Invasive aspergillosis (IA) is a disease typically affecting high-risk patients such as that undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Displaying apparently similar ‘‘immunocompromised’’ phenotypes, not all HSCT recipients eventually develop disease, suggesting that genetically-determined immune defects may play a role in defining susceptibility to IA [3]. DAMPs such as high mobility group box 1 (HMGB1) and S100 proteins mediate inflammatory reactions through interaction with the multiligand receptor for advanced glycation end products (RAGE) [10,11,12,13]. Ligand-RAGE engagement has been highlighted as an amplifying mechanism of inflammation in immune/inflammatory diseases through a positive feedback loop between ligand availability and receptor expression [14]
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