ORMDL3 and allergic asthma: From physiology to pathology

Abstract

There is a strong genetic component to asthma, and numerous genome-wide association studies have identified ORM1 (yeast)like protein 3 (ORMDL3) as a gene associated with asthma susceptibility. However, how ORMDL3 contributes to asthma pathogenesis and its physiologic functions is not well understood and a matter of great debate. This rostrum describes recent advances and new insights in understanding of the multifaceted functions of ORMDL3 in patients with allergic asthma. We also suggest a potential unifying paradigm and discuss molecular mechanisms for the pathologic functions of ORMDL3 in asthma related to its evolutionarily conserved role in regulation of sphingolipid homeostasis. Finally, we briefly survey the utility of sphingolipid metabolites as potential biomarkers for allergic asthma.

Metabolomics and allergy: Opening Pandora’s box

“…The mechanisms leading from sphingolipid metabolism to T H 2 expression will have to be further explored. The observation that the ORMDL3 gene, strongly associated with allergic asthma, may contribute to the modulation of sphingolipid levels in the lung 10 supports the data presented here, and suggests that similar alterations of sphingolipid metabolism may play a role in the pathogenesis of not only asthma but possibly also FA. From these demonstrations may derive the long-term perspective of therapeutic interventions on sphingolipid metabolites.…”

Untargeted metabolomic profiling identifies disease-specific signatures in food allergy and asthma

“…[43][44][45] This observation suggests a key role for sphingolipid homeostasis in lung allergic inflammation, offering candidate disease biomarkers and potential targets for therapeutic intervention. 46 The results of our studies similarly suggest an unexpected and potentially important role for sphingolipid metabolism in patients with FA and also the potential use of sphingolipid metabolites as disease biomarkers.…”

Role of early life immune regulation in asthma development

“…These genes are involved in multiple important processes like gene transcription, apoptosis, and sphingolipid synthesis. Importantly, also the calcium homeostasis in the endoplasmic reticulum is regulated by ORMDL3 with important consequences for T-cell activation and inflammation [46]. Since newborns carrying the genetic risk variant within the 17q21 locus showed significantly increased secretion of IL-17, a functional role of this locus on Th17 cell development during early immune maturation is suggested [47].…”