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- Title
STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis.
- Authors
Smeekens, Sanne P; Plantinga, Theo S; van de Veerdonk, Frank L; Heinhuis, Bas; Hoischen, Alexander; Joosten, Leo A B; Arkwright, Peter D; Gennery, Andrew; Kullberg, Bart Jan; Veltman, Joris A; Lilic, Desa; van der Meer, Jos W M; Netea, Mihai G
- Abstract
We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency.
- Publication
PloS one, 2011, Vol 6, Issue 12, pe29248
- ISSN
1932-6203
- Publication type
Journal Article
- DOI
10.1371/journal.pone.0029248