Immunological analysis of Blau syndrome, a unique autoinflammatory state

Autoinflammation typically arises from mutations affecting molecules such as inflammasome backbones that give rise to gain-of-function (GOF) pro-inflammatory activity requiring little or no normal ligand stimulation. This has been assumed to be the case in the auto-inflammation known as Blau syndrome wherein mutations usually present in the nucleotide oligomerization domain of the CARD15 gene encoding NOD2 result in widespread granulomatous inflammation, seemingly in the absence of NOD2 stimulation by its canonical ligand, muramyl dipeptide (MDP); moreover, despite such lack of ligand stimulation, NOD2 bearing a Blau mutation is thought to cause inflammation by initiating conventional downstream signaling that ultimately results in NF-κB activation. However, newer data concerning Blau syndrome pathogenesis suggest a more complex picture in which Blau CARD15 mutations cause inflammation by unconventional and/or loss of conventional signaling and which depend, at least in part, from a genetic defect which arises from loss-of-function pro-inflammatory activity. In this review, we present and analyze these newer data with the aim of defining a further pathway to the understanding and treatment of this disease.