Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the
nucleotide-binding oligomerization domain 2 (NOD2) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to
muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory
cytokines. Clinical manifestations of
Blau syndrome appear in patients before the age of four.
Skin manifestations resolve spontaneously in some cases; however, joint and
eye manifestations are progressive, and lead to serious complications, such as joint
contracture and
blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral
steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new
therapies have been reported, including
JAK inhibitors, anti-IL-6 and anti-IL-1
therapies, anti-TNF
therapy plays a central role in the treatment of
Blau syndrome. We recently performed an ex vivo study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal
cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with
Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in NOD2 lead to
granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of
Blau syndrome.