The NOD2 Defect in Blau Syndrome Does Not Result in Excess Interleukin-1 Activity

Objective. Blau syndrome is a rare, autosomal-dominant, autoinflammatory disorder characterized by granulomatous arthritis, uveitis, and dermatitis. Genetics studies have shown that the disease is caused by single nonsynonymous substitutions in NOD-2, a member of the NOD-like receptor or NACHT-leucine-rich repeat (NLR) family of intracellular proteins. Several NLRs function in the innate immune system as sensors of pathogen components and participate in immunemediated cellular responses via the caspase 1 inflammasome. Mutations in a gene related to NOD-2, NLRP3, are responsible for excess caspase 1-dependent interleukin-1 beta (IL-1 beta) in cryopyrinopathies such as Muckle-wells syndrome. Furthermore, functional studies demonstrate that caspase 1-mediated release of IL-1 beta also involves NOD-2. The aim of this study was to test the hypothesis that IL-1 beta may mediate the inflammation seen in patients with Blau syndrome. Methods. IL-1 beta release was measured in peripheral blood mononuclear cells cultured in vitro, obtained from 5 Blau syndrome individuals with a NOD2 (CARD15) mutation. Results. We observed no evidence for increased IL-1 beta production in cells obtained from subjects with Blau syndrome compared with healthy control subjects. Furthermore, we presented 2 cases of Blau syndrome in which recombinant human IL-1 receptor antagonist (anakinra) was ineffective treatment. Conclusion. Taken together, these data suggest that in contrast to related IL-1 beta-dependent autoinflammatory cryopyrinopathies, Blau syndrome is not mediated by excess IL-1 beta or other IL-1 activity.