抄録
Sporadic early-onset sarcoidosis (EOS) and familial Blau syndrome (BS) form a distinct set of autoinflammatory diseases, both of which onset in infancy and show a clinical triad of dermatitis, arthritis and uveitis histologically composed of noncaseating epithelioid cell granuloma. The responsible gene for EOS/BS is NOD2, encoding an intracellular receptor for muramyl dipeptide (MDP), the common component of bacterial cell wall peptidoglycan. The gain-of-function NOD2 mutations with MDP-independent basal NF-κB activation cause EOS/BS, while its loss-of-function mutations with impaired MDP-dependent NF-κB activation are associated with Crohn's disease and a part of sarcoidosis. As the result of analyzing genotype-phenotype relationship of Japanese EOS/BS cases, somewhat positive correlation was recognized between mutant NOD2-causing basal NF-κB activation and clinical severity, especially of ocular complications. Role of the basal NF-κB activation in monocytes has also been suggested by an inhibitory effect of thalidomide on ex vivo giant cell formation from EOS/BS patients' monocytes. Analysis of mutant NOD2-introduced human monocytic THP-1 cells, as well as the patients' samples, would provide further detailed molecular mechanisms of EOS/BS pathogenesis, in which a single point missense mutation causes a distinct pathological change forming epithelioid cell granuloma.
