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 immune-mediated cellular responses via the caspase 1 inflammasome. Mutations in a gene related to NOD-2, NLRP3, are responsible for excess caspase 1-dependent interleukin-1beta (IL-1beta) in cryopyrinopathies such as Muckle-Wells syndrome. Furthermore, functional studies demonstrate that caspase 1-mediated release of IL-1beta also involves NOD-2. The aim of this study was to test the hypothesis that IL-1beta may mediate the inflammation seen in patients with Blau syndrome.


METHODS
IL-1beta 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-1beta 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.


CONCLUSIONS
Taken together, these data suggest that in contrast to related IL-1beta-dependent autoinflammatory cryopyrinopathies, Blau syndrome is not mediated by excess IL-1beta or other IL-1 activity.
Martin
Tammy M
TM
Oregon Health & Science University, Portland, OR 79239, USA. martint@ohsu.edu
Zhang
Zili
Z
Kurz
Paul
P
Rosé
Carlos D
CD
Chen
Hong
H
Lu
Huiying
H
Planck
Stephen R
SR
Davey
Michael P
MP
Rosenbaum
James T
JT
D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D003872:Dermatitis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013577:Syndrome; D017211:Treatment Failure; D014605:Uveitis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger