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Ann Paediatr Rheum. 2012; 1(Supplement 1): 6-6

Preliminary Results on Functional Analysis of a Card15/Nod2 Mutation (p.E383K) in Patients with Blau Syndrome

Paola Galozzi, Eliana Greco, Alessandra Gava, Paolo Sfriso, Daniela Basso, Mario Plebani, Leonardo Punzi.

Background: Blau syndrome (BS) is a rare, autosomal dominant autoinflammatory disease, characterized by granulomatous dermatitis, symmetrical arthritis and recurrent uveitis. To date, 11 mutations in CARD15/NOD2 gene have been identified as responsible for BS. Several in vitro observations have reported an elevated basal NF-κB activity and a “gain of function” hypothesis has been proposed, suggesting a spontaneous release of inflammatory cytokines from BS patients. We aimed at studying the functional profile of CARD15/NOD2 gene in patients carrying p.E383K mutation compared to healthy controls; in particular we focused on the cytokine levels since there is no evidence in literature.

Methods:IL-1β, IL-6, IL-8 and TNF-α releases were measured by ELISA assays in peripheral blood mononuclear cells (PBMC) obtained from 3 patients with p.E383K mutation. All patients were members of the only Italian affected family. Cells were cultured in vitro either with or without stimulation of MDP, LPS or a combination of both. Statistical comparisons were made between the means of patients and controls data, using multiple comparison with Fisher post hoc analysis.

Results: Stimulation with LPS or MDP did not risen cytokine levels in PBMC of both controls and patients as in non stimulated cells. Besides, the cytokine levels in patients appeared to be attenuated compared with the control group.
Both in patients and controls, there were no statistically significant differences in each cytokine release comparing LPS or MDP stimuli and no stimulation, except for IL-8 (p=0.011 and p=0.045, after LPS stimulation in patients and in controls respectively).
The synergistic stimulatory effect of the combination of MDP and LPS is observed for each cytokine only in control group (IL-1β, p=0.027; IL-6, p=0.001 and IL-8, p=0.002 referred to MDP; TNF-α, p=0.000 and 0.04 referred to MDP and LPS respectively).

Our findings for p.E383K mutation correlate with those reported in literature for patients carrying p.R334W/Q mutations, showing a similar cytokine profile of BS patients. It seems there isn’t a primarily mediation of IL-1β in Blau syndrome. More experiments should be performed in order to justify our results.

Key words: Card15/Nod2 Mutation, Blau Syndrome

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