Background/Purpose: Yao Syndrome (YS) is a systemic autoinflammatory disease formerly termed Nucleotide-binding oligomerization domain 2 (NOD2)-associated AutoInflammatory Disease (NAID) due to its association with specific genetic variants in NOD2. This study examined the function of NOD2 in YS patients.

Methods:

Study subjects (10 YS patients and 5 healthy individuals) were screened for NOD2 variants by sequencing or TaqMan probes. Plasma cytokine levels, NOD2 expression, and transcript splicing were measured by ELISA, qRT-PCR, and PCR, respectively. Functional assays were performed with peripheral blood mononuclear cells to assess NOD2activation in response to its ligand, muramyl dipeptide. The efficacy of tocilizumab therapy was examined in a YS patient.

Results: All YS patients were heterozygous for the NOD2 IVS8⁺¹⁵⁸ variant and 4 were compound heterozygous for R702W. Plasma levels of TNFα, IL-1β, IFNγ, and S100A12 were unaltered in YS patients as compared to healthy individuals. Splicing of intron 8 was unaffected by carriage of the IVS8⁺¹⁵⁸ variant; however, NOD2 expression was elevated in IVS8⁺¹⁵⁸ heterozygous patients but not in IVS8⁺¹⁵⁸/R702W compound heterozygotes. MDP-stimulated NFκB activity was suppressed uniquely in compound heterozygotes and correlated with lower TNFα secretion. IL-6 secretion was enhanced specifically in IVS8⁺¹⁵⁸ heterozygotes and anti-IL6 receptor antibody (tocilizumab) treatment of a YS patient with this NOD2 genotype resulted in significant clinical improvement.

Conclusion:

Our findings indicate that YS is associated with dysfunction of NOD2, and specific NOD2 genotypes associate with distinct functional subtypes. This study suggests that NOD2 genotype could be used as a biomarker in the selection of therapeutic modalities for YS and warrants further investigation in clinical trials.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/functional-consequences-of-nod2-gene-variants-in-patients-with-nod2-associated-autoinflammatory-disease/