Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome

Abstract

Yao syndrome (YAOS) is a systemic autoinflammatory disease (SAID), formerly termed nucleotide-binding oligomerization domain-2 (NOD2)-associated autoinflammatory disease. Due to the recent identification of YAOS, the molecular mechanisms underlying its disease pathogenesis are unclear. With specific NOD2 variants as characteristic genotypic features of YAOS, our study examined NOD2 expression, transcript splicing, signaling pathway activation, and cytokine profiles in peripheral blood mononuclear cells (PBMCs) from 10 YAOS patients and six healthy individuals. All participants were genotyped for NOD2 variants; all YAOS patients were heterozygous for the NOD2 IVS8⁺¹⁵⁸ variant (IVS8⁺¹⁵⁸) and four patients also carried a concurrent NOD2 R702W variant (IVS8⁺¹⁵⁸/R702W haplotype). Resembling other SAIDs, plasma levels of TNFα, IL-1β, IL-6, IFNγ, and S100A12 were unaltered in YAOS patients. Intron-8 splicing of NOD2 transcripts was unaffected by carriage of NOD2 IVS8⁺¹⁵⁸. However, NOD2 transcript level and basal p38 mitogen-activated protein kinase (MAPK) activity were significantly elevated in PBMCs from IVS8⁺¹⁵⁸ YAOS patients. Moreover, these patients’ cells had elevated basal IL-6 secretion that was enhanced by muramyl dipeptide (MDP) stimulation. Tocilizumab treatment of a YAOS IVS8⁺¹⁵⁸ patient resulted in marked clinical improvement. In contrast, MDP-stimulated NF-κB activity was uniquely suppressed in haplotype IVS8⁺¹⁵⁸/R702W patients, as was TNFα secretion. Our study demonstrates for the first time that NOD2 expression and pathway activation are aberrant in YAOS, and specific NOD2 genotypes result in distinct NOD2 expression and cytokine profiles. These findings may also help select therapeutic strategies in the future.

Keywords:

• Autoinflammatory disease
• NOD2
• Yao syndrome
• anti-cytokine therapy
• genetics

Acknowledgements

We thank Xiaobo Liu for her assistance with the statistical analyses of the data and all the members of the laboratory for their support. We are grateful for patients and healthy individuals for their participation in the study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Department of Defense (PR110887 to C.M.); the National Institutes of Health Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences Component of the National Institutes of Health and NIH Roadmap for Medical Research; and the Cleveland Clinic Department of Rheumatic and Immunologic Disease. The study sponsors were not involved in the study design, acquisition of data, or interpretation of results.