a Department of Pathobiology , Lerner Research Institute, Cleveland Clinic , Cleveland , OH , USA.
b Department of Rheumatic and Immunologic Disease , Orthopaedic and Rheumatologic Institute, Cleveland Clinic , Cleveland , OH , USA.
Autoimmunity. 2018 Mar;51(2):53-61. doi: 10.1080/08916934.2018.1442442. Epub 2018 Feb 22.
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 variant (IVS8) and four patients also carried a concurrent NOD2 R702W variant (IVS8/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. However, NOD2 transcript level and basal p38 mitogen-activated protein kinase (MAPK) activity were significantly elevated in PBMCs from IVS8 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 patient resulted in marked clinical improvement. In contrast, MDP-stimulated NF-κB activity was uniquely suppressed in haplotype IVS8/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.
姚综合征（YAOS）是一种系统性自身炎症性疾病（SAID），以前称为核苷酸结合寡聚化结构域-2（NOD2）相关自身炎症性疾病。由于最近发现了 YAOS，其发病机制的分子机制尚不清楚。由于 YAOS 的特征性基因型特征是特定的 NOD2 变体，因此我们的研究检查了 10 名 YAOS 患者和 6 名健康个体的外周血单核细胞（PBMC）中的 NOD2 表达，转录剪接，信号通路激活和细胞因子谱。所有参与者均进行了 NOD2 变体的基因分型；所有 YAOS 患者均为 NOD2 IVS8 变体（IVS8）杂合子，有 4 名患者还携带 NOD2 R702W 变体（IVS8/R702W 单体型）。与其他 SAIDs 相似，YAOS 患者的血浆 TNFα，IL-1β，IL-6，IFNγ和 S100A12 水平没有改变。携带 NOD2 IVS8 不会影响 NOD2 转录本的内含子 8 剪接。但是，IVS8 YAOS 患者的 PBMC 中 NOD2 转录本水平和基础 p38 丝裂原活化蛋白激酶（MAPK）活性显着升高。此外，这些患者的细胞具有基础 IL-6 分泌，该分泌受 muramyl dipeptide（MDP）刺激增强。托珠单抗治疗 YAOS IVS8 患者可导致明显的临床改善。相反，MDP 刺激的 NF-κB 活性仅在单体型 IVS8/R702W 患者中受到抑制，TNFα 分泌也是如此。我们的研究首次表明，NOD2 的表达和途径激活在 YAOS 中异常，并且特定的 NOD2 基因型导致不同的 NOD2 表达和细胞因子谱。这些发现将来也可能有助于选择治疗策略。
