Development of CINCA syndrome therapy based upon the pathophysiology of CINCA syndrome elucidated by cytoengineering.

CINCA综合征是一种由NLRP 3基因突变引起的自身炎症性疾病，伴有发热、荨麻疹、无菌性脑膜炎和关节炎。通过桑格测序，已知40%的CINCA综合征患者缺乏NLRP 3突变。最近，我们报道了“突变阴性”CINCA综合征可以由NLRP 3体细胞嵌合体引起。在这项研究中，我们收集了全球范围内的“突变阴性“CINCA患者，并证明69%的“突变阴性“CINCA患者是由NLRP 3嵌合体引起的。我们还开发了一种更简单，劳动密集度更低的方法，通过下一代测序来鉴定NLRP 3嵌合体。此外，我们还创造了源自CINCA综合征的诱导多能干细胞（iPSC），并开发了将iPSC分化为巨噬细胞和软骨细胞的方法，可用于阐明CINCA综合征病理生理学的研究。

CINCA syndrome is an autoinflammatory disease with fever, urticarial rash, aseptic meningitis, and arthritis caused by NLRP3 gene mutations. It has been known that 40% of the CINCA syndrome patients lack NLRP3 mutations by Sanger sequencing. Recently we have reported"mutation-negative"CINCA syndrome can be caused by NLRP3 somatic mosaicism. In this study, we have collected"mutation-negative"CINCA patients worldwide and demonstrated that 69% of the"mutation-negative"CINCA patients are caused by NLRP3 mosaicism. We also developed an easier and less labor-intensive method to identify NLRP3 mosaicism by next-generation sequencing. Furthermore, we created induced pluripotent stem cells(iPSC) derived from CINCA syndrome and developed methods to differentiate the iPSC to macrophages and chondrocytes, which can be utilized for research on the elucidation of the pathophysiology of the CINCA syndrome.