Transcriptomic profiling of human SHARPIN deficiency

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN, and is essential for proper immune responses. Patients with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage. In mice, the loss of Sharpin leads to severe dermatitis due to excessive cell death in keratinocytes. Here we report two patients with SHARPIN deficiency manifesting autoinflammatory symptoms but unexpectedly, no dermatologic manifestations. Patient fibroblasts and B cells showed attenuated canonical NF-κB response and propensity to cell death mediated by TNF superfamily members. Both SHARPIN- and HOIP-deficient patients showed substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient patient with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical role of LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans. RNAseq using the pre- and post-treatment whole blood RNA from a patient with a biallelic loss-of-function mutation in SHARPIN

线性泛素组装复合体（linear ubiquitin assembly complex, LUBAC）由HOIP、HOIL-1与SHARPIN三种亚基构成，是机体维持正常免疫应答所必需的核心复合物。HOIP与HOIL-1缺陷患者会表现出重度免疫缺陷、自身炎症反应及糖原贮积病症。在小鼠模型中，Sharpin缺失会因角质形成细胞过度死亡引发重度皮炎。本研究报道两例SHARPIN缺陷患者，其临床表现为自身炎症症状，但出乎意料地未出现皮肤病症。患者的成纤维细胞与B细胞呈现经典NF-κB信号通路应答减弱，且更易发生肿瘤坏死因子（tumor necrosis factor, TNF）超家族成员介导的细胞死亡。SHARPIN缺陷与HOIP缺陷患者均出现次级淋巴器官生发中心B细胞发育显著受损的表型。对其中一例SHARPIN缺陷患者采用抗TNF疗法治疗后，其自身炎症反应在临床与转录组层面均得到完全缓解。上述研究结果证实，LUBAC作为调控人类细胞死亡介导的免疫失调的关键守门蛋白，发挥着至关重要的作用。本研究使用携带SHARPIN双等位基因功能丧失突变患者的治疗前后全血RNA开展了RNA测序（RNAseq）。