The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.

线性泛素组装复合物 (LUBAC) 由 HOIP、HOIL-1 和 SHARPIN 组成，对于正确的免疫反应至关重要。 HOIP 和 HOIL-1 缺陷的个体会出现严重的免疫缺陷、自身炎症和糖原累积病。在小鼠中， Sharpin的缺失会因角质形成细胞过度死亡而导致严重的皮炎。在这里，我们报告了两名患有 SHARPIN 缺陷的个体，他们表现出自身炎症症状，但出乎意料的是没有皮肤病问题。这些个体的成纤维细胞和 B 细胞表现出减弱的典型 NF-κB 反应以及由 TNF 超家族成员介导的细胞死亡倾向。 SHARPIN 缺陷和 HOIP 缺陷的个体均表现出次级淋巴生发中心 B 细胞发育的显着减少。用抗 TNF 疗法治疗一名 SHARPIN 缺陷个体，使自身炎症在临床和转录组学上得到彻底解决。这些发现强调了 LUBAC 作为人类细胞死亡介导的免疫失调的看门人的关键功能。