美国国立卫生研究院Daniel L. Kastner等研究人员合作发现，双等位人类SHARPIN功能缺失会诱发自身炎症和免疫缺陷症。相关论文于2024年4月12日在线发表在《自然—免疫学》杂志上。

研究人员表示，线性泛素组装复合物（LUBAC）由HOIP、HOIL-1和SHARPIN组成，对于适当的免疫反应至关重要。缺乏HOIP和HOIL-1的个体会出现严重的免疫缺陷、自身炎症和糖原贮积症。在小鼠中，由于角质细胞过度死亡，Sharpin的缺失会导致严重的皮炎。

研究人员报告了两名SHARPIN缺乏症患者，他们表现出自身炎症症状，但意外地没有皮肤病问题。这两个人的成纤维细胞和B细胞显示出典型的NF-κB反应减弱，以及由TNF超家族成员介导的细胞死亡倾向。SHARPIN缺陷者和HOIP缺陷者的继发性淋巴生发中心B细胞发育，均显著减少。用抗TNF疗法治疗一名SHARPIN缺陷个体后，自身炎症的临床和转录组学症状完全消失。这些发现凸显了LUBAC作为细胞死亡介导的人体免疫失调守门员的关键功能。

附：英文原文

Title: Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency

Author: Oda, Hirotsugu, Manthiram, Kalpana, Chavan, Pallavi Pimpale, Rieser, Eva, Veli, nay, Kaya, yk, Rauch, Charles, Nakabo, Shuichiro, Kuehn, Hye Sun, Swart, Maril, Wang, Yanli, elik, Nisa Ilgim, Molitor, Anne, Ziaee, Vahid, Movahedi, Nasim, Shahrooei, Mohammad, Parvaneh, Nima, Alipour-olyei, Nasrin, Carapito, Raphael, Xu, Qin, Preite, Silvia, Beck, David B., Chae, Jae Jin, Nehrebecky, Michele, Ombrello, Amanda K., Hoffmann, Patrycja, Romeo, Tina, Deuitch, Natalie T., Matthasardttir, Brynja, Mullikin, James, Komarow, Hirsh, Stoddard, Jennifer, Niemela, Julie, Dobbs, Kerry, Sweeney, Colin L., Anderton, Holly, Lawlor, Kate E., Yoshitomi, Hiroyuki, Yang, Dan, Boehm, Manfred, Davis, Jeremy, Mudd, Pamela, Randazzo, Davide, Tsai, Wanxia Li, Gadina, Massimo, Kaplan, Mariana J., Toguchida, Junya, Mayer, Christian T., Rosenzweig, Sergio D., Notarangelo, Luigi D., Iwai, Kazuhiro, Silke, John, Schwartzberg, Pamela L., Boisson, Bertrand, Casanova, Jean-Laurent, Bahram, Seiamak, Rao, Anand Prahalad, Peltzer, Nieves

Issue&Volume: 2024-04-12

Abstract: 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.

DOI: 10.1038/s41590-024-01817-w

Source: https://www.nature.com/articles/s41590-024-01817-w