Human LUBAC deficiency leads to autoinflammation and immunodeficiency by dysregulation in TNF-mediated cell death

作者：Hirotsugu Oda, Kalpana Manthiram, Pallavi Pimpale Chavan, Shuichiro Nakabo, Hye Sun Kuehn, David B. Beck, Jae Jin Chae, Michele Nehrebecky, Amanda K. Ombrello, Tina Romeo, Natalie Deuitch, Brynja Matthíasardóttir, Jim Mullikin, Jennifer Stoddard, Julie E. Niemela, Holly Anderton, Kate E. Lawlor, Hiroyuki Yoshitomi, Dan Yang, Manfred Boehm, Jeremy L. Davis, Pamela Mudd, Davide Randazzo, Wanxia Li Tsai, Massimo Gadina, Mariana J. Kaplan, Junya Toguchida, Christian T. Mayer, Sergio D. Rosenzweig, Kazuhiro Iwaï, John Silke, Bertrand Boisson, Jean‐Laurent Casanova, Anand Rao, Najoua Lalaoui, Ivona Aksentijevich, Daniel L. Kastner · 发表于：medRxiv · 年份：2022 · DOI：10.1101/2022.11.09.22281431 · 被引用次数：7 · 研究领域：Ubiquitin and proteasome pathways、interferon and immune responses、NF-κB Signaling Pathways

ABSTRACT The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL1 and SHARPIN, and is essential for proper immune responses. Patients with HOIP and HOIL1 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 the first patient with SHARPIN deficiency, manifesting fever, arthritis, colitis, chronic otitis media and hepatic glycogenosis but unexpectedly, not associated with dermatologic manifestations. Mechanistically, fibroblasts and B cells from patients with all three LUBAC deficiencies showed attenuated canonical NF-B response and propensity to apoptosis mediated by TNF superfamily members. Furthermore, the SHARPIN deficient patient showed substantial reduction of adenoidal germinal center B cell development. Treatment of the 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 apoptosis-mediated immune dysregulation in humans.