학술논문
Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency
Document Type
Original Paper
Author
Oda, Hirotsugu; Manthiram, Kalpana; Chavan, Pallavi Pimpale; Rieser, Eva; Veli, Önay; Kaya, Öykü; Rauch, Charles; Nakabo, Shuichiro; Kuehn, Hye Sun; Swart, Mariël; Wang, Yanli; Çelik, 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.; Matthíasardóttir, 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; Walczak, Henning; Lalaoui, Najoua; Aksentijevich, Ivona; Kastner, Daniel L.
Source
Nature Immunology. 25(5):764-777
Subject
Language
English
ISSN
1529-2908
1529-2916
1529-2916
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.
Here, the authors describe biallelic loss-of-function variants in human SHARPIN in individuals with autoinflammation and immunodeficiency, termed sharpenia. They also successfully treat one of these individuals with TNF inhibitors.
Here, the authors describe biallelic loss-of-function variants in human SHARPIN in individuals with autoinflammation and immunodeficiency, termed sharpenia. They also successfully treat one of these individuals with TNF inhibitors.