| Title: |
Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency |
| Authors: |
Oda, Hirotsugu; Manthiram, Kalpana; Chavan, Pallavi Pimpale; Rieser, Eva; Veli, Oenay; Kaya, Oeykue; Rauch, Charles; Nakabo, Shuichiro; Kuehn, Hye Sun; Swart, Mariel; Wang, Yanli; Celik, 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; Matthiasardottir, 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) pp. 764-777. (2024) |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2024 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
LUBAC; HOIP; HOIL-1; SHARPIN; autoinflammation; cell death |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10202615/1/Biallelic.pdf; https://discovery.ucl.ac.uk/id/eprint/10202615/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10202615/1/Biallelic.pdf; https://discovery.ucl.ac.uk/id/eprint/10202615/ |
| Rights: |
open |
| Accession Number: |
edsbas.D4E06757 |
| Database: |
BASE |