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DOI 10.1038/s41590-024-01817-w

Медицинская библиотека · Nature immunology · 2024

Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.

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

СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаКлинический случайПеревод в очереди

Аннотация

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.

Для цитирования: 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. Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.. Nature immunology. 2024. DOI: 10.1038/s41590-024-01817-w.

Предметные рубрики MeSH

HumansImmunologic Deficiency SyndromesFemaleMaleNF-kappa BUbiquitin-Protein LigasesInflammationB-LymphocytesLoss of Function MutationFibroblastsIntracellular Signaling Peptides and ProteinsAnimalsMiceAllelesNerve Tissue ProteinsUbiquitins
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