Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency

Oda, H; Manthiram, K; Chavan, PP; Rieser, E; Veli, &#214;; Kaya, &#214;; Rauch, C; Nakabo, S; Kuehn, HS; Swart, M; Wang, Y; &#199;elik, NI; Molitor, A; Ziaee, V; Movahedi, N; Shahrooei, M; Parvaneh, N; Alipour-Olyei, N; Carapito, R; Xu, Q; Preite, S; Beck, DB; Chae, JJ; Nehrebecky, M; Ombrello, AK; Hoffmann, P; Romeo, T; Deuitch, NT; Matth&#237;asard&#243;ttir, B; Mullikin, J; Komarow, H; Stoddard, J; Niemela, J; Dobbs, K; Sweeney, CL; Anderton, H; Lawlor, KE; Yoshitomi, H; Yang, D; Boehm, M; Davis, J; Mudd, P; Randazzo, D; Tsai, WL; Gadina, M; Kaplan, MJ; Toguchida, J; Mayer, CT; Rosenzweig, SD; Notarangelo, LD; Iwai, K; Silke, J; Schwartzberg, PL; Boisson, B; Casanova, JL; Bahram, S; Rao, AP; Peltzer, N; Walczak, H; Lalaoui, N; Aksentijevich, I; Kastner, DL

Author(s): Oda, H; Manthiram, K; Chavan, PP; Rieser, E; Veli, Ö; Kaya, Ö; Rauch, C; Nakabo, S; Kuehn, HS; Swart, M; Wang, Y; Çelik, NI; Molitor, A; Ziaee, V; Movahedi, N; Shahrooei, M; Parvaneh, N; Alipour-Olyei, N; Carapito, R; Xu, Q; Preite, S; Beck, DB; Chae, JJ; Nehrebecky, M; Ombrello, AK; Hoffmann, P; Romeo, T; Deuitch, NT; Matthíasardóttir, B; Mullikin, J; Komarow, H; Stoddard, J; Niemela, J; Dobbs, K; Sweeney, CL; Anderton, H; Lawlor, KE; Yoshitomi, H; Yang, D; Boehm, M; Davis, J; Mudd, P; Randazzo, D; Tsai, WL; Gadina, M; Kaplan, MJ; Toguchida, J; Mayer, CT; Rosenzweig, SD; Notarangelo, LD; Iwai, K; Silke, J; Schwartzberg, PL; Boisson, B; Casanova, JL; Bahram, S; Rao, AP; Peltzer, N; Walczak, H; Lalaoui, N; Aksentijevich, I; Kastner, DL;
Details: Publication Year 2024-05,Volume 25,Issue #5,Page 764-777
Journal Title: Nature immunology
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.
Publisher: Springer Nature
Keywords: Humans; *Immunologic Deficiency Syndromes/genetics/immunology; Female; Male; NF-kappa B/metabolism; Ubiquitin-Protein Ligases/genetics; Inflammation/immunology/genetics; B-Lymphocytes/immunology; Loss of Function Mutation; Fibroblasts/metabolism/immunology; Intracellular Signaling Peptides and Proteins/genetics/metabolism; Animals; Mice; Alleles; *Nerve Tissue Proteins; *Ubiquitins
Research Division(s): Inflammation
PubMed ID: 38609546
Publisher's Version: https://doi.org/10.1038/s41590-024-01817-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-04-18 09:15:19

Last Modified: 2024-05-09 09:00:53