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Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency

Oda, Hirotsugu; Manthiram, Kalpana; Chavan, Pallavi Pimpale; Rieser, Eva; Veli, Oenay; Kaya, Oeykue; Rauch, Charles; ... Kastner, Daniel L; + view all (2024) Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency. Nature Immunology , 25 (5) pp. 764-777. 10.1038/s41590-024-01817-w. Green open access

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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.

Type: Article
Title: Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41590-024-01817-w
Publisher version: https://doi.org/10.1038/s41590-024-01817-w
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: LUBAC; HOIP; HOIL-1; SHARPIN; autoinflammation; cell death
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery-pp.ucl.ac.uk/id/eprint/10202615
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