Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.
Hirotsugu OdaKalpana ManthiramPallavi Pimpale ChavanEva RieserÖnay VeliÖykü KayaCharles RauchShuichiro NakaboHye Sun KuehnMariël SwartYanli WangNisa Ilgim ÇelikAnne MolitorVahid ZiaeeNasim MovahediMohammad ShahrooeiNima ParvanehNasrin Alipour-OlyeiRaphaël CarapitoQin XuSilvia PreiteDavid B BeckJae Jin ChaeMichele NehrebeckyAmanda K OmbrelloPatrycja HoffmannTina RomeoNatalie T DeuitchBrynja MatthíasardóttirMay Christine V MalicdanHirsh KomarowJennifer StoddardJulie NiemelaA Kerry DobbsColin L SweeneyHolly AndertonKate E LawlorHiroyuki YoshitomiDan YangManfred BoehmJeremy DavisPamela MuddDavide RandazzoWanxia Li TsaiMassimo GadinaMariana J KaplanJunya ToguchidaChristian Thomas MayerSergio D RosenzweigLuigi Daniele NotarangeloKazuhiro IwaiJohn SilkePamela L SchwartzbergBertrand BoissonJean Laurent CasanovaSeiamak BahramAnand Prahalad RaoNieves PeltzerHenning WalczakNajoua LalaouiIvona AksentijevichDaniel L KastnerPublished in: Nature immunology (2024)
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.
Keyphrases
- cell death
- immune response
- cell cycle arrest
- rheumatoid arthritis
- early onset
- endothelial cells
- oxidative stress
- wild type
- signaling pathway
- single cell
- lps induced
- cell proliferation
- rna seq
- toll like receptor
- intellectual disability
- type diabetes
- physical activity
- single molecule
- drug induced
- inflammatory response
- nuclear factor
- dendritic cells
- replacement therapy
- combination therapy
- insulin resistance