Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• The linear ubiquitin assembly complex (LUBAC), comprising HOIP, HOIL-1, and SHARPIN, is crucial for immune system regulation.
• Deficiencies in HOIP and HOIL-1 lead to severe immunodeficiency, autoinflammation, and glycogen storage disease.
• SHARPIN deficiency in mice causes severe dermatitis due to keratinocyte cell death.

Purpose of the Study:

• To investigate the clinical and cellular manifestations of SHARPIN deficiency in humans.
• To understand the role of SHARPIN in immune responses and cell death pathways.
• To explore potential therapeutic strategies for SHARPIN-related disorders.

Main Methods:

• Clinical case study of two individuals with SHARPIN deficiency.
• Analysis of fibroblast and B cell responses to TNF superfamily members.
• Assessment of NF-κB pathway activation and cell death propensity.
• Evaluation of secondary lymphoid germinal center B cell development.
• Clinical and transcriptomic analysis following anti-TNF therapy.

Main Results:

• SHARPIN-deficient individuals presented with autoinflammatory symptoms but lacked dermatological issues.
• Fibroblasts and B cells exhibited attenuated NF-κB responses and increased susceptibility to TNF-mediated cell death.
• Both SHARPIN- and HOIP-deficient individuals showed impaired germinal center B cell development.
• Anti-TNF therapy resulted in complete clinical and transcriptomic resolution of autoinflammation in one patient.

Conclusions:

• SHARPIN plays a critical role in preventing autoinflammation and regulating cell death in humans.
• LUBAC acts as a key regulator, controlling immune dysregulation driven by cell death.
• Targeting TNF pathways offers a promising therapeutic approach for SHARPIN deficiency.