Samaneh Zoghi, Austria
LBI_RUD Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesPresenter of 1 Presentation
HEM1 DEFICIENCY CAUSES ABERRANT B-CELL DEVELOPMENT AND AUTOIMMUNITY
Abstract
Background and Aims
HEM1 is a hematopoietic cell-specific essential subunit of the WAVE regulatory complex (WRC) that activates ARP2/3-mediated actin branching and lamellipodia formation. To date no human disease has been linked to mutations in HEM1 (also known as NCKAP1L) and the significance of HEM1 for immunity is unknown.
Methods
We performed exome sequencing of Patient1 (P1) to identify the underlying genetic defect. We used patient derived material and characterized a Hem1-/- mouse model for further molecular and cellular analysis.
Results
P1 was diagnosed with SLE due to skin rashes, oral ulcers, photosensitivity, joint pain and positive serum levels of anti-dsDNA antibodies at early age. P2 presented with recurrent upper respiratory tract infections. At a cellular level, HEM1-deficiency led to destabilization of the WRC, reduced filamentous actin and failure to assemble lamellipodia. We show that Hem1-/- mice display systemic autoimmunity and splenomegaly, phenocopying the human disease. Human and murine Hem1-deficient B cells show increased activated and immature/transitional cell populations. Single-cell sequencing of Hem1-/- cells identified dysregulated BAFFR levels suggesting aberrant B cell development resulting in increased B-cell apoptosis and biased differentiation towards autoreactive plasmablasts.
Conclusions
We identified HEM1 deficiency underlying an inborn error of immunity with systemic autoimmunity in the patients. HEM1 deficiency in humans and mice uncovers a pivotal role of the WRC in B-cell differentiation and immune homeostasis.