PT  - JOURNAL ARTICLE
AU  - Salzer, Elisabeth
AU  - Zoghi, Samaneh
AU  - Kiss, Máté G.
AU  - Kage, Frieda
AU  - Rashkova, Christina
AU  - Stahnke, Stephanie
AU  - Haimel, Matthias
AU  - Platzer, René
AU  - Caldera, Michael
AU  - Ardy, Rico Chandra
AU  - Hoeger, Birgit
AU  - Block, Jana
AU  - Medgyesi, David
AU  - Sin, Celine
AU  - Shahkarami, Sepideh
AU  - Kain, Renate
AU  - Ziaee, Vahid
AU  - Hammerl, Peter
AU  - Bock, Christoph
AU  - Menche, Jörg
AU  - Dupré, Loïc
AU  - Huppa, Johannes B.
AU  - Sixt, Michael
AU  - Lomakin, Alexis
AU  - Rottner, Klemens
AU  - Binder, Christoph J.
AU  - Stradal, Theresia E. B.
AU  - Rezaei, Nima
AU  - Boztug, Kaan
TI  - The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity
AID  - 10.1126/sciimmunol.abc3979
DP  - 2020 Jul 10
TA  - Science Immunology
PG  - eabc3979
VI  - 5
IP  - 49
4099  - http://immunology.sciencemag.org/content/5/49/eabc3979.short
4100  - http://immunology.sciencemag.org/content/5/49/eabc3979.full
SO  - Sci. Immunol.2020 Jul 10; 5
AB  - Diagnosis and treatment of inborn errors in immunity remains a challenge. Here, Salzer, et al. have studied two siblings who were hospitalized for recurrent pediatric infections. By carrying out exome sequencing and functional analyses, they have identified homozygous loss-of-function mutations in genes encoding the protein HEM1 in both individuals. HEM1 is a component of actin-remodeling complexes that have a wide range of functions, from cell migration to cell division. By studying immune cells from these individuals and by generating HEM1-deficient mice, the authors have established HEM1 as a key regulator of T and B cell functions. They have characterized in-depth the role of HEM1 in B cells and propose that HEM1 modulates signaling downstream of the B cell receptor.The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1−/− mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity.