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Human immunodeficiency reveals the Zn2+-dependence of B cell development

ABSTRACT: Despite the known importance of zinc for human immunity, molecular insights into its roles remain limited. Here we report a novel autosomal recessive disease characterised by early-onset infections, absent B cells and agammaglobulinaemia in five unrelated families. The immunodeficiency results from a series of hypomorphic and null alleles of SLC39A7, which encodes the endoplasmic-reticulum-to-cytoplasm zinc transporter, ZIP7. Using CRISPR-Cas9 editing and homologous recombination we have modelled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic lethality, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited increased phosphatase activity and decreased phosphorylation of signalling molecules that lie downstream of the pre-B and B cell receptors. Our findings highlight a specific role for Zn2+ in modulating B cell receptor signal strength and positive selection, and suggest how Zn2+ could modulate outcome in a variety of signalling contexts.

ORGANISM(S): Mus musculus

PROVIDER: GSE108178 | GEO | 2018/11/19

REPOSITORIES: GEO

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