Consuelo Anzilotti, United Kingdom

Oxford University Hospitals NHS Foundation Trust Clinical Immunology
I did my Specialty in Clinical Immunology, followed by my PhD in autoimmune conditions, in Italy (2000-2008). I moved to the UK in 2009 and have been doing research on immunodeficiency since, mainly focussing on defects of B lymphocytes. I work part time in the Clinical Immunology Department and part time for the University of Oxford, maintaining my clinical and research interests. I have two kids, one husband and a garden to look after in my spare time!

Presenter Of 2 Presentations

INGID No Topic Needed

DERMATOLOGICAL ISSUES

Lecture Time
11:50 - 12:15
Room
Silver
Date
19.09.2019, Thursday
Session Time
11:00 - 12:30
Presentation Topic
No Topic Needed
Oral Communications B Cell Biology

AN ESSENTIAL ROLE FOR THE ZN2+ TRANSPORTER ZIP7 IN B CELL DEVELOPMENT

Lecture Time
11:20 - 11:30
Room
Gold
Date
20.09.2019, Friday
Session Time
11:00 - 12:40
Presentation Topic
B Cell Biology

Abstract

Background and Aims

Agammaglobulinaemia with absent B cells comprises diseases due to mutations in BTK, molecules signalling downstream of the BCR, and components of the BCR itself; in about 5% of cases the genetic cause remains unclear. Here we describe a novel human immunodeficiency, characterised by agammaglobulinaemia and B-lymphopenia, due to hypomorphic mutations in ZIP7, a ubiquitously expressed zinc transporter. whose absence leads to cell death through ER stress.

Methods

By whole exome sequencing, we identified biallelic hypomorphic mutations of ZIP7 in 6 patients affected by agammaglobulinaemia and B-lymphopenia. We introduced one of the identified mutations in mice using CRISPR/Cas9, obtaining a series of alleles around the targeted position, and performed detailed cellular and immunologic analyses.

Results

Mice bearing homozygous null mutation of ZIP7 could not be obtained, implying embryonic lethality. In contrast, animals with hypomorphic ZIP7 function were viable and lacked B cells, phenocopying affected patients. We found reduced levels of cytoplasmic zinc in primary B cell lines derived from mutant mice. Late-pre and immature B cells lacked signatures of ER stress, but showed increased phosphatase activity, reduced signalling downstream of the BCR and failure to progress through the transitional stages to fully mature B cells.

Conclusions

We identify a novel and indispensable role of ZIP7 in B cell development. Intact ZIP7 is necessary to regulate subcellular Zn distribution, reducing phosphatase activity and allowing signalling downstream of the nascent BCR. B cell development is highly dependent on the integrity of BCR signalling; this is the first study describing the role of zinc in this process.

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