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Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations

Hou, TZ; Verma, N; Wanders, J; Kennedy, A; Soskic, B; Janman, D; Halliday, N; (2017) Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations. Blood 10.1182/blood-2016-10-745174. (In press).

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Abstract

Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency (CVID) with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T cell function associated with impaired ability to control levels of the CTLA-4 ligands, CD80 and CD86. However, additional mutations affecting the CTLA-4 pathway, such as those recently reported for LRBA, indirectly affect CTLA-4 expression resulting in clinically similar disorders. Robust phenotyping approaches sensitive to defects in the CTLA-4 pathway are therefore required to inform understanding of such immune dysregulation syndromes. Here we describe assays capable of distinguishing a variety of defects in the CTLA-4 pathway. Assessing total CTLA-4 expression levels was found to be optimal when restricting analysis to the CD45RA-negative Foxp3+ fraction. CTLA-4 induction following stimulation, and the use of lysosomal blocking compounds, distinguished CTLA-4 from LRBA mutations. Short term T cell stimulation improved the capacity for discriminating the Foxp3+ Treg compartment, clearly revealing Treg expansions in these disorders. Finally, we developed a functionally orientated assay to measure ligand uptake by CTLA-4, which is sensitive to ligand-binding or trafficking mutations, that would otherwise be difficult to detect and that is appropriate for testing novel mutations in CTLA-4 pathway genes. These approaches are likely to be of value in interpreting the functional significance of mutations in the CTLA-4 pathway identified by gene sequencing approaches.

Type: Article
Title: Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations
Location: United States
DOI: 10.1182/blood-2016-10-745174
Publisher version: https://doi.org/10.1182/blood-2016-10-745174
Language: English
Additional information: Copyright © 2017 American Society of Hematology. This research was originally published in Blood as: Hou, TZ; Verma, N; Wanders, J; Kennedy, A; Soskic, B; Janman, D; Halliday, N; (2017) Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations. Blood. Prepublished online 3 February 2017; DOI 10.1182/blood-2016-10-745174
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health
URI: http://discovery.ucl.ac.uk/id/eprint/1540911
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