%0 Journal Article
%A Hou, Tie Zheng
%A Verma, Nisha
%A Wanders, Jennifer
%A Kennedy, Alan
%A Soskic, Blagoje
%A Janman, Daniel
%A Halliday, Neil
%A Rowshanravan, Behzad
%A Worth, Austen
%A Qasim, Waseem
%A Baxendale, Helen
%A Stauss, Hans
%A Seneviratne, Suranjith
%A Neth, Olaf
%A Olbrich, Peter
%A Hambleton, Sophie
%A Arkwright, Peter D
%A Burns, Siobhan O
%A Walker, Lucy S K
%A Sansom, David M
%T Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations.
%D 2017
%U http://hdl.handle.net/10668/10837
%X Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T-cell (Treg) 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-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.
%K CTLA-4 Antigen
%K Immunotherapy
%K Immunobiology
%K Mutation
%K Lysosomes
%~