RT Journal Article
T1 Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations.
A1 Hou, Tie Zheng
A1 Verma, Nisha
A1 Wanders, Jennifer
A1 Kennedy, Alan
A1 Soskic, Blagoje
A1 Janman, Daniel
A1 Halliday, Neil
A1 Rowshanravan, Behzad
A1 Worth, Austen
A1 Qasim, Waseem
A1 Baxendale, Helen
A1 Stauss, Hans
A1 Seneviratne, Suranjith
A1 Neth, Olaf
A1 Olbrich, Peter
A1 Hambleton, Sophie
A1 Arkwright, Peter D
A1 Burns, Siobhan O
A1 Walker, Lucy S K
A1 Sansom, David M
K1 CTLA-4 Antigen
K1 Immunotherapy
K1 Immunobiology
K1 Mutation
K1 Lysosomes
AB 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.
PB American Society of Hematology
YR 2017
FD 2017-02-03
LK http://hdl.handle.net/10668/10837
UL http://hdl.handle.net/10668/10837
LA en
NO Hou TZ, Verma N, Wanders J, Kennedy A, Soskic B, Janman D. et al. Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations. Blood. 2017 Mar 16;129(11):1458-1468.
DS RISalud
RD Apr 17, 2025