| Title: |
Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations |
| Authors: |
Hou, TZ; Verma, N; Wanders, J; Kennedy, A; Soskic, B; Janman, D; Halliday, N; Rowshanravan, B; Worth, A; Qasim, W; Baxendale, H; Stauss, H; Seneviratne, S; Neth, O; Olbrich, P; Hambleton, S; Arkwright, PD; Burns, SO; Walker, LS; Sansom, DM |
| Source: |
Blood , 129 pp. 1458-1468. (2017) |
| Publication Year: |
2017 |
| Collection: |
University College London: UCL Discovery |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/1540911/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/1540911/1/Hou%20complete%20pre-publication.pdf; https://discovery.ucl.ac.uk/id/eprint/1540911/ |
| Rights: |
open |
| Accession Number: |
edsbas.C8A4D845 |
| Database: |
BASE |