| Title: |
Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects |
| Authors: |
Schwab, C; Gabrysch, A; Olbrich, P; Patiño, V; Warnatz, K; Wolff, D; Hoshino, A; Kobayashi, M; Imai, K; Takagi, M; Dybedal, I; Haddock, JA; Sansom, DM; Lucena, JM; Seidl, M; Schmitt-Graeff, A; Reiser, V; Emmerich, F; Frede, N; Bulashevska, A; Salzer, U; Schubert, D; Hayakawa, S; Okada, S; Kanariou, M; Kucuk, ZY; Chapdelaine, H; Petruzelkova, L; Sumnik, Z; Sediva, A; Slatter, M; Arkwright, PD; Cant, A; Lorenz, H-M; Giese, T; Lougaris, V; Plebani, A; Price, C; Sullivan, KE; Moutschen, M; Litzman, J; Freiberger, T; van de Veerdonk, FL; Recher, M; Albert, MH; Hauck, F; Seneviratne, S; Pachlopnik Schmid, J; Kolios, A; Unglik, G; Klemann, C; Speckmann, C; Ehl, S; Leichtner, A; Blumberg, R; Franke, A; Snapper, S; Zeissig, S; Cunningham-Rundles, C; Giulino-Roth, L; Elemento, O; Dückers, G; Niehues, T; Fronkova, E; Kanderová, V; Platt, CD; Chou, J; Chatila, TA; Geha, R; McDermott, E; Bunn, S; Kurzai, M; Schulz, A; Alsina, L; Casals, F; Deyà-Martinez, A; Hambleton, S; Kanegane, H; Taskén, K; Neth, O; Grimbacher, B |
| Source: |
Journal of Allergy and Clinical Immunology , 142 (6) pp. 1932-1946. (2018) |
| Publication Year: |
2018 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
Cytotoxic T-lymphocyte antigen 4; abatacept; autoimmunity; common variable immunodeficiency; hematopoietic stem cell transplantation; hypogammaglobulinemia; immune dysregulation; primary immunodeficiency; sirolimus |
| Description: |
BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10049658/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10049658/1/Sansom_1-s2.0-S0091674918306304-main.pdf; https://discovery.ucl.ac.uk/id/eprint/10049658/ |
| Rights: |
open |
| Accession Number: |
edsbas.A1745E24 |
| Database: |
BASE |