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Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects

Lookup NU author(s): Professor Mary Slatter, Professor Andrew Cant, Professor Sophie HambletonORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


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 humans.Objective To characterize the penetrance, the clinical features and the best treatment options in 133 CTLA4 mutation carriers.Methods Genetics, clinical features, laboratory values, and outcome of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers.Results We identified 133 individuals from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting the clinical penetrance of at least 67%; median age of onset was 11 years, and mortality rate within affected mutation carriers was 16% (n=15).Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), respiratory- (68%), gastrointestinal- (59%), or neurological features (29%). Eight affected mutation carriers developed lymphoma, three gastric cancer. An EBV association was found in six malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and NK-cell counts. Successful targeted therapies included the application of CTLA-4-fusion-proteins, mTOR-inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in two affected mutation carriers under immunosuppression.Conclusions Affected mutation carriers with CTLA-4 insufficiency may present in any medical specialty. Family members should be counseled, as disease manifestation may occur as late as age 50. EBV- and CMV-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.Clinical Implication This large cohort of affected CTLA4 mutation carriers gives first insights into different possible treatment options and presents available clinical information on treatment response and survival. With this knowledge, affected mutation carriers will benefit from an individualized management.

Publication metadata

Author(s): 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 D, Lucena JM, Seidl M, SchmittGräff 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, vandeVeerdonk FL, Recher M, Albert MH, Hauck F, Seneviratne S, Schmid JP, 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 T, 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

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2018

Volume: 142

Issue: 6

Pages: 1932-1946

Print publication date: 01/12/2018

Online publication date: 04/05/2018

Acceptance date: 25/02/2017

Date deposited: 25/05/2018

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Elsevier


DOI: 10.1016/j.jaci.2018.02.055


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