Schwab, Charlotte and Gabrysch, Annemarie and Olbrich, Peter and Patino, Virginia and Warnatz, Klaus and Wolff, Daniel and Hoshino, Akihiro and Kobayashi, Masao and Imai, Kohsuke and Takagi, Masatoshi and Dybedal, Ingunn and Haddock, Jamanda A. and Sansom, David M. and Lucena, Jose M. and Seidl, Maximilian and Schmitt-Graeff, Annette and Reiser, Veronika and Emmerich, Florian and Frede, Natalie and Bulashevska, Alla and Salzer, Ulrich and Schubert, Desiree and Hayakawa, Seiichi and Okada, Satoshi and Kanariou, Maria and Kucuk, Zeynep Yesim and Chapdelaine, Hugo and Petruzelkova, Lenka and Sumnik, Zdenek and Sediva, Anna and Slatter, Mary and Arkwright, Peter D. and Cant, Andrew and Lorenz, Hanns-Martin and Giese, Thomas and Lougaris, Vassilios and Plebani, Alessandro and Price, Christina and Sullivan, Kathleen E. and Moutschen, Michel and Litzman, Jiri and Freiberger, Tomas and van de Veerdonk, Frank L. and Recher, Mike and Albert, Michael H. and Hauck, Fabian and Seneviratne, Suranjith and Schmid, Jana Pachlopnik and Kolios, Antonios and Unglik, Gary and Klemann, Christian and Speckmann, Carsten and Ehl, Stephan and Leichtner, Alan and Blumberg, Richard and Franke, Andre and Snapper, Scott and Zeissig, Sebastian and Cunningham-Rundles, Charlotte and Giulino-Roth, Lisa and Elemento, Olivier and Dueckers, Gregor and Niehues, Tim and Fronkova, Eva and Kanderova, Veronika and Platt, Craig D. and Chou, Janet and Chatila, Talal A. and Geha, Raif and McDermott, Elizabeth and Bunn, Su and Kurzai, Monika and Schulz, Ansgar and Alsina, Laia and Casals, Ferran and Deya-Martinez, Angela and Hambleton, Sophie and Kanegane, Hirokazu and Tasken, Kjetil and Neth, Olaf and Grimbacher, Bodo (2018) Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 142 (6). pp. 1932-1946. ISSN 0091-6749, 1097-6825
Full text not available from this repository. (Request a copy)Abstract
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 affectedmutation 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | STEM-CELL TRANSPLANTATION; IMMUNE DYSREGULATION; LRBA DEFICIENCY; CTLA-4 HAPLOINSUFFICIENCY; GERMLINE MUTATIONS; PATIENT; DISEASE; CLASSIFICATION; AUTOIMMUNITY; FAMILY; Cytotoxic T-lymphocyte antigen 4; primary immunodeficiency; autoimmunity; hypogammaglobulinemia; hematopoietic stem cell transplantation; abatacept; sirolimus; immune dysregulation; common variable immunodeficiency |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2019 10:30 |
| Last Modified: | 04 Oct 2019 10:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13449 |
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