; Lucena, Jose M. ; Seidl, Maximilian ; Schmitt-Graeff, Annette ; Reiser, Veronika ; Emmerich, Florian ; Frede, Natalie ; Bulashevska, Alla ; Salzer, Ulrich
; Schubert, Desirée ; Hayakawa, Seiichi ; Okada, Satoshi
; Kanariou, Maria ; Kucuk, Zeynep Yesim ; Chapdelaine, Hugo ; Petruzelkova, Lenka ; Sumnik, Zdenek
; Sediva, Anna ; Slatter, Mary ; Arkwright, Peter D. ; Cant, Andrew ; Lorenz, Hanns-Martin ; Giese, Thomas ; Lougaris, Vassilios ; Plebani, Alessandro ; Price, Christina ; Sullivan, Kathleen E. ; Moutschen, Michel ; Litzman, Jiri
; Freiberger, Tomas
; van de Veerdonk, Frank L. ; Recher, Mike ; Albert, Michael H. ; Hauck, Fabian
; Seneviratne, Suranjith ; Pachlopnik Schmid, Jana ; Kolios, Antonios
; Unglik, Gary ; Klemann, Christian
; Speckmann, Carsten
; Ehl, Stephan ; Leichtner, Alan ; Blumberg, Richard ; Franke, Andre ; Snapper, Scott ; Zeissig, Sebastian ; Cunningham-Rundles, Charlotte ; Giulino-Roth, Lisa ; Elemento, Olivier ; Dückers, Gregor ; Niehues, Tim ; Fronkova, Eva ; Kanderová, Veronika ; Platt, Craig D. ; Chou, Janet ; Chatila, Talal A.
; Geha, Raif ; McDermott, Elizabeth ; Bunn, Su ; Kurzai, Monika ; Schulz, Ansgar ; Alsina, Laia
; Casals, Ferran ; Deyà-Martinez, Angela ; Hambleton, Sophie ; Kanegane, Hirokazu ; Taskén, Kjetil
; Neth, Olaf ; Grimbacher, Bodo | Dokumentenart: | Artikel | ||||
|---|---|---|---|---|---|
| Titel eines Journals oder einer Zeitschrift: | Journal of Allergy and Clinical Immunology | ||||
| Verlag: | MOSBY-ELSEVIER | ||||
| Ort der Veröffentlichung: | NEW YORK | ||||
| Band: | 142 | ||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 6 | ||||
| Seitenbereich: | S. 1932-1946 | ||||
| Datum: | 2018 | ||||
| Institutionen: | Medizin > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) | ||||
| Identifikationsnummer: |
| ||||
| Stichwörter / 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 | ||||
| Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
| Status: | Veröffentlicht | ||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||
| An der Universität Regensburg entstanden: | Ja | ||||
| Dokumenten-ID: | 46547 |
Zusammenfassung
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 ...

Zusammenfassung
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.
Metadaten zuletzt geändert: 28 Jul 2021 16:54
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