학술논문
Evolution and long‐term outcomes of combined immunodeficiency due to CARMIL2 deficiency
Document Type
article
Author
Kolukisa, Burcu; Baser, Dilek; Akcam, Bengu; Danielson, Jeffrey; Eltan, Sevgi Bilgic; Haliloglu, Yesim; Sefer, Asena Pinar; Babayeva, Royale; Akgun, Gamze; Charbonnier, Louis‐Marie; Schmitz‐Abe, Klaus; Demirkol, Yasemin Kendir; Zhang, Yu; Gonzaga‐Jauregui, Claudia; Heredia, Raul Jimenez; Kasap, Nurhan; Kiykim, Ayca; Yucel, Esra Ozek; Gok, Veysel; Unal, Ekrem; Kisaarslan, Aysenur Pac; Nepesov, Serdar; Baysoy, Gokhan; Onal, Zerrin; Yesil, Gozde; Celkan, Tulin Tiraje; Cokugras, Haluk; Camcioglu, Yildiz; Eken, Ahmet; Boztug, Kaan; Lo, Bernice; Karakoc‐Aydiner, Elif; Su, Helen C; Ozen, Ahmet; Chatila, Talal A; Baris, Safa
Source
Allergy. 77(3)
Subject
Language
Abstract
BackgroundBiallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations.MethodsThe presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cTFH ) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape.ResultsMean age at disease onset was 38 ± 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4+ T cells, Treg, and cTFH cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years).ConclusionThis cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.