Kolukısa, BurcuBaşer, DilekAkçam, BengüDanielson, JeffreyBilgiç Eltan, SevgiHaliloğlu, YeşimSefer, Asena PınarBabayeva, RoyaleAkgün, GamzeCharbonnier, Louis-MarieSchmitz-Abe, KlausKendir Demirkol, YaseminZhang, YuGonzaga-Jauregui, ClaudiaHeredia, Raul JimenezKasap, NurhanKıykım, AyçaÖzek Yücel, EsraGök, VeyselÜnal, EkremPaç Kısaarslan, AyşenurNepesov, SerdarBaysoy, GökhanÖnal, ZerrinYeşil, GözdeCelkan, Tülin TirajeÇokuğraş, HalukCamcıoğlu, YıldızEken, AhmetBoztug, KaanLo, BerniceKarakoç Aydıner, ElifSu, Helen C.Özen, AhmetChatila, Talal A.Barış, Safa2022-12-282022-12-282022Kolukısa, B., Başer, D., Akçam, B., Danielson, J., Bilgiç Eltan, S., Haliloğlu, Y. ... Barış, S. (2022). Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency. Allergy: European Journal of Allergy and Clinical Immunology, 77(3), 1004-1019. https://doi.org/10.1111/all.150100105-45381398-9995https://doi.org/10.1111/all.15010https://hdl.handle.net/20.500.12511/10208Background Biallelic 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. Methods The 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 (cT(FH)) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape. Results Mean 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 cT(FH) 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). Conclusion This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.eninfo:eu-repo/semantics/embargoedAccessCARMIL2CD28 Co-SignalingCombined Immune DeficiencyInflammatory Bowel DiseaseLong-Term Follow-UpArticle7731004101910.1111/all.15010Q10006793056000012-s2.0-8511151881834287962Q1