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Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency

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dc.contributor.authorÖZEN, AHMET OĞUZHAN
dc.contributor.authorsKolukisa, 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
dc.date.accessioned2022-03-12T22:59:15Z
dc.date.available2022-03-12T22:59:15Z
dc.description.abstractBackground 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.
dc.identifier.doi10.1111/all.15010
dc.identifier.eissn1398-9995
dc.identifier.issn0105-4538
dc.identifier.pubmed34287962
dc.identifier.urihttps://hdl.handle.net/11424/237289
dc.identifier.wosWOS:000679305600001
dc.language.isoeng
dc.publisherWILEY
dc.relation.ispartofALLERGY
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectCARMIL2
dc.subjectCD28 co-signaling
dc.subjectcombined immune deficiency
dc.subjectinflammatory bowel disease
dc.subjectlong-term follow-up
dc.subjectT-CELLS
dc.subjectMUTATIONS
dc.subjectRLTPR
dc.subjectCOSTIMULATION
dc.subjectAUTOIMMUNITY
dc.subjectDERMATITIS
dc.subjectDOCK8
dc.subjectCD28
dc.titleEvolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency
dc.typearticle
dspace.entity.typePublication
local.avesis.id099c00d3-7af2-4699-b7b8-c27d1950524e
local.import.packageSS17
local.indexed.atWOS
local.indexed.atSCOPUS
local.indexed.atPUBMED
local.journal.numberofpages16
oaire.citation.titleALLERGY
relation.isAuthorOfPublication3e9c297b-e636-4836-8f61-dc9c8b7c29cf
relation.isAuthorOfPublication.latestForDiscovery3e9c297b-e636-4836-8f61-dc9c8b7c29cf

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