Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency
Burcu Kolukisa
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorDilek Baser
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorBengu Akcam
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorJeffrey Danielson
Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, Maryland, USA
Clinical Genomics Program, NIAID, NIH, Bethesda, Maryland, USA
Search for more papers by this authorSevgi Bilgic Eltan
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorYesim Haliloglu
Department of Medical Biology, Erciyes University School of Medicine, Kayseri, Turkey
Search for more papers by this authorAsena Pinar Sefer
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorRoyale Babayeva
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorGamze Akgun
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorLouis-Marie Charbonnier
Boston Children's Hospital and Department of Pediatrics, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorKlaus Schmitz-Abe
Boston Children's Hospital, Division of Immunology and Newborn Medicine, Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorYasemin Kendir Demirkol
Genomic Laboratory (GLAB), Umraniye Teaching and Research Hospital, University of Health Sciences, Istanbul, Turkey
Search for more papers by this authorYu Zhang
Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, Maryland, USA
Clinical Genomics Program, NIAID, NIH, Bethesda, Maryland, USA
Search for more papers by this authorClaudia Gonzaga-Jauregui
Regeneron Genetics Center, Tarrytown, New York, USA
Search for more papers by this authorRaul Jimenez Heredia
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
Search for more papers by this authorNurhan Kasap
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorAyca Kiykim
Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey
Search for more papers by this authorEsra Ozek Yucel
Istanbul Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University, Istanbul, Turkey
Search for more papers by this authorVeysel Gok
Erciyes University School of Medicine, Pediatric Hematology and Oncology, Kayseri, Turkey
Search for more papers by this authorEkrem Unal
Erciyes University School of Medicine, Pediatric Hematology and Oncology, Kayseri, Turkey
Search for more papers by this authorAysenur Pac Kisaarslan
Erciyes University School of Medicine, Pediatric Rheumatology, Kayseri, Turkey
Search for more papers by this authorSerdar Nepesov
Department of Pediatric Allergy and Immunology, Medipol University Medical Faculty, Istanbul, Turkey
Search for more papers by this authorGokhan Baysoy
Department of Pediatric Gastroenterology, Medipol University Medical Faculty, Istanbul, Turkey
Search for more papers by this authorZerrin Onal
Department of Pediatric Gastroenterology, Hepatology and Nutrition, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
Search for more papers by this authorGozde Yesil
Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
Search for more papers by this authorTulin Tiraje Celkan
Faculty of Medicine, Division of Pediatric Hematology and Oncology, Istanbul University-Cerrahpasa, Istanbul, Turkey
Search for more papers by this authorHaluk Cokugras
Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey
Search for more papers by this authorYildiz Camcioglu
Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey
Search for more papers by this authorAhmet Eken
Department of Medical Biology, Erciyes University School of Medicine, Kayseri, Turkey
Search for more papers by this authorKaan Boztug
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
Search for more papers by this authorBernice Lo
Research Branch, Division of Translational Medicine, Sidra Medicine, Doha, Qatar
College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
Search for more papers by this authorElif Karakoc-Aydiner
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorHelen C. Su
Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, Maryland, USA
Clinical Genomics Program, NIAID, NIH, Bethesda, Maryland, USA
Search for more papers by this authorAhmet Ozen
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorTalal A. Chatila
Boston Children's Hospital and Department of Pediatrics, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorCorresponding Author
Safa Baris
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Correspondence
Safa Baris, Division of Pediatric Allergy/Immunology, Marmara University, Fevzi Çakmak Mah, No: 41, Pendik, Istanbul, Turkey.
Email: [email protected]
Search for more papers by this authorBurcu Kolukisa
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorDilek Baser
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorBengu Akcam
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorJeffrey Danielson
Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, Maryland, USA
Clinical Genomics Program, NIAID, NIH, Bethesda, Maryland, USA
Search for more papers by this authorSevgi Bilgic Eltan
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorYesim Haliloglu
Department of Medical Biology, Erciyes University School of Medicine, Kayseri, Turkey
Search for more papers by this authorAsena Pinar Sefer
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorRoyale Babayeva
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorGamze Akgun
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorLouis-Marie Charbonnier
Boston Children's Hospital and Department of Pediatrics, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorKlaus Schmitz-Abe
Boston Children's Hospital, Division of Immunology and Newborn Medicine, Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorYasemin Kendir Demirkol
Genomic Laboratory (GLAB), Umraniye Teaching and Research Hospital, University of Health Sciences, Istanbul, Turkey
Search for more papers by this authorYu Zhang
Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, Maryland, USA
Clinical Genomics Program, NIAID, NIH, Bethesda, Maryland, USA
Search for more papers by this authorClaudia Gonzaga-Jauregui
Regeneron Genetics Center, Tarrytown, New York, USA
Search for more papers by this authorRaul Jimenez Heredia
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
Search for more papers by this authorNurhan Kasap
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorAyca Kiykim
Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey
Search for more papers by this authorEsra Ozek Yucel
Istanbul Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University, Istanbul, Turkey
Search for more papers by this authorVeysel Gok
Erciyes University School of Medicine, Pediatric Hematology and Oncology, Kayseri, Turkey
Search for more papers by this authorEkrem Unal
Erciyes University School of Medicine, Pediatric Hematology and Oncology, Kayseri, Turkey
Search for more papers by this authorAysenur Pac Kisaarslan
Erciyes University School of Medicine, Pediatric Rheumatology, Kayseri, Turkey
Search for more papers by this authorSerdar Nepesov
Department of Pediatric Allergy and Immunology, Medipol University Medical Faculty, Istanbul, Turkey
Search for more papers by this authorGokhan Baysoy
Department of Pediatric Gastroenterology, Medipol University Medical Faculty, Istanbul, Turkey
Search for more papers by this authorZerrin Onal
Department of Pediatric Gastroenterology, Hepatology and Nutrition, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
Search for more papers by this authorGozde Yesil
Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
Search for more papers by this authorTulin Tiraje Celkan
Faculty of Medicine, Division of Pediatric Hematology and Oncology, Istanbul University-Cerrahpasa, Istanbul, Turkey
Search for more papers by this authorHaluk Cokugras
Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey
Search for more papers by this authorYildiz Camcioglu
Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey
Search for more papers by this authorAhmet Eken
Department of Medical Biology, Erciyes University School of Medicine, Kayseri, Turkey
Search for more papers by this authorKaan Boztug
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
Search for more papers by this authorBernice Lo
Research Branch, Division of Translational Medicine, Sidra Medicine, Doha, Qatar
College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
Search for more papers by this authorElif Karakoc-Aydiner
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorHelen C. Su
Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, Maryland, USA
Clinical Genomics Program, NIAID, NIH, Bethesda, Maryland, USA
Search for more papers by this authorAhmet Ozen
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Search for more papers by this authorTalal A. Chatila
Boston Children's Hospital and Department of Pediatrics, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorCorresponding Author
Safa Baris
Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
Correspondence
Safa Baris, Division of Pediatric Allergy/Immunology, Marmara University, Fevzi Çakmak Mah, No: 41, Pendik, Istanbul, Turkey.
Email: [email protected]
Search for more papers by this authorAbstract
Background
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 (cTFH) 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 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).
Conclusion
This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.
Graphical Abstract
CARMIL2 deficiency results in variable phenotypes encompassing skin disease, combined immune deficiency, early-onset inflammatory bowel disease, and allergic manifestations. Patients have impaired differentiation of mainly CD4+ T cells, resulting in elevated naïve CD4+ T cells. Gastrointestinal involvement and EBV-related smooth muscle tumors are major determinants of poor prognosis.
Abbreviations: CARMA, CARD-Containing MAGUK Protein; CARMIL, capping protein regulator and myosin 1 linker 2; CBR, C-terminal domain including a capping protein binding region; CP, capping protein; HD, homodimerization domain; EBV, Epstein-Barr virus; LRR, leucine-rich repeat; NF-κB, nuclear factor kappa B; PH, pleckstrin homolog; PKCθ, protein kinase C theta; PRR, proline-rich region; SMT, smooth muscle tumor
CONFLICT OF INTEREST
Dr. Baris obtained grant from Scientific and Technological Research Council of Turkey (318S202). Dr. Chatila received grants from National Institutes of Health (R01AI065617 and R01AI128976). Dr. Su supported by Intramural Research Program of the National Institute of Allergy and Infectious Diseases (1ZIAAI001059). Dr. Lo received grant from the Sidra Precision Medicine Program, under project SDR400013. B.K, D.B, B.A, J.D, S.B.E, Y.H, A.P.S, R.B, G.A, L.M.C, K.S.A, Y.K.D, Y.Z, C.G.J, R.J.H, N.K, A.K, E.O.Y, V.G, E.U, A.P.K, S.N, G.B, Z.O, G.Y, T.T.C, H.C, Y.C, A.E, K.B, E.K.A, and A.O have no conflict of interest to disclose.
Supporting Information
| Filename | Description |
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| all15010-sup-0001-FigS1.pdfPDF document, 120.1 KB | Fig S1 |
| all15010-sup-0002-FigS2.pdfPDF document, 2 MB | Fig S2 |
| all15010-sup-0003-FigS3.pdfPDF document, 81.1 KB | Fig S3 |
| all15010-sup-0004-FigS4.pdfPDF document, 74.3 KB | Fig S4 |
| all15010-sup-0005-TableS1.docxapplication/vnd.openxmlformats-officedocument.wordprocessingml.document:.docx, 17 KB | Table S1 |
| all15010-sup-0006-TableS2.docxapplication/vnd.openxmlformats-officedocument.wordprocessingml.document:.docx, 20.6 KB | Table S2 |
| all15010-sup-0007-Supinfo.docxapplication/vnd.openxmlformats-officedocument.wordprocessingml.document:.docx, 50.6 KB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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