Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency

Romain Lévy; Florian Gothe; Mana Momenilandi; Thomas Magg; Marie Materna; Philipp Peters; Johannes Raedler; Quentin Philippot; Anita Lena Rack-Hoch; David Langlais; Mathieu Bourgey; Anna-Lisa Lanz; Masato Ogishi; Jérémie Rosain; Emmanuel Martin; Sylvain Latour; Natasha Vladikine; Marco Distefano; Taushif Khan; Franck Rapaport; Marian S Schulz; Ursula Holzer; Anders Fasth; Georgios Sogkas; Carsten Speckmann; Arianna Troilo; Venetia Bigley; Anna Roppelt; Yael Dinur-Schejter; Ori Toker; Karen Helene Bronken Martinsen; Roya Sherkat; Ido Somekh; Raz Somech; Dror S Shouval; Jörn-Sven Kühl; Winnie Ip; Elizabeth M McDermott; Lucy Cliffe; Ahmet Ozen; Safa Baris; Hemalatha G Rangarajan; Emmanuelle Jouanguy; Anne Puel; Jacinta Bustamante; Marie-Alexandra Alyanakian; Mathieu Fusaro; Yi Wang; Xiao-Fei Kong; Aurélie Cobat; David Boutboul; Martin Castelle; Claire Aguilar; Olivier Hermine; Morgane Cheminant; Felipe Suarez; Alisan Yildiran; Aziz Bousfiha; Hamoud Al-Mousa; Fahad Alsohime; Deniz Cagdas; Roshini S Abraham; Alan P Knutsen; Borre Fevang; Sagar Bhattad; Ayca Kiykim; Baran Erman; Tugba Arikoglu; Ekrem Unal; Ashish Kumar; Christoph B Geier; Ulrich Baumann; Bénédicte Neven; Meino Rohlfs; Christoph Walz; Laurent Abel; Bernard Malissen; Nico Marr; Christoph Klein; Jean-Laurent Casanova; Fabian Hauck; Vivien Béziat; CARMIL2 Consortium

doi:10.1084/jem.20220275

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Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency

Journal article

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Peer reviewed

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency

Romain Lévy, Florian Gothe, Mana Momenilandi, Thomas Magg, Marie Materna, Philipp Peters, Johannes Raedler, Quentin Philippot, Anita Lena Rack-Hoch, David Langlais, …

The Journal of experimental medicine, Vol.220(2)

06/02/2023

DOI: https://doi.org/10.1084/jem.20220275

PMID: 36515678

Abstract

CD28 Antigens - metabolism

CD4-Positive T-Lymphocytes

Humans

Microfilament Proteins - genetics

Mutation - genetics

Phenotype

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

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Title: Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency
Creators - without role: Romain Lévy - Inserm
Florian Gothe - Ludwig-Maximilians-Universität München
Mana Momenilandi - Inserm
Thomas Magg - Ludwig-Maximilians-Universität München
Marie Materna - Inserm
Philipp Peters - Ludwig-Maximilians-Universität München
Johannes Raedler - Ludwig-Maximilians-Universität München
Quentin Philippot - Imagine Institute for Genetic Diseases
Anita Lena Rack-Hoch - Ludwig-Maximilians-Universität München
David Langlais - McGill University
Mathieu Bourgey - McGill University
Anna-Lisa Lanz - Ludwig-Maximilians-Universität München
Masato Ogishi - Rockefeller University
Jérémie Rosain - Inserm
Emmanuel Martin - Imagine Institute for Genetic Diseases
Sylvain Latour - Imagine Institute for Genetic Diseases
Natasha Vladikine - Inserm
Marco Distefano - Inserm
Taushif Khan - Qatar Airways
Franck Rapaport - Rockefeller University
Marian S Schulz - University Hospital Leipzig
Ursula Holzer - University Children's Hospital Tübingen
Anders Fasth - University of Gothenburg
Georgios Sogkas - Medizinische Hochschule Hannover
Carsten Speckmann - University of Freiburg
Arianna Troilo - University of Freiburg
Venetia Bigley - NIHR Newcastle Biomedical Research Centre
Anna Roppelt - Dept. of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
Yael Dinur-Schejter - Hadassah Medical Center
Ori Toker - Shaare Zedek Medical Center
Karen Helene Bronken Martinsen - Oslo University Hospital
Roya Sherkat - Isfahan University of Medical Sciences
Ido Somekh - Schneider Children's Medical Center
Raz Somech - Schneider Children's Medical Center
Dror S Shouval - Ben-Gurion University of the Negev
Jörn-Sven Kühl - University Hospital Leipzig
Winnie Ip - Great Ormond Street Hospital
Elizabeth M McDermott - Nottingham University Hospitals NHS Trust
Lucy Cliffe - Nottingham University Hospitals NHS Trust
Ahmet Ozen - Marmara University
Safa Baris - Marmara University
Hemalatha G Rangarajan - Nationwide Children's Hospital
Emmanuelle Jouanguy - Rockefeller University
Anne Puel - Inserm
Jacinta Bustamante - Inserm
Marie-Alexandra Alyanakian - Hôpital Necker-Enfants Malades
Mathieu Fusaro - Imagine Institute for Genetic Diseases
Yi Wang - Inserm
Xiao-Fei Kong - Rockefeller University
Aurélie Cobat - Inserm
David Boutboul - Hôpital Saint-Louis
Martin Castelle - Imagine Institute for Genetic Diseases
Claire Aguilar - Assistance Publique – Hôpitaux de Paris
Olivier Hermine - Imagine Institute for Genetic Diseases
Morgane Cheminant - Imagine Institute for Genetic Diseases
Felipe Suarez - Imagine Institute for Genetic Diseases
Alisan Yildiran - Dept. of Pediatric Immunology and Allergy, Ondokuz Mayis University Medical School, Samsun, Turkey
Aziz Bousfiha - Casablanca
Hamoud Al-Mousa - King Faisal Specialist Hospital & Research Centre
Fahad Alsohime - King Saud Medical City
Deniz Cagdas - Hacettepe University Hospital
Roshini S Abraham - Nationwide Children's Hospital
Alan P Knutsen - Cardinal Glennon Children’s Medical Center
Borre Fevang - Oslo University Hospital
Sagar Bhattad - Dept. of Pediatrics, Aster CMI Hospital, Bangalore, India
Ayca Kiykim - Istanbul University-Cerrahpaşa
Baran Erman - Hacettepe University
Tugba Arikoglu - Mersin University
Ekrem Unal - Erciyes University
Ashish Kumar - Cincinnati Children's Hospital Medical Center
Christoph B Geier - University of Freiburg
Ulrich Baumann - Medizinische Hochschule Hannover
Bénédicte Neven - Imagine Institute for Genetic Diseases
Meino Rohlfs - Ludwig-Maximilians-Universität München
Christoph Walz - Ludwig-Maximilians-Universität München
Laurent Abel - Inserm
Bernard Malissen - Centre d’Immunologie de Marseille-Luminy
Nico Marr - Qatar Airways
Christoph Klein - Ludwig-Maximilians-Universität München
Jean-Laurent Casanova - Inserm
Fabian Hauck - Ludwig-Maximilians-Universität München
Vivien Béziat - Inserm
CARMIL2 Consortium
Publication Details: The Journal of experimental medicine, Vol.220(2)
Grant note: UL1 TR001866 / NCATS NIH HHS R01 AI163029 / NIAID NIH HHS UM1 HG006504 / NHGRI NIH HHS K08 DK128631 / NIDDK NIH HHS MR/W01677X/1 / Medical Research Council Howard Hughes Medical Institute R01 AI088364 / NIAID NIH HHS S10 OD018521 / NIH HHS U24 HG008956 / NHGRI NIH HHS
Identifiers: 9948852608331
Academic Unit: King Saud University
Language: English
Resource Type: Journal article