Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency-Reference-Cited by-同舟云学术

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

Published:2022-12-14 Issue:2 Volume:220 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
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Author:

Lévy Romain¹²³⁴^ORCID,Gothe Florian⁵^ORCID,Momenilandi Mana¹²^ORCID,Magg Thomas⁵^ORCID,Materna Marie¹²^ORCID,Peters Philipp⁵^ORCID,Raedler Johannes⁵^ORCID,Philippot Quentin¹²^ORCID,Rack-Hoch Anita Lena⁵^ORCID,Langlais David⁶^ORCID,Bourgey Mathieu⁶^ORCID,Lanz Anna-Lisa⁵^ORCID,Ogishi Masato⁴^ORCID,Rosain Jérémie¹²^ORCID,Martin Emmanuel²⁷^ORCID,Latour Sylvain²⁷^ORCID,Vladikine Natasha¹²^ORCID,Distefano Marco¹²^ORCID,Khan Taushif⁸^ORCID,Rapaport Franck⁴^ORCID,Schulz Marian S.⁹^ORCID,Holzer Ursula¹⁰^ORCID,Fasth Anders¹¹¹²^ORCID,Sogkas Georgios¹³^ORCID,Speckmann Carsten¹⁴^ORCID,Troilo Arianna¹⁵^ORCID,Bigley Venetia¹⁶^ORCID,Roppelt Anna¹⁷^ORCID,Dinur-Schejter Yael¹⁸^ORCID,Toker Ori¹⁹^ORCID,Bronken Martinsen Karen Helene²⁰^ORCID,Sherkat Roya²¹^ORCID,Somekh Ido²²^ORCID,Somech Raz²³^ORCID,Shouval Dror S.²⁴^ORCID,Kühl Jörn-Sven⁹^ORCID,Ip Winnie²⁵^ORCID,McDermott Elizabeth M.²⁶^ORCID,Cliffe Lucy²⁶^ORCID,Ozen Ahmet²⁷^ORCID,Baris Safa²⁷^ORCID,Rangarajan Hemalatha G.²⁸^ORCID,Jouanguy Emmanuelle¹²⁴^ORCID,Puel Anne¹²⁴^ORCID,Bustamante Jacinta¹²⁴²⁹^ORCID,Alyanakian Marie-Alexandra³⁰^ORCID,Fusaro Mathieu²²⁹^ORCID,Wang Yi¹²^ORCID,Kong Xiao-Fei⁴^ORCID,Cobat Aurélie¹²⁴^ORCID,Boutboul David³¹^ORCID,Castelle Martin²³^ORCID,Aguilar Claire³²^ORCID,Hermine Olivier²³³^ORCID,Cheminant Morgane²³³^ORCID,Suarez Felipe²³³^ORCID,Yildiran Alisan³⁴^ORCID,Bousfiha Aziz³⁵^ORCID,Al-Mousa Hamoud³⁶^ORCID,Alsohime Fahad³⁷³⁸^ORCID,Cagdas Deniz³⁹^ORCID,Abraham Roshini S.⁴⁰^ORCID,Knutsen Alan P.⁴¹^ORCID,Fevang Borre⁴²^ORCID,Bhattad Sagar⁴³^ORCID,Kiykim Ayca⁴⁴^ORCID,Erman Baran⁴⁵⁴⁶^ORCID,Arikoglu Tugba⁴⁷^ORCID,Unal Ekrem⁴⁸^ORCID,Kumar Ashish⁴⁹^ORCID,Geier Christoph B.¹⁵^ORCID,Baumann Ulrich⁵⁰^ORCID,Neven Bénédicte²³^ORCID,Calas Julie,Feuille Elizabeth,Chan Angela,Yesil Gozde,Nammour Justine,Bandet Élise,Picard Capucine,Benhsaien Ibtihal,Lang Peter,Atschekzei Faranaz,Warnatz Klaus,Hambleton Sophie,Desai Mukesh,Karakoc-Aydiner Elif,Kolukisa Burcu,Al-Muhsen Saleh,Alosaimi Mohammed F.,Cipe Funda,Alazami Anas M.,Hancioglu Gonca,Can Meydan Bilge,Sorte Hanne S.,Stray-Pedersen Asbjørg,Mammayil Geetha,Tökmeci Nazan,Shcherbina Anna,Stepensky Polina,NaserEddin Adeeb,Rouzaud Claire,Hoshino Akihiro,Shamriz Oded,Ledder Oren,Maccari Maria Elena,Castro Carla N.,Grimbacher Bodo,Schmidt Reinhold E.,Collin Matthew,Zakharova Victorya,Rohlfs Meino⁵^ORCID,Walz Christoph⁵¹^ORCID,Abel Laurent¹²⁴^ORCID,Malissen Bernard⁵²^ORCID,Marr Nico⁸^ORCID,Klein Christoph⁵^ORCID,Casanova Jean-Laurent¹²⁴⁵³⁵⁴^ORCID,Hauck Fabian⁵^ORCID,Béziat Vivien¹²⁴^ORCID,

Affiliation:

1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France 1

2. Imagine Institute, University of Paris-Cité, Paris, France 2

3. Pediatric Immunology-Hematology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France 3

4. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 4

5. Dept. of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany 5

6. Dept. of Human Genetics, McGill University, Montreal, Quebec, Canada 6

7. Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Paris, France 7

8. Research Branch, Sidra Medicine, Doha, Qatar 8

9. Dept. of Women and Child Health, Hospital for Children and Adolescents, Hospitals University of Leipzig, Leipzig, Germany 9

10. Children’s Hospital, University of Tübingen, Tübingen, Germany 10

11. Dept. of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden 11

12. The Queen Silvia Children’s Hospital, Gothenburg, Sweden 12

13. Dept. of Immunology and Rheumatology, Medical School Hannover, Hanover, Germany 13

14. Dept. of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology and Center for Chronic Immunodeficiency (CCI), Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany 14

15. Dept. of Rheumatology and CCI for Chronic Immunodeficiency, Division of Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany 15

16. Translational and Clinical Research Institute and NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 16

17. Dept. of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia 17

18. Dept. of Bone Marrow Transplantation, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel 18

19. Faculty of Medicine, Hebrew University of Jerusalem, The Allergy and Clinical Immunology Unit, Shaare Zedek Medical Center, Jerusalem, Israel 19

20. Dept. of Pediatric Immunology, Rikshospitalet, Oslo University Hospital, Oslo, Norway 20

21. Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran 21

22. Dept. of Pediatric Hematology/Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel 22

23. The Institute of Gastroenterology, Nutrition and Liver diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel, and The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 23

24. The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv Israel; The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel; Ben-Gurion University of the Negev, Beer Sheva, Israel 24

25. Dept. of Immunology, Great Ormond Street Hospital, London, UK 25

26. Dept. of Pediatrics, Nottingham University Hospitals NHS Trust, Nottingham, UK 26

27. Dept. of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey 27

28. Division of Hematology, Oncology and Bone Marrow Transplant, Dept. of Pediatrics, Nationwide Children’s Hospital, Columbus, OH 28

29. Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France 29

30. Dept. of Immunology, Necker Hospital for Sick Children, AP-HP, Paris, France 30

31. Dept. of Clinical Immunology, AP-HP, Saint-Louis Hospital, Paris, France 31

32. Necker Pasteur Center for Infectious Diseases and Tropical Medicine, Necker Hospital for Sick Children, AP-HP, Paris, France 32

33. Dept. of Clinical Hematology, Necker Hospital for Sick Children, AP-HP, Paris, France 33

34. Dept. of Pediatric Immunology and Allergy, Ondokuz Mayis University Medical School, Samsun, Turkey 34

35. Clinical Immunology, Inflammation and Auto-immunity Laboratory, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University, Casablanca, Morocco 35

36. Translational Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia 36

37. Pediatric Intensive Care Unit, Dept. of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia 37

38. Immunology Research Laboratory, Dept. of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia 38

39. Section of Pediatric Immunology, Hacettepe University, Ihsan Dogramaci Children’s Hospital, Ankara, Turkey 39

40. Dept. of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH 40

41. Pediatric Allergy and Immunology, Cardinal Glennon Children’s Hospital, St. Louis, MO 41

42. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway 42

43. Dept. of Pediatrics, Aster CMI Hospital, Bangalore, India 43

44. Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine, Pediatric Immunology and Allergy, Istanbul, Turkey 44

45. Institute of Child Health, Hacettepe University, Ankara, Turkey 45

46. Can Sucak Research Laboratory for Translational Immunology, Hacettepe University, Ankara, Turkey 46

47. Dept. of Pediatrics, Division of Pediatric Allergy and Immunology, Mersin University Faculty of Medicine, Mersin, Turkey 47

48. Division of Pediatric Hematology Oncology, Dept. of Pediatrics, Erciyes University Faculty of Medicine, Kayseri, Turkey 48

49. Division of Bone Marrow Transplantation and Immune Deficiency, Dept. of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 49

50. Dept. of Paediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany 50

51. Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany 51

52. Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, INSERM, CNRS, Marseille, France 52

53. Howard Hughes Medical Institute, New York, NY 53

54. Dept. of Pediatrics, Necker Hospital for Sick Children, Paris, France 54

Abstract

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.

Funder

Institut National de la Santé et de la Recherche Médicale

Agence Nationale de Recherches sur le Sida et les Hépatites Virales

Deutsche Forschungsgemeinschaft

Care-For-Rare Foundation

Munich Clinician Scientist Program

German Center for Infection Research

Else Kröner-Fresenius Stiftung

German Federal Ministry of Education and Research

Fonds de la Recherche Québec-Santé

Leona M. and Harry B. Helmsley Charitable Trust

Howard Hughes Medical Institute