Human Carmil2 Deficiency Underlies a Broader Immunological and Clinical Phenotype Than Cd28 Deficiency

Human Carmil2 Deficiency Underlies a Broader Immunological and Clinical Phenotype Than Cd28 Deficiency Publisher

Levy R^{1, 2, 3, 4} ; Gothe F⁵ ; Momenilandi M^{1, 2} ; Magg T⁵ ; Materna M^{1, 2} ; Peters P⁵ ; Raedler J⁵ ; Philippot Q^{1, 2} ; Rackhoch AL⁵ ; Langlais D⁶ ; Bourgey M⁶ ; Lanz AL⁵ ; Ogishi M⁴ ; Rosain J^{1, 2} Show All Authors

Levy R^{1, 2, 3, 4}
Gothe F⁵
Momenilandi M^{1, 2}
Magg T⁵
Materna M^{1, 2}
Peters P⁵
Raedler J⁵
Philippot Q^{1, 2}
Rackhoch AL⁵
Langlais D⁶
Bourgey M⁶
Lanz AL⁵
Ogishi M⁴
Rosain J^{1, 2}
Martin E^{2, 7}
Latour S^{2, 7}
Vladikine N^{1, 2}
Distefano M^{1, 2}
Khan T⁸
Rapaport F⁴
Schulz MS⁹
Holzer U¹⁰
Fasth A^{11, 12}
Sogkas G¹³
Speckmann C¹⁴
Troilo A¹⁵
Bigley V¹⁶
Roppelt A¹⁷
Dinurschejter Y¹⁸
Toker O¹⁹
Martinsen KHB²⁰
Sherkat R²¹
Somekh I²²
Somech R^{23, 24}
Shouval DS^{24, 25, 26, 57}
Kuhl JS⁹
Ip W²⁷
Mcdermott EM²⁸
Cliffe L²⁸
Ozen A²⁹
Baris S²⁹
Rangarajan HG³⁰
Jouanguy E^{1, 2, 4}
Puel A^{1, 2, 4}
Bustamante J^{1, 2, 4, 31}
Alyanakian MA³²
Fusaro M^{2, 31}
Wang Y^{1, 2}
Kong XF⁴
Cobat A^{1, 2, 4}
Boutboul D³³
Castelle M^{2, 3}
Aguilar C³⁴
Hermine O^{2, 35}
Cheminant M^{2, 35}
Suarez F^{2, 35}
Yildiran A³⁶
Bousfiha A³⁷
Almousa H³⁸
Alsohime F^{39, 40}
Cagdas D⁴¹
Abraham RS⁴²
Knutsen AP⁴³
Fevang B⁴⁴
Bhattad S⁴⁵
Kiykim A⁴⁶
Erman B^{47, 48}
Arikoglu T⁴⁹
Unal E⁵⁰
Kumar A⁵¹
Geier CB¹⁵
Baumann U⁵²
Neven B^{2, 3}
Rohlfs M⁵
Walz C⁵³
Abel L^{1, 2, 4}
Malissen B⁵⁴
Marr N⁸
Klein C⁵
Casanova JL^{1, 2, 4, 55, 56}
Hauck F⁵
Beziat V^{1, 2, 4}
Calas J^{1, 2}
Feuille E⁶⁶
Chan A⁶⁷
Yesil G⁶⁸
Nammour J^{1, 2}
Bandet E¹
Picard C²
Benhsaien I³⁷
Lang P¹⁰
Atschekzei F⁵⁸
Warnatz K⁶⁰
Hambleton S^{69, 70}
Desai M⁷¹
Karakocaydiner E⁶³
Kolukisa B⁶³
Almuhsen S⁶⁴
Alosaimi MF⁶⁴
Cipe F⁷²
Alazami AM³⁸
Hancioglu G⁷³
Meydan BC⁷⁴
Sorte HS⁴⁴
Straypedersen A⁴⁴
Mammayil G⁷⁵
Tokmeci N⁶⁵
Shcherbina A⁶¹
Stepensky P⁶²
Eddin AN⁶²
Rouzaud C³⁴
Hoshino A^{2, 7}
Shamriz O⁷⁶
Ledder O⁷⁷
Maccari ME⁵⁹
Castro CN⁵⁹
Grimbacher B^{60, 78, 79, 80, 81}
Schmidt RE⁵⁸
Collin M¹⁶
Zakharova V⁸²

Show Affiliations

1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France
2. Imagine Institute, University of Paris-Cite, Paris, France
3. Pediatric Immunology-Hematology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France
4. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States
5. Dept. of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universitat Munich, Munich, Germany
6. Dept. of Human Genetics, McGill University, Montreal, QC, Canada
7. Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Paris, France
8. Research Branch, Sidra Medicine, Doha, Qatar
9. Dept. of Women and Child Health, Hospital for Children and Adolescents, Hospitals University of Leipzig, Leipzig, Germany
10. Children’s Hospital, University of Tubingen, Tubingen, Germany
11. Dept. of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
12. The Queen Silvia Children’s Hospital, Gothenburg, Sweden
13. Dept. of Immunology and Rheumatology, Medical School Hannover, Hanover, Germany
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
15. Dept. of Rheumatology and CCI for Chronic Immunodeficiency, Division of Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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, United Kingdom
17. Dept. of Immunology, Dmitry Rogachev NationalMedical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
18. Dept. of Bone Marrow Transplantation, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel
19. Faculty of Medicine, Hebrew University of Jerusalem, The Allergy and Clinical Immunology Unit, Shaare Zedek Medical Center, Jerusalem, Israel
20. Dept. of Pediatric Immunology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
21. Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
22. Dept. of Pediatric Hematology/ Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel
23. The Institute of Gastroenterology, Nutrition and Liver diseases, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel
24. The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
25. The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Hospital, Petach-Tikva, Israel
26. Ben-Gurion University of the Negev, Beer Sheva, Israel
27. Dept. of Immunology, Great Ormond Street Hospital, London, United Kingdom
28. Dept. of Pediatrics, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
29. Dept. of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkiye
30. Division of Hematology, Oncology and Bone Marrow Transplant, Dept. of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
31. Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France
32. Dept. of Immunology, Necker Hospital for Sick Children, AP-HP, Paris, France
33. Dept. of Clinical Immunology, AP-HP, Saint-Louis Hospital, Paris, France
34. Necker Pasteur Center for Infectious Diseases and Tropical Medicine, Necker Hospital for Sick Children, AP-HP, Paris, France
35. Dept. of Clinical Hematology, Necker Hospital for Sick Children, AP-HP, Paris, France
36. Dept. of Pediatric Immunology and Allergy, Ondokuz Mayis University Medical School, Samsun, Turkiye
37. Clinical Immunology, Inflammation and Auto-immunity Laboratory, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University, Casablanca, Morocco
38. Translational Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
39. Pediatric Intensive Care Unit, Dept. of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
40. Immunology Research Laboratory, Dept. of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
41. Section of Pediatric Immunology, Hacettepe University, Ihsan Dogramaci Children’s Hospital, Ankara, Turkiye
42. Dept. of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
43. Pediatric Allergy and Immunology, Cardinal Glennon Children’s Hospital, St. Louis, MO, United States
44. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway
45. Dept. of Pediatrics, Aster CMI Hospital, Bangalore, India
46. Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine, Pediatric Immunology and Allergy, Istanbul, Turkiye
47. Institute of Child Health, Hacettepe University, Ankara, Turkiye
48. Can Sucak Research Laboratory for Translational Immunology, Hacettepe University, Ankara, Turkiye
49. Dept. of Pediatrics, Division of Pediatric Allergy and Immunology, Mersin University Faculty of Medicine, Mersin, Turkiye
50. Division of Pediatric Hematology Oncology, Dept. of Pediatrics, Erciyes University Faculty of Medicine, Kayseri, Turkiye
51. Division of Bone Marrow Transplantation and Immune Deficiency, Dept. of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
52. Dept. of Paediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany
53. Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universitat Munchen, Munich, Germany
54. Centre d’Immunologie de Marseille-Luminy, Aix- Marseille Universite, INSERM, CNRS, Marseille, France
55. Howard Hughes Medical Institute, New York, NY, United States
56. Dept. of Pediatrics, Necker Hospital for Sick Children, Paris, France
57. Pediatric Immunology-Hematology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique–Hopitaux de Paris (AP-HP), Paris, France
58. Department of Immunology and Rheumatology, Medical School Hannover, Hanover, Germany
59. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology and Center for Chronic Immunodeficiency, Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
60. Department of Rheumatology and Clinical Immunology and Center for Chronic Immunodeficiency, Division of Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
61. Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
62. Department of Bone Marrow Transplantation, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel
63. Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkiye
64. Immunology Research Laboratory, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
65. Department of Pediatrics, Division of Pediatric Allergy and Immunology, Mersin University Faculty of Medicine, Mersin, Turkiye
66. Weill Cornell Medicine, New York, NY, United States
67. Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States
68. Department of Medical Genetics, Istanbul University Faculty of Medicine, Istanbul, Turkiye
69. Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, United Kingdom
70. Great North Children’s Hospital, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, United Kingdom
71. Department of Immunology, B.J. Wadia Hospital for Children, Mumbai, India
72. Department of Pediatric Allergy and Immunology, Istinye University, Istanbul, Turkiye
73. Department of Pediatric Immunology and Allergy, Ondokuz Mayis University Medical School, Samsun, Turkiye
74. Department of Pathology, Ondokuz Mayis University Medical School, Samsun, Turkiye
75. Department of Pediatrics, Aster Medcity Hospital, Kochi, India
76. Allergy and Clinical Immunology Unit, Hadassah Medical Organization, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
77. Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
78. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Germany
79. German Center for Infection Research, Satellite Center Freiburg, Freiburg im Breisgau, Germany
80. Center for Integrative Biological Signaling Studies, Albert-Ludwigs University, Freiburg, Germany
81. RESIST—Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg im Breisgau, Germany
82. Molecular Biology Laboratory, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation

Source: Journal of Experimental Medicine Published:2023

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. © 2022 Levy et al.

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Style	Citing Format
MLA	Levy R, et al.. "Human Carmil2 Deficiency Underlies a Broader Immunological and Clinical Phenotype Than Cd28 Deficiency." Journal of Experimental Medicine, vol. 220, no. 2, 2023, pp. -.
APA	Levy R, Gothe F, Momenilandi M, Magg T, Materna M, Peters P, Raedler J, Philippot Q, Rackhoch AL, Langlais D, Bourgey M, Lanz AL, Ogishi M, Rosain J, Martin E, Latour S, Vladikine N, Distefano M, Khan T, ... Zakharova V (2023). Human Carmil2 Deficiency Underlies a Broader Immunological and Clinical Phenotype Than Cd28 Deficiency. Journal of Experimental Medicine, 220(2), -.
Chicago	Levy R, Gothe F, Momenilandi M, Magg T, Materna M, Peters P, Raedler J, et al.. "Human Carmil2 Deficiency Underlies a Broader Immunological and Clinical Phenotype Than Cd28 Deficiency." Journal of Experimental Medicine 220, no. 2 (2023): -.
Harvard	Levy R et al. (2023) 'Human Carmil2 Deficiency Underlies a Broader Immunological and Clinical Phenotype Than Cd28 Deficiency', Journal of Experimental Medicine, 220(2), pp. -.
Vancouver	Levy R, Gothe F, Momenilandi M, Magg T, Materna M, Peters P, et al.. Human Carmil2 Deficiency Underlies a Broader Immunological and Clinical Phenotype Than Cd28 Deficiency. Journal of Experimental Medicine. 2023;220(2):-.
BibTex	@article{ author = {Levy R and Gothe F and Momenilandi M and Magg T and Materna M and Peters P and Raedler J and Philippot Q and Rackhoch AL and Langlais D and Bourgey M and Lanz AL and Ogishi M and Rosain J and Martin E and Latour S and Vladikine N and Distefano M and Khan T and Rapaport F and Schulz MS and Holzer U and Fasth A and Sogkas G and Speckmann C and Troilo A and Bigley V and Roppelt A and Dinurschejter Y and Toker O and Martinsen KHB and Sherkat R and Somekh I and Somech R and Shouval DS and Kuhl JS and Ip W and Mcdermott EM and Cliffe L and Ozen A and Baris S and Rangarajan HG and Jouanguy E and Puel A and Bustamante J and Alyanakian MA and Fusaro M and Wang Y and Kong XF and Cobat A and Boutboul D and Castelle M and Aguilar C and Hermine O and Cheminant M and Suarez F and Yildiran A and Bousfiha A and Almousa H and Alsohime F and Cagdas D and Abraham RS and Knutsen AP and Fevang B and Bhattad S and Kiykim A and Erman B and Arikoglu T and Unal E and Kumar A and Geier CB and Baumann U and Neven B and Rohlfs M and Walz C and Abel L and Malissen B and Marr N and Klein C and Casanova JL and Hauck F and Beziat V and Calas J and Feuille E and Chan A and Yesil G and Nammour J and Bandet E and Picard C and Benhsaien I and Lang P and Atschekzei F and Warnatz K and Hambleton S and Desai M and Karakocaydiner E and Kolukisa B and Almuhsen S and Alosaimi MF and Cipe F and Alazami AM and Hancioglu G and Meydan BC and Sorte HS and Straypedersen A and Mammayil G and Tokmeci N and Shcherbina A and Stepensky P and Eddin AN and Rouzaud C and Hoshino A and Shamriz O and Ledder O and Maccari ME and Castro CN and Grimbacher B and Schmidt RE and Collin M and Zakharova V}, title = {Human Carmil2 Deficiency Underlies a Broader Immunological and Clinical Phenotype Than Cd28 Deficiency}, journal = {Journal of Experimental Medicine}, volume = {220}, number = {2}, pages = {-}, year = {2023} }
RIS	TY - JOUR AU - Levy R AU - Gothe F AU - Momenilandi M AU - Magg T AU - Materna M AU - Peters P AU - Raedler J AU - Philippot Q AU - Rackhoch AL AU - Langlais D AU - Bourgey M AU - Lanz AL AU - Ogishi M AU - Rosain J AU - Martin E AU - Latour S AU - Vladikine N AU - Distefano M AU - Khan T AU - Rapaport F AU - Schulz MS AU - Holzer U AU - Fasth A AU - Sogkas G AU - Speckmann C AU - Troilo A AU - Bigley V AU - Roppelt A AU - Dinurschejter Y AU - Toker O AU - Martinsen KHB AU - Sherkat R AU - Somekh I AU - Somech R AU - Shouval DS AU - Kuhl JS AU - Ip W AU - Mcdermott EM AU - Cliffe L AU - Ozen A AU - Baris S AU - Rangarajan HG AU - Jouanguy E AU - Puel A AU - Bustamante J AU - Alyanakian MA AU - Fusaro M AU - Wang Y AU - Kong XF AU - Cobat A AU - Boutboul D AU - Castelle M AU - Aguilar C AU - Hermine O AU - Cheminant M AU - Suarez F AU - Yildiran A AU - Bousfiha A AU - Almousa H AU - Alsohime F AU - Cagdas D AU - Abraham RS AU - Knutsen AP AU - Fevang B AU - Bhattad S AU - Kiykim A AU - Erman B AU - Arikoglu T AU - Unal E AU - Kumar A AU - Geier CB AU - Baumann U AU - Neven B AU - Rohlfs M AU - Walz C AU - Abel L AU - Malissen B AU - Marr N AU - Klein C AU - Casanova JL AU - Hauck F AU - Beziat V AU - Calas J AU - Feuille E AU - Chan A AU - Yesil G AU - Nammour J AU - Bandet E AU - Picard C AU - Benhsaien I AU - Lang P AU - Atschekzei F AU - Warnatz K AU - Hambleton S AU - Desai M AU - Karakocaydiner E AU - Kolukisa B AU - Almuhsen S AU - Alosaimi MF AU - Cipe F AU - Alazami AM AU - Hancioglu G AU - Meydan BC AU - Sorte HS AU - Straypedersen A AU - Mammayil G AU - Tokmeci N AU - Shcherbina A AU - Stepensky P AU - Eddin AN AU - Rouzaud C AU - Hoshino A AU - Shamriz O AU - Ledder O AU - Maccari ME AU - Castro CN AU - Grimbacher B AU - Schmidt RE AU - Collin M AU - Zakharova V TI - Human Carmil2 Deficiency Underlies a Broader Immunological and Clinical Phenotype Than Cd28 Deficiency JO - Journal of Experimental Medicine VL - 220 IS - 2 SP - EP - PY - 2023 ER -

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