Impaired respiratory burst contributes to infections in PKCδ-deficient patients-Reference-Cited by-同舟云学术

Impaired respiratory burst contributes to infections in PKCδ-deficient patients

Published:2021-07-15 Issue:9 Volume:218 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Neehus Anna-Lena¹²³^ORCID,Moriya Kunihiko¹²^ORCID,Nieto-Patlán Alejandro¹²⁴⁵^ORCID,Le Voyer Tom¹²^ORCID,Lévy Romain¹²⁶^ORCID,Özen Ahmet⁷^ORCID,Karakoc-Aydiner Elif⁷^ORCID,Baris Safa⁷^ORCID,Yildiran Alisan⁸^ORCID,Altundag Engin⁹^ORCID,Roynard Manon¹²^ORCID,Haake Kathrin³^ORCID,Migaud Mélanie¹²^ORCID,Dorgham Karim¹⁰^ORCID,Gorochov Guy¹⁰^ORCID,Abel Laurent¹²¹¹^ORCID,Lachmann Nico³^ORCID,Dogu Figen¹²^ORCID,Haskologlu Sule¹²^ORCID,İnce Erdal¹³^ORCID,El-Benna Jamel¹⁴¹⁵^ORCID,Uzel Gulbu¹⁶^ORCID,Kiykim Ayca¹⁷¹⁸^ORCID,Boztug Kaan¹⁹²⁰²¹²²^ORCID,Roderick Marion R.²³^ORCID,Shahrooei Mohammad²⁴²⁵^ORCID,Brogan Paul A.²⁶^ORCID,Abolhassani Hassan²⁷²⁸^ORCID,Hancioglu Gonca⁸^ORCID,Parvaneh Nima²⁹²⁸^ORCID,Belot Alexandre³⁰^ORCID,Ikinciogullari Aydan¹²^ORCID,Casanova Jean-Laurent¹²¹¹³¹^ORCID,Puel Anne¹²¹¹^ORCID,Bustamante Jacinta¹²¹¹³²^ORCID

Affiliation:

1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR 1163, Paris, France

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

3. Institute of Experimental Hematology, REBIRTH Research Center for Translational and Regenerative Medicine, Hannover Medical School, Hannover, Germany

4. Research and Development in Bioprocess Unit, National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico

5. National Laboratory for Specialized Services of Investigation, Development and Innovation for Pharma Chemicals and Biotechnological Products, LANSEIDI-FarBiotec-CONACyT, Mexico City, Mexico

6. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France

7. Department of Pediatrics, Division of Allergy and Immunology, Marmara University, School of Medicine, Istanbul, Turkey

8. Department of Pediatric Immunology and Allergy, Ondokuz Mayıs University School of Medicine, Samsun, Turkey

9. Department of Medical Genetics, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey

10. Sorbonne University, Institut National de la Santé et de la Recherche Médicale, Center for Immunology and Microbial Infections, CIMI-Paris, Assistance Publique–Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Immunology, Paris, France

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

12. Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey

13. Department of Pediatric Infectious Disease, Ankara University School of Medicine, Ankara, Turkey

14. University of Paris, Institut National de la Santé et de la Recherche Médical U1149, Centre National de la Recherche Scientifique-ERL8252, Paris, France

15. Center for Research on Inflammation, Laboratory of Excellence Inflamex, Faculty of Medicine, Xavier Bichat, Paris, France

16. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

17. Pediatric Allergy and Immunology, Marmara University Pediatric Training and Research Hospital, Istanbul, Turkey

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

19. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

20. St. Anna Children’s Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

21. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria

22. St. Anna Children’s Cancer Research Institute, Vienna, Austria

23. Pediatric Immunology and Infectious Disease, Bristol Royal Hospital for Children, Bristol, UK

24. Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran

25. Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, Katholieke Universiteit Leuven, Leuven, Belgium

26. Infection, Inflammation, and Rheumatology Section, Infection, Immunity, Inflammation and Physiological Medicine Programme, University College London Institute of Child Health, London, UK

27. Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden

28. Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran

29. Department of Pediatrics, Division of Allergy and Clinical Immunology, Tehran University of Medical Sciences, Tehran, Iran

30. Reference Center for Rare Rheumatic and Autoimmune Diseases in Children, Pediatric Rheumatology, Hospices Civils de Lyon, Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, UMS3444/US8 Lyon University, Lyon, France

31. Howard Hughes Medical Institute, New York, NY

32. Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris, Paris, France

Abstract

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients’ circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.

Funder

Yale Center for Mendelian Genomics

National Human Genome Research Institute

National Institute of Allergy and Infectious Diseases

National Center for Research Resources

National Center for Advancing Translational Sciences

National Institutes of Health

Rockefeller University

St. Giles Foundation

INSERM

University of Paris

French Foundation for Medical Research