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.
Impaired respiratory burst contributes to infections in PKCδ-deficient patients
Disclosures: P.A. Brogan reported personal fees from Sobi, Novartis, Roche, and GSK, and grants from Sobi outside the submitted work. No other disclosures were reported.
F. Dogu, S. Haskologlu, E. İnce, J. El-Benna, G. Uzel, A. Kiykim, K. Boztug, M.R. Roderick, M. Shahrooei, P.A. Brogan, H. Abolhassani, G. Hancioglu, N. Parvaneh, A. Belot, and A. Ikinciogullari contributed equally to this paper.
N. Lachmann's present address is Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, RESIST Cluster of Excellence, Hannover, Germany.
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Anna-Lena Neehus, Kunihiko Moriya, Alejandro Nieto-Patlán, Tom Le Voyer, Romain Lévy, Ahmet Özen, Elif Karakoc-Aydiner, Safa Baris, Alisan Yildiran, Engin Altundag, Manon Roynard, Kathrin Haake, Mélanie Migaud, Karim Dorgham, Guy Gorochov, Laurent Abel, Nico Lachmann, Figen Dogu, Sule Haskologlu, Erdal İnce, Jamel El-Benna, Gulbu Uzel, Ayca Kiykim, Kaan Boztug, Marion R. Roderick, Mohammad Shahrooei, Paul A. Brogan, Hassan Abolhassani, Gonca Hancioglu, Nima Parvaneh, Alexandre Belot, Aydan Ikinciogullari, Jean-Laurent Casanova, Anne Puel, Jacinta Bustamante; Impaired respiratory burst contributes to infections in PKCδ-deficient patients. J Exp Med 6 September 2021; 218 (9): e20210501. doi: https://doi.org/10.1084/jem.20210501
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