Abstract
Purpose
Protein kinase C δ (PKCδ) deficiency is a rare genetic disorder identified as a monogenic cause of systemic lupus erythematosus in 2013. Since the first cases were described, the phenotype has expanded to include children presenting with autoimmune lymphoproliferative syndrome—related syndromes and infection susceptibility similar to chronic granulomatous disease or combined immunodeficiency. We review the current published data regarding the pathophysiology, clinical presentation, investigation and management of PKCδ deficiency.
Methods
Literature review was performed using MEDLINE.
Results
Twenty cases have been described in the literature with significant heterogeneity.
Conclusion
The variation in clinical presentation delineates the broad and critical role of PKCδ in immune tolerance and effector functions against pathogens.
Similar content being viewed by others
Data Availability
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
References
Belot A, Kasher PR, Trotter EW, Foray AP, Debaud AL, Rice GI, et al. Protein Kinase Cδ Deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum. 2013;65(8):2161–71.
Salzer E, Santos-Valente E, Klaver S, Ban SA, Emminger W, Prengemann NK, et al. B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ. Blood. 2013;121(16):3112–6.
Kuehn HS, Niemela JE, Rangel-Santos A, Zhang M, Pittaluga S, Stoddard JL, et al. Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans. Blood. 2013;121(16):3117–25.
Huppi K, Siwarski D, Goodnight J, Mischak H. Assignment of the protein kinase C delta polypeptide gene (PRKCD) to human chromosome 3 and mouse chromosome 14. Genomics. 1994;19(1):161–2.
Duquesnes N, Lezoualc’h F, Crozatier B. PKC-delta and PKC-epsilon: foes of the same family or strangers? J Mol Cell Cardiol. 2011;51(5):665–73.
Salzer E, Santos-Valente E, Keller B, Warnatz K, Boztug K. Protein kinase C δ: a gatekeeper of immune homeostasis. J Clin Immunol. 2016;36(7):631–40.
Neehus AL, Moriya K, Nieto-Patlán A, Le Voyer T, Lévy R, Özen A, et al. Impaired respiratory burst contributes to infections in PKCδ-deficient patients. J Exp Med [Internet]. J Exp Med 2021;218(9):e20210501. https://doi.org/10.1084/jem.20210501
Limnander A, Zikherman J, Lau T, Leitges M, Weiss A, Roose JP. Protein kinase Cδ promotes transitional B cell-negative selection and limits proximal B cell receptor signaling to enforce tolerance. Mol Cell Biol. 2014;34(8):1474–85.
Guo B, Rothstein TL. A novel Lyn-protein kinase Cδ/ε-protein kinase D axis is activated in B cells by signalosome-independent alternate pathway BCR signaling. Eur J Immunol. 2013;43(6):1643–50.
Fukao S, Haniuda K, Tamaki H, Kitamura D. Protein kinase Cδ is essential for the IgG response against T-cell-independent type 2 antigens and commensal bacteria. eLife. 2021;10:e72116.
Gorelik G, Sawalha AH, Patel D, Johnson K, Richardson B. T cell PKCδ kinase inactivation induces lupus-like autoimmunity in mice. Clin Immunol Orlando Fla. 2015;158(2):193–203.
Gruber T, Barsig J, Pfeifhofer C, Ghaffari-Tabrizi N, Tinhofer I, Leitges M, et al. PKCdelta is involved in signal attenuation in CD3+ T cells. Immunol Lett. 2005;96(2):291–3.
Schwegmann A, Guler R, Cutler AJ, Arendse B, Horsnell WGC, Flemming A, et al. Protein kinase C δ is essential for optimal macrophage-mediated phagosomal containment of Listeria monocytogenes. Proc Natl Acad Sci. 2007;104(41):16251–6.
Contreras X, Mzoughi O, Gaston F, Peterlin MB, Bahraoui E. Protein kinase C-delta regulates HIV-1 replication at an early post-entry step in macrophages. Retrovirology. 2012;9(1):37.
Li X, Cullere X, Nishi H, Saggu G, Durand E, Mansour MK, et al. PKC-δ activation in neutrophils promotes fungal clearance. J Leukoc Biol. 2016;100(3):581–8.
Sheats MK, Sung EJ, Adler KB, Jones SL. In vitro neutrophil migration requires protein kinase c-delta (δ-PKC) mediated MARCKS (myristoylated alanine rich C-kinase substrate) phosphorylation. Inflammation. 2015;38(3):1126–41.
Mecklenbräuker I, Saijo K, Zheng NY, Leitges M, Tarakhovsky A. Protein kinase Cdelta controls self-antigen-induced B-cell tolerance. Nature. 2002;416(6883):860–5.
Moreews M, Mathieu AL, Pouxvielh K, Reuschlé Q, Drouillard A, Dessay P, et al. mTOR activation underlies enhanced B cell proliferation and autoimmunity in PrkcdG510S/G510S mice. J Immunol. 2023;210(9):1209–21.
Yanase N, Hayashida M, Kanetaka-Naka Y, Hoshika A, Mizuguchi J. PKC-δ mediates interferon-α-induced apoptosis through c-Jun NH2-terminal kinase activation. BMC Cell Biol. 2012;21(13):7.
Yoshida K, Miki Y, Kufe D. Activation of SAPK/JNK signaling by protein kinase Cdelta in response to DNA damage. J Biol Chem. 2002;277(50):48372–8.
Yang H, Hu Z, Zhang J, Lowire DB, Liu TF, Fan XY, et al. Disseminated BCG disease with defective immune metabolism caused by protein kinase C delta deficiency. J Allergy Clin Immunol Pract. 2022;S2213–2198(22):00865.
Neehus AL, Tuano K, Le Voyer T, Nandiwada SL, Murthy K, Puel A, et al. Chronic granulomatous disease-like presentation of a child with autosomal recessive PKCδ deficiency. J Clin Immunol. 2022;42(6):1244–53.
Kiykim A, Ogulur I, Baris S, Salzer E, Karakoc-Aydiner E, Ozen AO, et al. Potentially beneficiaSl effect of hydroxychloroquine in a patient with a novel mutation in protein kinase Cδ deficiency. J Clin Immunol. 2015;35(6):523–6.
Kuehn HS, Niemela JE, Rangel-Santos A, Zhang M, Pittaluga S, Stoddard JL, et al. Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans. Blood. 2013;121(16):3117–25.
Gu H, Chen Z, Ma J, Wang J, Zhang R, Wu R, et al. Sirolimus is effective in autoimmune lymphoproliferative syndrome-type III: a pedigree case report with homozygous variation PRKCD. Int J Immunopathol Pharmacol. 2021;35:20587384211025936.
Nanthapisal S, Omoyinmi E, Murphy C, Standing A, Eisenhut M, Eleftheriou D, et al. Early-onset juvenile SLE associated with a novel mutation in protein kinase C δ. Pediatrics. 2017;139(1):e20160781. https://doi.org/10.1542/peds.2016-0781
Lei L, Muhammad S, Al-Obaidi M, Sebire N, Cheng IL, Eleftheriou D, et al. Successful use of ofatumumab in two cases of early-onset juvenile SLE with thrombocytopenia caused by a mutation in protein kinase C δ. Pediatr Rheumatol Online J. 2018;16(1):61.
Sharifinejad N, Azizi G, Behniafard N, Zaki-Dizaji M, Jamee M, Yazdani R, et al. Protein kinase C-delta defect in autoimmune lymphoproliferative syndrome-like disease: first case from the National Iranian Registry and review of the literature. Immunol Invest. 2020;13:1–12.
Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110–21.
Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet Lond Engl. 2013;382(9894):819–31.
Roderick MR, Jefferson L, Renton W, Belot A, PRKCD Consortium. Compound heterozygous mutations in PRKCD associated with early-onset lupus and severe and invasive infections in siblings. J Clin Immunol. 2023;43(4):703-705. https://doi.org/10.1007/s10875-022-01416-0
Gorelik G, Fang JY, Wu A, Sawalha AH, Richardson B. 2007 Impaired T cell protein kinase C delta activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus. J Immunol Baltim Md. 1950;179(8):5553–63.
Rieux-Laucat F, Magérus-Chatinet A, Neven B. The autoimmune lymphoproliferative syndrome with defective FAS or FAS-ligand functions. J Clin Immunol. 2018;38(5):558–68.
Chuang SS, Lee JK, Mathew PA. Protein kinase C is involved in 2B4 (CD244)-mediated cytotoxicity and AP-1 activation in natural killer cells. Immunology. 2003;109(3):432–9.
Author information
Authors and Affiliations
Contributions
LJ and MR performed the literature review and initial drafts. All authors significantly contributed to this manuscript by collecting and analysing data, preparing and editing the manuscript.
Corresponding authors
Ethics declarations
Ethical Approval
No ethics approval was required for this review.
Consent for Publication
As a review of the available literature, no consent was acquired for this publication. The authors have consent from one kindred whose clinical data is currently pending publication.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The following disclosures are declared but do not directly relate to the work presented herein. SJ has received support for conferences, speaker, advisory boards, trials, data and safety monitoring boards, and projects with CSL Behring, Takeda, Swedish Orphan Biovitrum, Biotest, Binding Site, Grifols, BPL, Octapharma, LFB, Pharming, GSK, Weatherden, Zarodex, Sanofi, and UCB Pharma.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Jefferson, L., Ramanan, A.V., Jolles, S. et al. Phenotypic Variability in PRKCD: a Review of the Literature. J Clin Immunol 43, 1692–1705 (2023). https://doi.org/10.1007/s10875-023-01579-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-023-01579-4