Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation.

Belot, A. et al. (2013) Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis and Rheumatism, 65(8), pp. 2161-2171. (doi: 10.1002/art.38008) (PMID:23666743) (PMCID:PMC4066615)

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OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal-recessive form of SLE. METHODS: We studied 3 siblings with juvenile-onset SLE from 1 consanguineous kindred and used next-generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology. RESULTS: We identified a homozygous missense mutation in PRKCD, encoding protein kinase δ (PKCδ), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor- and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype. CONCLUSION: Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE.

Item Type:Articles
Additional Information:Supported by specific funding from the Hospices Civilsde Lyon, the Re´seaux The´matiques de Recherche TranslationelleINSERM, the Fondation pour la Recherche Me´dicale, the Re´gionRhone-Alpes, and the Socie´te´ Franc¸aise de Rhumatologie (all toDr. Belot) and by institutional grants from INSERM and Universite´deLyon (to Dr. Bonnefoy). Dr. Gaffney’s work was supported by the NIH(grants RC2-AR-058959 and R01-AI-063274). Dr. Brognard’s workwas supported by Cancer Research UK (grant C5759/A12328). Workperformed in the Crow laboratory contributing to this researchreceived funding from the European Union Seventh FrameworkProgramme (FP7/2007-2013 project NIMBL; 241779).
Glasgow Author(s) Enlighten ID:Dickerson, Dr Jonathan
Authors: Belot, A., Kasher, P. R., Trotter, E. W., Foray, A.-P., Debaud, A.-L., Rice, G. I., Szynkiewicz, M., Zabot, M.-T., Rouvet, I., Bhaskar, S. S., Daly, S. B., Dickerson, J. E., Mayer, J., O'Sullivan, J., Juillard, L., Urquhart, J. E., Fawdar, S., Marusiak, A. A., Stephenson, N., Waszkowycz, B., W Beresford, M., Biesecker, L. G., C M Black, G., René, C., Eliaou, J.-F., Fabien, N., Ranchin, B., Cochat, P., Gaffney, P. M., Rozenberg, F., Lebon, P., Malcus, C., Crow, Y. J., Brognard, J., and Bonnefoy, N.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Arthritis and Rheumatism
Publisher:John Wiley & Sons, Inc.
ISSN (Online):1529-0131
Published Online:26 July 2013

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