We thank Dr. Richardson and his colleagues for their comments. In our study, we demonstrated that a missense PRKCD mutation (c.1528G>A; p.G510S) leads to resistance in B cell receptor– and calcium-dependent apoptosis, resulting in increased B cell proliferation. Our findings are consistent with the recent demonstration that PKCδ is involved in an ERK-dependent signaling pathway of B cell negative selection through Ca2+-dependent apoptosis ([1]). In addition, adoptive transfer and transgenic B cell receptor (BCR) experiments in PRKCD-knockout mice showed B cell proliferation and BCR-dependent autoimmunity ([2, 3]). Kuehn et al described a patient with PRKCD mutations and demonstrated that the knockdown of PRKCD in lymphocytes was associated with increased proliferation of B cells but not T cells, thus seemingly emphasizing the major role of B cells in disease pathogenesis ([4]). Our experiments did not show evidence of either a deficiency of T cell ontogenesis or an activation anomaly of T cells. In contrast, B cells and natural killer cells do demonstrate impaired differentiation (Belot A: personal observations).

DNA demethylation is an interesting mechanism that has been widely studied in autoimmune diseases. This process is not restricted to CD4 T cells, having been implicated in B cells or epithelial cells in the context of systemic lupus erythematosus (SLE) and Sjögren's syndrome ([5, 6]). In accordance with the work performed by Richardson and colleagues in this field, we can speculate that PRKCD mutations may impact on DNMT-1 and CD4 T cell demethylation. Thus, further “methylome-related” experiments are warranted to determine whether T cell dysfunction is relevant to the pathogenesis of this new Mendelian cause of SLE. At this time, however, we would hold that the case remains unproven.

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    Limnander A, Depeille P, Freedman TS, Liou J, Leitges M, Kurosaki T, et al.STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development.Nat Immunol2011;12:42533.
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    Mecklenbrauker I, Saijo K, Zheng NY, Leitges M, Tarakhovsky A.Protein kinase Cδ controls self-antigen-induced B-cell tolerance.Nature2002;416:8605.
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    Miyamoto A, Nakayama K, Imaki H, Hirose S, Jiang Y, Abe M, et al.Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ.Nature2002;416:8659.
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    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.Blood2013;121:311725.
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    Thabet Y, Le Dantec C, Ghedira I, Devauchelle V, Cornec D, Pers JO, et al.Epigenetic dysregulation in salivary glands from patients with primary Sjögren's syndrome may be ascribed to infiltrating B cells.J Autoimmun2013;41:17581.
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    Garaud S, Le Dantec C, Jousse-Joulin S, Hanrotel-Saliou C, Saraux A, Mageed RA, et al.IL-6 modulates CD5 expression in B cells from patients with lupus by regulating DNA methylation.J Immunol2009;182:562332.