Article first published online: 30 DEC 2013
Copyright © 2014 by the American College of Rheumatology
Arthritis & Rheumatology
Volume 66, Issue 1, pages 229–230, January 2014
How to Cite
Belot, A., Brognard, J., Crow, Y. J. and Bonnefoy, N. (2014), Reply. Arthritis & Rheumatology, 66: 229–230. doi: 10.1002/art.38234
- Issue published online: 30 DEC 2013
- Article first published online: 30 DEC 2013
- Accepted manuscript online: 21 OCT 2013 11:22AM EST
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 (). 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 (). 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.