HDAC mediated regulation of the sphingolipids
In addition, recently role of epigenetic regulation in allergic disorders has gained interest. The most common mechanisms are DNA methylation, histone modification and noncoding RNA’s. There are 4 subclasses of HDAC enzymes of which classI/II have been most widely studied.Evidence suggests contribution of HDAC enzymes in allergic disorders primarily in two areas; one is regulation of cells contributing to allergy (Tcells, macrophages) and the other is with various allergic phenotypes(37). Grausenburger et al showed in conditional HDAC1 knockout mice that HDAC was important for development of Th2 cytokine production and allergic airway inflammation(38). We found significantly raised levels of HDAC1 and 6 when mast cells were exposed to IgE along with increased levels of S1PR1and 3 receptors, similar to published reports(39). Increased S1PR1 and 3 expressions that internalize the S1P seem to target HDAC for transcriptional modulation in mast cells. However, further studies are required to study the role of HDAC enzymes in pathogenesis of VKC.
One of the drawbacks of our study was that all samples were analyzed only in the active stage and not compared with the quiet stage of the disease to further delineate the cause and effect of the sphingolipids. Besides this was the first time that role of sphingolipid metabolism was being evaluated in VKC and not all the species of the sphingolipids including various ceramides in the tear were estimated. However, altered enzymes expression, receptor levels and corresponding variation in the levels of specific sphingolipids confirmed an altered metabolism in VKC which is differential in R-VKC in terms of relatively lower levels of ceramide and specific S1P compared to NR-VKC.
To summarize, this study brings forth for the very first time an association between altered sphingolipid metabolism and pathogenesis of VKC which was observed both at ocular and systemic levels. In addition it unveils a possible explanation for the severe or refractory cases of VKC as compared to the seasonal ones and thus opens up fresh avenues in therapeutic intervention.
Acknowledgement : We acknowledge High Precision Bioanalytical Facility (HPBAF) with Mass spectrometry (LC-MS/MS) at Ocular Pharmacology and Pharmacy Division, RP Center, AIIMS, New Delhi, India.