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.