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Current Laboratory Studies

MicroRNA expression profiles as biomarkers of minor salivary gland inflammation in Sjögren’s syndrome

Sjögren’s syndrome is characterized by features of systemic autoimmunity and dysfunction and inflammation in the exocrine glands. The exact cause of exocrine dysfunction in SS has not been delineated, but it is thought that both immunologically mediated and non-immune mechanisms contribute significantly.

The diagnosis is based on the combination of subjective symptoms and objective signs of dry mouth and/or dry eyes, the presence of autoantibodies, and an inflammatory infiltrate in the minor salivary glands. The intensity of infiltrate varies considerably and is described by the focus score, which can range between 0 and 12, the latter representing diffuse lymphocytic infiltrate.

MicroRNAs (miRNAs) are a group of small RNAs, 21-24 nucleotides in length, involved in the regulation of a wide variety of cellular and physiologic processes. They exert their effects by two mechanisms: messenger RNA degradation and disruption of translation. A single mRNA is usually translated into a single protein; however, a single miRNA is capable of regulating the translation of a multitude of genes involved in a certain function.

Changes in mRNA levels can be ultimately modulated or nullified by post‑transcriptional regulation, and thus may be less representative of the physiological status of the cell than microRNA.

MicroRNA expression patterns have in our preliminary experiments shown to accurately distinguish glands from controls and SS patients with either low or high degree of inflammation. We validated two microRNAs by quantitative real-time PCR as markers of inflammation and we are in the process of creating a standardized assay for examination of those markers in a larger clinical cohort.

 

MicroRNA alterations in Sjögren’s syndrome affecting salivary flow.

Loss of secretory function of salivary glands is one of the most important functional consequences of Sjögren’s syndrome. Previous studies have reported the presence of Epstein Barr Virus (EBV) DNA in salivary glands of SS patients. We have identified a specific EBV microRNA that is significantly over-expressed in the minor salivary glands of Sjögren’s syndrome patients, independent of degree of inflammatory infiltrate, when compared to the expression in minor salivary glands from healthy volunteers. After validating the increased expression of this miRNA, we examined its effect on one of its predicted targets that has been shown to play an important role in salivary gland function. This predicted target is an endoplasmic reticulum calcium sensor that is important in calcium influx in epithelial cells, which in turn is critical for salivary secretions.

We identified a significant decrease in the amount of this protein in the salivary gland epithelial cells of Sjögren’s syndrome patients when compared to healthy controls in cells overexpressing this EBV microRNA. We are planning to test the effect of this microRNA in laboratory animals and assess its potential use as a target for treatment.

 

Characterization of the microRNA content of salivary microvesicles and global characterization of microRNA and other short non-coding RNAs in human salivary glands.

We previously showed that salivary microvesicles (most likely exosomes) carry microRNAs, which can be identified with TaqMan real time PCR and microarrays. Our current effort is to isolate microRNAs and other small RNAs in large quantities that will allow for sequencing of their small RNA content.  The objective of this project is to determine the global expression of microRNAs and other non-coding short RNAs present in salivary exosomes and salivary glands in Sjögren’s syndrome patients and healthy volunteers, which we believe will be of considerable use in allowing the development of diagnostic and disease progression biomarkers that can reflect the physiological status of the salivary gland without the need of a biopsy and invasive procedures.

Our work so far has identified 6 novel, never previously discovered microRNAs, some of which are differentially expressed in the saliva and minor salivary glands of Sjögren’s patients.

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This page last updated: February 26, 2014