Sjögren’s syndrome (SjS) is an autoimmune condition that primarily affects salivary and lacrimal glands, causing loss of secretion. We have previously shown that microRNA-146a (miR-146a) is over-expressed in the salivary glands and peripheral blood mononuclear cells (PBMC) of SjS-prone mice (C57BL/6.NOD-Aec1Aec2, B6DC) and in PBMC of SjS patients. The purpose of this research was to first identify the role of miR-146a in innate immune responses and second, to identify SjS-specific miRNA profiles in innate immune CD14+ monocytes. In silico analyses initially identified costimulatory molecule CD80 as a novel target of miR-146a. I found miR-146a directly inhibited CD80 protein expression and examination of B6DC salivary glands revealed a reduction in CD80 protein. More interestingly, a reduction in CD80 was detected in the salivary gland epithelial cell population, which was associated with elevated miR-146a expression. Since T-cell costimulation by antigen presenting cells is critical for initiation and function of CD4+ T-cells in SjS, I also evaluated B6DC mice for potential dyregularities in T-cell numbers or function. I identified Foxp3+ regulatory T-cells in B6DC mice displayed a more pro-inflammatory phenotype. Finally, CD14+ peripheral blood monocytes were examined to determine miRNA expression profiles in healthy
control, SjS, rheumatoid arthritis, and systemic lupus erythematosus patients. Interestingly, SjS patients’ monocytes displayed a unique set of upregulated miRNAs in comparison to control groups, which may prove useful in improving the differential diagnosis of SjS. Additionally; these SjS-associated miRNAs were also predicted to regulate transforming growth factor-beta and mitogen-activated protein kinase signaling pathways, which appear to be critical in SjS pathogenesis. Altogether, my findings are the first indications that salivary gland epithelial cells and monocyte populations display upregulated miRNAs that may be critically involved in autoimmune SjS progression.
|School:||University of Florida|
|School Location:||United States -- Florida|
|Source:||DAI-B 78/05(E), Dissertation Abstracts International|
|Keywords:||Autoimmunity, CD14+ monocyte, Costimulation, MicroRNA, Sjorgren's syndrome, T cell|
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