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miRNAs are short, non-coding RNA molecules that post-transcriptionally repress gene expression. miRNAs are released into the extracellular space and are stable while in bodily fluids, such as plasma.
Because of their stability and their presence in biofluids, circulating miRNAs can be detected by non-invasive and reliable methods, making them very appealing as quantifiable biomarkers for monitoring various diseases, including those of the immune system.
Exosomes and the immune system
One of the functions of the immune system is to secrete substances into circulating body fluids to signal to other cells. One way the immune system does this is by the secretion from lymphocytes of microscopic miRNA-containing exosomes.
The circulating miRNAs contained within exosomes can serve as serum biomarkers and provide information about the state of the immune response in health and disease. Moreover, recent evidence supports the role of miRNAs as ideal biomarkers for diseases of the immune system.
For example, following lymphocyte activation, there is a significant increase in serum miR-150 levels in humans immunized with flu vaccine. This serves as a proof of principle that circulating miRNAs can serve as biomarkers of vaccination and adaptive immune responses (de Candia et al., 2013).
This particular study identified a 17 miRNA signature linked to exosomes released specifically by CD4+ T cells. Moreover, increased levels of serum miR-150 following vaccination correlated with antibody response. Interestingly, while circulating levels of miR-150 increased, the researchers detected a rapid reduction in the intracellular miR-150 because of its accumulation in exosomes.
Circulating miRNAs as markers of immune disease
Many recent studies support the notion that circulating miRNAs can be indicative of immune dysfunction. Duroux-Richard et al. (2014) quantified miR-126b levels in blood and serum of rheumatoid arthritis (RA) patients. This miRNA was significantly elevated in the serum of RA patients as well as patients with other forms of chronic inflammatory arthritis.
Importantly, elevated levels of this miRNA also correlated with good clinical response to treatment with rituximab several months later. Prediction of rituximab response was not only limited to RA patients but also associated with rituximab treatment in patients with B lymphomas. Because of this, miR-126b has potential as a biomarker not just for RA or chronic inflammatory arthritis, but also for therapeutic response.
Another recent study used microarray analysis to look at the expression of total serum miRNAs associated with disease from RA patients, as well as those with the inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC; Krissansen 2015). Serum levels of miR-595 and miR-1246 were significantly upregulated in active colonic CD, UC and RA patients compared with healthy controls.
Interestingly, miR-595 impairs epithelial tight junctions by targeting the neural cell adhesion molecule-1 and fibroblast growth factor receptor 2, which are involved in maintaining tight junctions. As for miR-1246, it is involved in activating the proinflammatory nuclear factor in activated T cells. Both mechanisms are targets in inflammatory bowel diseases.
The identification of circulating miRNA signatures may provide information regarding the state of the immune system, immune activation and dysfunction. As miRNAs are present in circulating biofluids and can be easily quantified, they are an excellent candidate for use as biomarkers of immune diseases.
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