Malfunctioning microRNAs Linked to Development of Lupus in Mouse Models

Another important regulatory role has been identified for microRNA, this time in activating molecular pathways leading to development of the severe autoimmune disorder lupus.

Lupus, which affects more than five million people worldwide, is a chronic autoimmune disease of connective tissue that causes the body's immune system to become hyperactive and attack normal, healthy tissue. The processes leading to development of lupus have so far not been identified.

In an effort to rectify the situation, investigators at Virginia Polytechnic Institute and State University (Blacksburg, USA) used miRNA microarray assays and RT- (real-time)-PCR to measure miRNA expressions in splenic lymphocytes from three mouse lupus models (MRL-lpr, B6-lpr, and NZB/WF1) with different genetic backgrounds. The different models were distinguished by the age at which the animals began to develop lupus (as early as three months or as late as nine months, depending on the strain).

Results published in the December 10, 2010, online edition of the journal PLoS One revealed that despite the genetic differences among the three lupus stains, a common set of dysregulated miRNAs (miR-182-96-183 cluster, miR-31, and miR-155) was present in splenocytes that differed from the miRNAs found in age-matched control mice. The association of these miRNAs with the disease was highlighted by the observation that this miRNA expression pattern became evident in NZB/WF1 mice only at the age when lupus disease was manifested.

Given that miRNAs are conserved, with regard to both evolution and function, the observation of a common lupus disease-associated miRNA expression pattern in mouse lupus models is likely to have significant pathogenic, diagnostic, and/or therapeutic implications for human lupus.

"In the short term, we want to use our better understanding of the disease to develop a tool in the form of molecular markers for early, reliable diagnosis,” said senior author Dr. S. Ansar Ahmed, professor of immunology at Virginia Polytechnic Institute and State University. "The long-term goal is to offer entirely new therapeutic approaches, such as manipulation of lupus-related miRNA, to correct pathological conditions.”

"If we can do this in a mouse model and then to cure other animals, hopefully it can one day be done in humans,” said Dr. Ahmed. "This is long-range research but modern technology is narrowing the time it takes from mouse to human — speeding translation.”

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