Molecule Thought to Cause Autoimmune Diseases Offers Treatment Target

A molecule has been identified that shows a correlation between a specific molecule and the development of autoimmune diseases.

A study published in the journal Nature Immunology found a microRNA called miRNA that affects the immune system. MiRNA is a small non-coding RNA molecule that plays a role in the regulation of gene expression.

"This is a good target for future therapies," said co-senior author Changchun Xiao. "We now know that this is causative--it's not just a side effect."

Normally, B cells develop in the bone marrow and acquire receptors in a random assembly process to help prepare the body to fight off diseases. The body also has a system of B cell tolerance checkpoints in order to eliminate any self-reactive B cells which attack both germs and body tissues. This process relies on programmed cell death.

For patients with autoimmune diseases, the self-reactive B cells are not purged. Researchers used an engineered mouse model with an immune tolerance that could render all of the B cells self-reactive.

The results of the study showed that the cells were able to use a natural self-tolerance process to eliminate B cells from the body continuously.

However, it was observed that as the mice aged, there were some self-reactive B cells that managed to travel to the blood stream. This observation suggested a way to look for genes with dysregulation that promote autoimmune diseases.

It was believed that more than 1000 miRNAs could affect the gene expression that regulates the survival or death of self-reactive B cells. Researchers wanted to try and find which miRNA was responsible.

"This was a risky project because we weren't sure if any miRNA at all would regulate B cell tolerance," said first study author Alicia Gonzalez-Martin.

In order to pinpoint which miRNA was responsible, researchers generated self-reactive B cells by encouraging a virus to express a selection of miRNAs in stem cells that create blood cells and platelets called haematopoietic stem cells.

Next, the cells were put into the bone marrow in a mouse model. Some of the self-reactive B cells were able to travel into the spleens of the mice where researchers were able to analyze the expressed miRNAs.

It was found that miR-148a were responsible for the B cells escaping. This miRNA was able to suppress 3 genes that controlled apoptosis, which is responsible for purging the self-reactive mutants.

Researchers prompted an overexpression of miR-148a and tested it on their lupus laboratory mouse models. In these models, it was found that lupus developed faster than normal miR-148a expression. It’s also found that miR-148a is often overexpressed in patients with lupus.

"This brings us to a pathway that we might be able to regulate with a therapeutic," said co-senior study author David Nemazee.

Following this study, researchers will investigate the other functions of miR-148a in the body and explore whether or not inhibiting miR-148a's actions could have negative side effects.