Underlying Causes of Autoimmune Diseases

MicroRNA clusters may influence immune cell generation.

Unexpected findings in animal models revealed that members of a cluster of microRNAs (miRNAs) work together through different stages of immune cell generation, shedding new light on the causes of autoimmune diseases.

Study findings published in Nature Communications revealed that different members of the cluster dominate different stages as B cells develop.

“Although the miRNAs in the cluster are all expressed, it’s not like they’re playing the same role — different individual miRNAs within the cluster are more important than others in controlling different stages of B cell development,” said co-first study author Alicia Gonzalez Martin.

“At different stages, one miRNA is like the lead actor and another is like a supporting actor,” saidTSRI Professional Scientific Collaborator Maoyi Lai.

As the immune system’s B cells develop, they acquire specific receptors that allow them to recognize and attack harmful pathogens. This assembly process is random, and can sometimes result in potentially harmful cells, including B cells that produce antibodies against the body’s own tissues that results in the development of autoimmune disease such as lupus.

For healthy B cell development miRNAs appear to play a crucial role. In previous TSRI studies, researchers found that 6 miRNAs form a cluster called miR-17~92, which requires its expression to stay at a specific level in order to stop cells from triggering autoimmune disease or cancers. In the current study, researchers wanted to examine the roles of the 6 miRNAs in the cluster to determine if any could serve as potential targets for future treatments.

“miRNA-based therapies are usually designed for certain miRNAs, not a whole cluster,” Lai said. “If you can narrow it down to 1 or 2 important miRNAs, you can design miRNA mimics or anti-miRNAs to try to restore the normal expression level.”

The results of the current study showed that by disabling the expression of these select miRNAs in mouse models, the miRNA found in the cluster called miR-17 steps in early in B cell development. This provides B cells with the ability to progress through this stage and produce the receptors they require to fight infections later on.

Although the exact pathway for this action is still unknown, researchers found that B cells without miR-17 could not effectively develop and results in the weakening of the immune system.

Another miRNA in this cluster called miR-19, revealed that its expression is important later on in B cell development. miR-19 helps to regulate the quality control checkpoint system that stops harmful B cells from escaping bone marrow and causing the disease.

When miR-19 was overexpressed, researchers found that it led to the reduction of Pten expression. This allowed potentially autoimmune disease-causing cells to survive longer and get past the checkpoint.

“Pten has been the focus of oncology studies, so it’s interesting to see that this gene is also involved in tolerance checkpoints,” Lai said.

Although there are other miRNAs in this cluster that are involved in both of these processes, they appear to have minor roles, according to the study.

The research team plans to continue their investigation in the roles of different miRNAs at the tolerance checkpoint stage, as well as their roles in autoimmunity.