In Autoimmune Diseases Like Lupus, Researchers Discover Molecule that May Be Cause

A collaborative research project conducted between The Scripps Research Institute in La Jolla, California; Yale University  in New Haven, Connecticut; and National Biotechnology Center in Madrid, Spain, has identified a small molecule called miR-148a as a key regulator of immune cells, where higher levels appear to cause autoimmune diseases.

The paper, “The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity,” was published this week in the Nature Immunology journal.

Autoimmune diseases such as lupus are identified by widespread inflammation and tissue damage caused by the continuous attacks of the immune system towards its own healthy cells. The immune system contains white blood cells (B-cells) produced in bone marrow, which develop receptors with random fashions used to fight against foreign invaders like micro-organisms and viruses. The immune system also contains B-cell tolerance checkpoints programmed to get rid of self-reactive B-cells, responsible for attacks not only on foreign invaders, but also return against the healthy body cells. This process, known as apoptosis (programmed cell death), is impaired in patients with autoimmune diseases.

In this study, the researchers genetically engineered mice with all self-reactive B-cells. As a result, the mice had no B-cells as they constantly eliminate themselves through self-tolerance processes, and as the mice aged, the researchers observed that some self-reactive B-cells leaked into the blood stream. They speculated that the leakage might be linked to what is called microRNA (miRNAs), long thought to be genetic junk, and where more than 1,000 known miRNAs could influence gene expression responsible for survival or elimination of self-reactive B cells.

To track these miRNAs, the research team utilized a virus to produce self-reactive B-cells with a specific expressed miRNA, then injected these cells into the genetically engineered mouse.

During the process, some of the self-reactive B-cells leaked into the mice spleens that the researchers extracted and analyzed. “This was a risky project because we weren’t sure if any miRNA at all would regulate B-cell tolerance,” said Alicia Gonzalez-Martin, research associate in the Xiao lab and first author of the new study.

The results showed increased levels of an miRNA called miR-148a responsible for leakage of the self-reactive B cells into the blood stream, which  afterward turn against the body and attack its healthy cells. “This is the first miRNA implicated in the regulation of B-cell tolerance,” added Alicia.

Other results suggested that mice models of lupus forced to overexpress miR-148a developed lupus quickly if compared to similar mice with normal miR-148a expression. Additionally, overexpression of miR-148a is observed in numerous human patients with lupus.

In the future, researchers planned to explore other functions of miR-148a to figure out if its inhibition will induce undesirable side effects.

“This is a good target for future therapies,” said TSRI associate Prof. Changchun Xiao, who was co-senior author of the study with TSRI Prof. David Nemazee. “We now know that this is causative — it’s not just a side effect.”