Lupus Autoimmune B-cells Escape miRNA Quality Control, Study Shows
Scientists at The Scripps Research Institute identified key mechanisms contributing to the generation of autoimmune B-cells that attack the body’s own tissues in diseases like systemic lupus eurythematosus. In a cluster of microRNA (miRNA) molecules, the research team found one factor with exaggerated presence that allows faulty cells to sneak past quality control checkpoints.
The study, “Regulation of B Cell Development and Tolerance by Different Members of the miR-17~92 Family MicroRNAs,” published in the journal Nature Communications, shows a part of the puzzle that one day might allow scientists to target miRNA factors to control lupus and other autoimmune conditions.
The Scripps team, led by Changchun Xiao and David Nemaze, was working on a cluster of miRNAs called miR-17~92 when they realized that individual miRs in the group play their parts during different stages of immune B-cells development.
“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,” Alicia Gonzalez Martin, a research associate and first author of the study said in a news release.
To allow B-cells to identify intruders or faulty cells, these immune soldiers are equipped with many receptors on their surfaces. The particular composition of receptors they acquire is determined by random processes, and sometimes a cell is born with receptors allowing it to attack the body’s own tissues — as in lupus.
In earlier research, the team found that levels of the individual miRs in the miR-17~92 cluster need to be just right to produce healthy B-cells.
In the new study, they were able to pinpoint two molecules in the cluster — miR-17 and miR-19 — that seemed to play major roles in the development of the cells. miR-17 was needed for the normal development of the cells. Without it, the immune system became weak and inefficient.
Later on in the developmental process of the cells, miR-19 stepped in and turned out to be crucial for the quality control checks of newly formed B-cells before they leave the bone marrow, where they are born.
If too much miR-19 was present, a gene called Pten which normally works to control the survival and release of dangerous B-cells was turned off, allowing autoimmune cells past the quality controls.
“Pten has been the focus of oncology studies, so it’s interesting to see that this gene is also involved in tolerance checkpoints,” said Maoyi Lai, a scientific collaborator and co-author of the study.
The researchers on the Scripps team are keeping bu. On August 1, they published a study showing the involvement of another miRNA, miR-155, in the development of immunity.
Xiao and his team are continuing to focus on the role of miRNAs in the quality control system allowing autoimmune B-cells to get past the checkpoints. Their aim is to tease out which miRNA might be suitable to target in the fight against autoimmune disease.
“miRNA-based therapies are usually designed for certain miRNAs, not a whole cluster,” said Lai. “If you can narrow it down to one or two important miRNAs, you can design miRNA mimics or anti-miRNAs to try to restore the normal expression level.