Research into MicroRNA May Lead to New Lupus Therapy, Better Vaccines

New research into a microRNA that helps to produce antibodies offering long-term protection against disease takes science a step close to finding a way to boost vaccine responses, and possibly to understanding how the molecule might be used to counter the development of autoimmune diseases like lupus.

The study, “A miR-155–Peli1–c-Rel pathway controls the generation and function of T follicular helper cells,” published in The Journal of Experimental Medicine, describes the role of the microRNA, called miR-155, in the production of antigen-specific antibodies required for long-term immunity.

When the body first detects pathogens, such as virus or bacteria, a sequential process that ultimately leads to the generation of antibody-producing B-cells (against foreign pathogens) is initiated. This process involves the proliferation of immune cells, called T follicular helper (Tfh) cells, and their migration to a specific site on the lymph nodes, where they interact with B-cells.

“They do a sort of tango,” the study’s co-lead author, Professor Changchun Xiao of the Scripts Research Institute (TSRI), said in a press release.

This interaction induces B-cell maturation and promotes the expression of highly specific antibodies against the “invaders,” eventually leading to long-term protection against infection by these pathogens.

Researchers were interested in understanding the molecular mechanisms that led to Tfh differentiation and function during the first contact with a specific pathogen. Their interest was based on evidence showing that these cells are essential to controlling chronic virus infection, and that high levels of Tfh can lead to autoimmunity.

Because a number of studies have shown that microRNAs, small DNA molecules that control gene expression, are critical regulators of Tfh and B-cell interaction, scientists focused their attention on Tfh-derived microRNAs.

“People know miRNAs are involved in immune response, but they don’t know which miRNAs and how exactly,” said Zhe Huang, a TSRI research associate and the study’s co-first author.

Through a technique that quantifies gene expression, called deep sequencing, the researchers identified miR-155 as a key player in this process. Studies in mice genetically engineered to lack miR-155 revealed it represses the expression of a protein called Peli1. This, in turn, leaves a molecule called c-Rel free to induce normal T-cell proliferation and produce a specific ligand, called CD40L, that is essential for Tfh and B-cell interaction.

The researchers believe that their findings may help increase the efficacy and durability of vaccines. A number of vaccines lose their effectiveness after a decade, and some are only effective in 80 percent of the people vaccinated.

“If you could increase T cell proliferation using a molecule that mimics miR-155, maybe you could boost that to 90 to 95 percent,” said Xiao.

In addition, the findings may also lead to the development of miR-155 inhibitors that could be useful in the setting of autoimmune diseases, where T-cell proliferation and antibody production are excessive.