‘Rare’ Molecule in Immune System Turns Out to Be Common, and May Be Part of What Goes Wrong in MS

Researchers have discovered that a type of immune molecule — called “spliced epitopes,” once believed to be very rare  — in fact makes up a large part of the molecules labeling cells as belonging to the body, and those that are invaders. The finding may well change our understanding of multiple sclerosis (MS) and other autoimmune diseases.

The study, “A large fraction of HLA class I ligands are proteasome-generated spliced peptides,” recently published in the journal Science, may explain both the great flexibility of the immune system and its inclination to err. This new view of the immune system may forward research not only into MS, but also in other immune-related areas, including cancer.

When cells of the immune system scan their surroundings for invading microbes, they are not able to “see” an entire bacterium or virus. Instead, they recognize protein fragments.

As certain immune cells encounter the first microbes during an infection, they ingest them and break down their proteins into pieces. These pieces, called antigens, are then brought to the surface of the cells to flag that an infection is ongoing. In this way, an immune cell does not have to encounter a live microbe to be alerted to its presence. All cells in the body carry the same kind of flags on their surface. Immune cells recognize these labels as safe, and leave them alone.

Earlier studies found that some of these protein pieces consisted of two parts fused together. While working to map cancer mutations, researchers at Imperial College London, and Charité – Universitätsmedizin Berlin and the Berlin Institute of Health, took a new approach to map the surface of cells.

To their surprise, they discovered that fused proteins — which researchers refer to as spliced epitopes — made up nearly one-third of such fragments on human cells.

“While we were aware of the existence of these combined epitopes, we always considered them to be rather rare,” Dr. Michele Mishto at the Berlin Institute, the study’s senior author, said in a press release. “However, our results suggest that they are very frequent and are a key element in the immune response. Finding out their exact function and mode of operation may change our understanding of the immune system.”

“High numbers of spliced epitopes provide the immune system with additional options when identifying and fighting pathogens,” said Dr. Juliane Liepe, the study’s first author and a researcher at Imperial College. “However, there is also a risk of more errors occurring, such as when the epitopes produced from pathogens are identical to some of the body’s own epitopes.”

The research team believes that such errors may contribute to the development of MS and other autoimmune conditions.