Revolutionary immune system discovery could be a double-edged sword

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We may have finally come closer to understand how autoimmune diseases occur

Credit: Pixabay
Credit: Pixabay

What happens when a baby sees a mirror for the first time? Well, she would most probably smile and babble at the little person looking back at her and take a few more months to reach the “self-recognition” milestone. The same happens in our immune system, only that it happens much faster and is fundamental to our survival.

The immune system is attuned to our inner and outer environment and is continuously sifting through the body for intruders. Every cell in the body has a marker, like a nametag, with which the immune system is able to identify self from non-self, thus making it possible for the millions of cells and the friendly microbes to coexist in the body.

HLA (Human Leukocyte Antigen) is a gene complex that code for these self-markers or cell surface proteins on all the body cells. The immune system uses the HLAs to differentiate self-cells from non-self cells. Any cell displaying a different HLA type does not belong to them and, therefore, is an invader, eventually mounting an immune response.

The “cut and merge” creates a case of mistaken identity!

A cellular machinery called proteasome helps in breaking down the body’s own damaged or unneeded proteins, along with foreign proteins from bacteria and viruses by proteolysis. During the degradation process, proteins are broken down into shorter sections called epitopes and are translocated through the cell wall, and presented at the cell surface like tiny flags. This tagging allows the immune system to recognise foreign proteins, which are subsequently attacked and destroyed.

In a study published in Science, the researchers used a new technique for mapping the surfaces of cells and discovered that there were thousands of entities called ‘spliced epitopes’. Spliced epitopes are formed by joining two different fragments from the same protein and combining them to form a new amino acid sequence.

Prior to this study, it was unknown that peptides were cut from different parts of the same protein, merged and then displayed on the cells’ surface.

“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.”

Old player in a new avatar: Spliced epitopes add complexity to the immune repertoire

These extra epitopes, which are longer in length, give the immune system more possibilities of detecting disease. On the flip side, as the spliced epitopes are mixed sequences, they also have the potential to overlap with the self-peptides and be misidentified as harmful. When the immune system mistakes molecules of the self as non-self, autoimmune diseases such as rheumatoid arthritis and Diabetes Type-I, occur.

Graphic illustration by Divya Raghuram, Biotechin.Asia
Graphic illustration by Divya Raghuram, Biotechin.Asia

“For example, the discovery could influence new immunotherapies and vaccines by providing new target epitopes for boosting the immune system, but it also means we need to screen for many more epitopes when designing personalised medicine approaches.” said the study’s lead author, Dr Juliane Liepe from the Department of Life Sciences at Imperial.

Spliced and non-spliced epitopes are produced by a complex molecular machine -- the proteasome -- und subsequently transported to the cell surface. Here, they act as tiny flags to mark cells. These flags are used by other immune cells to distinguish between healthy and infected cells. CREDIT Michele Mishto, Charitè.
Spliced and non-spliced epitopes are produced by a complex molecular machine — the proteasome — und subsequently transported to the cell surface. Here, they act as tiny flags to mark cells. These flags are used by other immune cells to distinguish between healthy and infected cells.
CREDIT Michele Mishto, Charitè.