Scientists have managed to map a central part of the immune system

A new article in Science Advances details how scientists have been able to map a central part of the immune system — HLA class II molecules — while accurately predicting how they display fragments of pathogens on the surface of cells.

When we are sick, our immune system – in order to heal us – relies on our cells to show on their surface that there is something foreign inside. Immune cells — specifically T cells — latch on to the cell’s surface and kill the cancer, virus, or whatever pathogen is there as long as they can identify the threat.

Our cells alert the immune system to its intruder through special proteins called human leukocyte antigen (HLA) molecules. They are responsible for notifying the immune system that something is wrong.

“When a cell becomes infected, whatever is inside it is hidden from the immune system, which lives outside the cells. The reason the body can detect that something is hiding inside the cell is the HLA class molecules and the fact that they take fragments of proteins from the pathogen inside the cell, transport them to the surface and display them. If the fragments have properties that are not recognizable to you, the immune system starts a reaction that kills the cell,” says Morten Nielsen, who is a professor at DTU Health Technology and corresponding author of a new paper in Science Advances announcing the mapping of more than 96% of the entire HLA class II landscape.

He continue:

“But the rules about which protein fragments show up and which don’t, and what other properties it has, have been very unclear for many years because there are so many different HLA variants. You could say there are more than 50,000 ways to display our protein fragments.”

Morten Nielsen has been working on HLA for the past 20 years and has made significant contributions to the process behind developing treatments aimed at helping and training the immune system to fight disease. Much of the progress made in cancer immunotherapy has some connection to tools developed by Morten Nielsen.

In the paper – Accurate prediction of HLA class II antigen presentation at all loci using personalized data acquisition and advanced machine learning – published today in Science Advances, scientists from DTU, the University of Oklahoma, the University of Leiden and the company pureMHC have successfully completed the mapping of the entire system, or as the paper calls the “specificity tree”, of HLA class II.

20 years in the making

It took 20 years to complete the HLA class-specific landscape map for several reasons. For one thing, they are never the same from person to person. Their genes differ greatly, so different people have different HLA types that recognize different parts of the pathogen.

Although they all play a major role in the function of the immune system by displaying protein fragments, they affect our health in different ways. Some make us more likely to get autoimmune diseases, where the immune system attacks the body. Some make us more likely to reject an organ transplant. Some affect how well our immune system responds to treatments, such as vaccines or drugs.

Also, there are two parts to each HLA class II molecule: an alpha part and a beta part. These in turn come from three different groups of genes: DR, DP and DQ. The DR group has one primary gene, DRB1, and three other genes, DRB3, DRB4, and DRB5. The DP and DQ groups have two genes, DPA and DPB and DQA and DQB. Also, the alpha and beta parts can originate from the same gene or different chromosomes.

It is sometimes stated that knowledge of DRB1 is sufficient or that other combinations are less important in characterizing the HLA class II functional space. However, several other HLA class IIs appear to play an essential role in, for example, autoimmune diseases and in the non-rejection of transplanted organs. They may also be vital in the treatment of other diseases, so interest in creating immunotherapy treatments that recognize them is growing.

In any case, there are many possible combinations in the HLA class II system, and because only DRB1 molecules have been studied and mapped extensively, an understanding of the entire HLA class II complex is lacking.

Large-scale datasets and machine learning

To understand how the myriad HLA class II genes affect our health, Morten Nielsen and his colleagues needed to know what types of pathogens they recognize and how they present them to our immune system. To make this final push and understand the rules defining HLA class II, they integrated large-scale, high-quality datasets covering a wide variety of HLA class II molecules and their specificities. They used custom machine learning frameworks, thereby improving the ability to accurately predict how they function.

“Twenty years ago we were looking at 500 data points from a single molecule, but we soon learned that there are rules to this. We didn’t have to measure everything. So gradually our understanding grew and so did the technology available. We went from our first paper with a single molecule to our last paper covering 50,000 molecules. They are all described in detail,” says Morten Nielsen.

We have overcome every hurdle and fully understand what each HLA class II molecule does. For example, our tools have been used for the past 15 years in cancer immunotherapy development and have served as cornerstones for many cancer vaccine companies. And our tools are the most used. With this document, we offer the complete toolkit, a toolkit that can also be used for viral infections or autoimmune diseases. There will still be a lot of research in this area, but conceptually, I believe the journey is complete and I don’t believe anything more will happen.”

Morten Nielsen, Professor at DTU Health Technology