Scientists manage to map a central part of the immune system

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

When we’re sick, our immune system—to heal us—relies on our cells to signal to their surface that something foreign is inside. Immune cells—especially T cells—stick to the cell’s surface and kill the cancer, virus, or whatever pathogen is present as long as they can identify the threat.

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

“When a cell becomes infected, whatever’s inside 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 HLA class molecules and the fact that they take fragments of proteins from the pathogen inside the cell, bring them to the surface and display them. If the fragments have properties that are not recognizable as your own, the immune system starts a reaction that kills the cell,” says Morten Nielsen, professor from DTU Health Technology and corresponding author of a new paper in Science Advances announcing the mapping of 96% of the entire HLA class II landscape.

He continues:

“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 our protein fragments show up ».

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

On paper – Accurate prediction of HLA class II antigen presentation across loci using tailored data acquisition and sophisticated machine learning – published today in Science Advances, scientists from DTU, the University of Oklahoma, Leiden University and the company pureMHC have successfully completed the mapping of the entire system, or as the paper calls the HLA class II ‘specialty tree’.

20 years in the making

It took 20 years to complete the HLA class specialty landscape map for several reasons. First, it is never the same from person to person. Their genes are very different, so different people have different HLA types that recognize different parts of a pathogen.

While they all play a key role in immune system function 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 may come from the same gene or different chromosomes.

At times, it has been determined that knowledge of DRB1 was sufficient or that other combinations were less important for characterizing the HLA class II functional space. It turns out, however, that many other class II HLAs play an essential role, for example, in autoimmune disorders and in relation to the non-rejection of transplanted organs. They may also be vital for treating 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 since only the DRB1 molecules have been extensively investigated and mapped, an understanding of the entire HLA class II complex has been 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 kind of pathogens they recognize and how they present them to our immune system. To make this final push and understand the rules that define 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 would operate.

“Twenty years ago, we were looking at 500 data points from one molecule, but we soon learned that there were rules to it. We didn’t need to measure everything. So, gradually, our understanding grew, and so did the technology available. We went from our first paper with one molecule in our latest paper, which covers 50,000 molecules. Everything is 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 to develop cancer immunotherapy and have served as cornerstones for many companies developing cancer vaccines. And our tools are the most used. With the current work, we now 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 think the journey is complete and I don’t think anything more will happen.”

Morten Nielsen, Professor from DTU Health Technology