Scientists map the antigenic landscape

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A concatenated variant tree for HLA-DR, HLA-DP, and HLA-DQ. Orange molecules have a peptide sequence matching at least 50 high-confidence ligands, and blue molecules have a pseudo-sequence distance of at most 0.05 to the orange molecule. Logos in red frames correspond to uncoated molecules. Credit: Jonas Birkelund Nilsson

New paper inside Advances in science Scientists describe in detail how they succeeded in modeling HLA class II molecules, the central part of the immune system, to accurately predict how pathogens will display on the surface of cells.

When we are sick Immune system It depends on the signs on the cell surfaces that show that there is a foreign object inside. Immune cells—specifically T-cells—stick to the cell’s surface and kill cancer, viruses, or any pathogens they deem a threat.

Cells warn the immune system of the infection through special proteins Human leukocyte antigen (HLA) molecules. They are responsible for letting the immune system know that something is wrong.

“When a cell is infected, whatever is inside it is hidden from the immune system outside the cells,” said Morten Nielsen, professor of health technology at DTU and corresponding author of the paper. Advances in science Announcing the mapping of more than 96% of the total HLA class II landscape.

“The way the body knows there’s something hidden in the cell is because the HLA class picks up molecules and protein fragments from pathogens in the cell, transports them to the surface and displays them. Unbeknownst to you, the immune system initiates a response that kills the cells.”

“However, the rules for which protein fragments appear and do not appear and what other characteristics have been very unclear for many years because there are many different HLA variants. You can say that there are more than 50,000 ways to display our protein fragments.”

Nielsen has been working on HLA for the past 20 years and has been instrumental in developing therapies designed to help and train the immune system to fight disease. Many of the advances in cancer immunotherapy have some connection to tools developed by Nielsen.

In the newspaperAccurate prediction of HLA class II antigen presentation at all locations using customized data acquisition and refined machine learning“Scientists from DTU, 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 “diversity tree”.

20 years in the making

It took 20 years to complete the HLA class specification topographic map for several reasons. For one person, they are never the same from person to person. Their genes vary widely, so different people have different types of HLA that recognize different pathogens.

Although they all play a vital role in immune system function by expressing protein fragments, they affect health in different ways. Some predispose us to autoimmune diseases where the immune system attacks the body. Some increase the chance of organ failure. Some affect how well the immune system responds to treatments such as vaccines or medications.

Also, there are two parts to each HLA class II molecule: an alpha part and a beta part. They, in turn, come from three different groups of genes: DR, DP and DQ. The DR group has one major 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. The alpha and beta components can come from the same gene or from different chromosomes.

In some cases, it was determined that knowledge of DRB1 was sufficient or that other compounds were not essential in defining the functional HLA class II locus. But many other HLA class IIs play important roles, for example, in autoimmunity and rejection of transplanted organs. They can be very important in the treatment of other diseases, so there is an increasing need to create immunological treatments that recognize them.

However, there are many potential compounds in the HLA class II system, and since only DRB1 molecules have been investigated and extensively mapped, an understanding of the entire HLA class II complex has been lacking.

Large-scale data sets and machine learning

To understand how the myriad of HLA class II genes affect health, Nielsen and his colleagues had to figure out what pathogens they recognize and how they present them to our immune system. To make this final push and discover the rules that define HLA class II, they integrated large-scale, high-resolution datasets covering a wide variety of HLA class II molecules and their variants. They used the best Machine learning Frameworks, thereby improving the ability to predict exactly how they will work.

“Twenty years ago we were looking at 500 data points from one molecule, but soon we learned that there are rules for this. We don’t have to measure everything. So, little by little, our understanding is growing, and so is the available technology. From our first paper to 50,000 from one molecule to the last paper We have arrived Molecules. All of these are detailed,” says Nielsen.

“We have overcome every hurdle and fully understand what each HLA class II molecule does. For example, our tools have been used to develop anticancer therapies for the past 15 years and have served as cornerstones for many companies developing cancer vaccines. The tools are widely used.”

“With the current paper, we now present the complete toolbox, which can be used for viral infections or immunological diseases. There will still be a lot of research in this field, but in theory, I believe that the journey is complete, and I do not believe that there will be anything more.”

Additional information:
Jonas B. Nilsson et al., Accurate prediction of HLA class II antigen presentation in all environments using customized data acquisition and refined machine learning; Advances in science (2023) DOI: 10.1126/sciadv.adj6367

Quote: Scientists map the antigenic landscape (2023, November 27) Retrieved November 27, 2023 from

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