Scientists achieve mapping a central a part of the immune system

A brand new paper in Science Advances details how scientists have succeeded in mapping a central a part of the immune system – the HLA class II molecules – while accurately predicting how they display fragments of pathogens on the surface of cells.

After we are sick, our immune system – in curing us – relies on our cells to point out on their surface that something foreign is present inside. Immune cells – specifically T-cells – latch onto the cell’s surface and kill the cancer, virus, or whichever pathogen is there, as long as they’ll determine the threat.

Our cells alert the immune system of its intruder through special proteins called human leukocyte antigen (HLA) molecules. They’re chargeable for letting the immune system know that something is amiss.

“When a cell becomes infected, whatever is inside it’s hidden from the immune system, which lives outside the cells. The explanation the body can detect that something is hiding contained in the cell is HLA class molecules and the indisputable fact that they take fragments of proteins from the pathogen contained in the cell, transport them to the surface, and display them. If the fragments have properties that are not recognizably yours, the immune system starts a response which kills the cell,” says Morten Nielsen, who’s a professor from DTU Health Technology and corresponding writer of a brand new paper in Science Advances announcing the mapping of greater than 96% of the complete HLA class II landscape.

He continues:

“But the foundations for which protein fragments are displayed and which are usually not, and what other properties it had, have been very unclear for a few years because there are a lot of different HLA variants. You can say there are greater 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 method behind developing treatments aimed toward assisting and training the immune system in combatting diseases. Much of the progress made inside immunotherapy against cancer has some connections to tools developed by Morten Nielsen.

Within the paper – Accurate prediction of HLA class II antigen presentation across all loci using tailored data acquisition and refined machine learning – published today in Science Advances, scientists from DTU, University of Oklahoma, Leiden University and the corporate pureMHC successfully complete the mapping of the complete system, or, because it is known as within the paper the “specificity tree” of HLA class II.

20 years within the making

It has taken 20 years to finish the HLA class specificity landscape map for several reasons. For one, they’re never the identical from individual to individual. Their genes differ widely, so different people have different sorts of HLA that recognize different parts of a pathogen.

While all of them play a pivotal part within the function of the immune system by displaying the protein fragments, they affect our health in other ways. Some make us more prone to get autoimmune diseases, where the immune system attacks the body. Some make us more prone to reject an organ transplant. Some affect how well our immune system responds to treatments, similar to vaccines or drugs.

Also, there are two parts to every 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 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 come from the identical gene or different chromosomes.

At times, it has been stipulated that knowledge of DRB1 was sufficient or that other combos were less vital when characterizing the functional HLA class II space. It seems, nonetheless, that several other HLA class II play an important role in, for instance, autoimmune disorders and as regards to not repelling transplanted organs. They can also be vital in treating other diseases, so the interest in creating immunotherapy treatments that recognize them is rising.

In any case, there are a lot of possible combos within the HLA class II system, and since only the DRB1 molecules have been investigated and mapped extensively, the understanding of the complete complex of HLA class II has been lacking.

Large-scale datasets and machine learning

To grasp how the myriad HLA class II genes affect our health, Morten Nielsen and his colleagues needed to know what sorts of pathogens they recognize and the way they present them to our immune system. To make this final push and work out the foundations defining HLA class II, they integrated large-scale, high-quality datasets covering a wide range of HLA class II molecules and their specificities. They used tailored machine learning frameworks, thereby improving the power to accurately predict how they function.

“Twenty years ago, we were 500 data points from one molecule, but we soon learned that there have been rules to this. We didn’t must measure the whole lot. So, steadily, our understanding grew, in addition to the available technology. We now have gone from our first paper with one molecule to our latest paper, which covers 50,000 molecules. All of that are described intimately.” says Morten Nielsen.

We now have overcome every hurdle and completely understand what every HLA class II molecule does. As an illustration, our tools have been used for the past 15 years in developing cancer immunotherapy, and so they have served as cornerstones for a lot of corporations developing cancer vaccines. And our tools are essentially the most used. With the present paper, we now offer the complete toolbox, a toolbox that can also be used for viral infections or autoimmune diseases. There’ll still be plenty of research on this field, but conceptually, I imagine the journey is complete, and I do not believe anything more goes to occur.”

Morten Nielsen, Professor from DTU Health Technology