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Researchers crack final part of the immune system code

July 11, 2008

A group of researchers at the Technical University of Denmark and the University of Copenhagen have developed models of neural networks that make it possible to simulate how the body protects itself from disease and predict the immune system's access codes. The human body has its own natural inbuilt defence mechanism which uses access or "pincodes" to stop microorganisms that invade the body from discovering how the entire human immune system works. Every human being on the planet has their own unique version of this defence mechanism. But the sheer complexity of the immune system has, up until now, also made it difficult for researchers to understand how the immune system functions and develop precise immunological treatments. Last year, the research team led by Associate Professor Morten Nielsen and Professor Søren Buus successfully decoded some of the pincodes. Now, the team has completed work on their project and put together a complete picture of how the immune system checks the inner and outer components of our cells for dangerous invaders. The research could have significant consequences for the treatment of cancer, infectious diseases and also for transplant operations.
The challenge of decoding the immune system

That no two individuals react in precisely the same way to the diseases they encounter during their lives and that the world is still plagued by illnesses we neither can treat nor vaccinate against can be attributed to the same reason - the human immune system is extremely complex.

The immune system protects us against threats from e.g. bacteria, viruses and cancers by sending out T-cells to inspect the body's cells and check for infections, biological changes or defects. Small fragments or antigens sit on the outermost wall of the cells, which the T cells are able to recognise and react to. Fortunately, the T cells in our bodies are primed to ignore the antigens of our own cells and therefore only warn the immune system of a threat if they encounter antigens that do not belong to the body. Complications sometimes arise from organ transplants because of this, since the T cells of a recipient can discover antigens from the donors organ, leading the T cells to attack and reject the organ. With autoimmunediseases, the T cells in fact malfunction and become "sensitised" to the body's own antigens, drawing an attack response against the body itself.
Tissue type molecules inspect our cells

Normally, T cells only react when presented with a foreign antigen - a reaction which is set in motion by so-called tissue type molecules. Tissue type molecules are "samplers" which select fragments from all the proteins found in the body and display them to the T cells in (the biological equivalent of) two display windows. In the one window, Class I tissue type molecules display fragments from the interior compartment of our cells (this could, for example, be a virus). In the other display window, the class II tissue type molecules display the protein fragments from outside the cells. Depending on whether the invading microorganism has made its way directly into our cells or has 'just' made its way into the body, the immune system reads the threat in one or the other of the display windows. This information is critical if the immune system is to function correctly, with 'misunderstandings' in how the T cells read the fragments leading to serious illness or death.
The 'samplers' are the immune system's pincodes

The type of samples that are selected also play a key role in the functioning of the immune system; if a microorganism can evade the tissue type molecules/ samplers, then they also evade the entire immune system. To protect against this, the immune system is furnished with a vast number of both class I and class II tissue type molecules, which determine what kind of sample is to be presented in the two corresponding display windows. Each person has only a few variants of these molecules - our own immune system pincode - but the human race has thousands, which can combine to give an even larger number of variants.

The codes protect our immune system

The huge variation in tissue type molecules means that a microorganism can never know which combination of molecules it is encountering and even if it does unlock this information in one individual, the microorganism cannot apply this knowledge to the next individual it infects, where a different pincode will be in place.

"The defence strategy provides one of the most robust ways of protecting the immune system against infiltration - a little like PIN codes protecting our credit cards", explains professor Søren Buus from the Department of International Health, Immunology and Microbiology at the University of Copenhagen." At the same time, however, this defence mechanism presents a huge challenge for researchers who want to understand how the immune system works and find methods to treat patients on the basis of immunological principles.

"If we can understand how the T cells work, we can use this insight to discover, diagnose and treat diseases" continues Professor Buus. "In order to do this, however, we must first identify precisely which of the fragments the tissue type molecules are choosing to place in their display window. These fragments are the components that could form the basis for new treatments and vaccines, since it is only if the tissue type molecule displays the right kind of fragment in the right display window that the immune system reacts."

Today, researchers know that there are approximately 5000 different tissue type molecules in humans. Each of us expresses a unique combination of molecules and it is for this reason that two people never react in quite the same way to the diseases they contract during their lives. The vast number of tissue type molecules also explains the problems doctors face during organ transplants, where optimum tissue type compatibility is required in order to carry out an operation. If researchers can characterise and identify precisely which of the fragments all the different tissue type molecules choose to place in their display window- i.e identify all the pincodes - they can unlock the human immune system.

Up until now unlocking the codes of the immune system was considered to be a daunting and near impossible task as more tissue type molecules were being discovered than the scientists were able to decode. However, last year the research team led by Associate Professor Morten Nielsen and Professor Søren Buus did manage to characterise all the tissue type molecules that appear in display window I and now the same team have, with the aid of the artificial neural networks, have characterised the molecules that would appear in display window II of a cell.
Perspectives: Decoding the immune system to target disease

For the individual patient, the artifical neural networks mean that if scientists can identify the patient's tissue type molecules (pincodes), they can then predict all the possible samples that would be taken by the tissue type molecules and displayed in the two display windows. If the patients own immune system, for example, does not react to a particular disease the knowledge could be used to stimulate (find, isolate and produce) the necessary T cells that can see the disease antigens (viruses, cancer cells etc). On a global scale, the neural network method could help researchers to deal with all the variants/single components of a global epidemic.

"We'll be able to find candidates for vaccines which can both help the individual as well as the whole of humanity" explains professor Søren Buus. The neural networks provide the most comprehensive knowledge of the immune system to date.

The findings have been published in PLOS Computational Biology, 4 July 2008.

University of Copenhagen