Self-healing and Self-destruction – Part 2

Society

Event data

Datum: 4. 4. 2017
Host: Mini-Med Studium
Location: Van-Swieten-Saal der Medizinischen Universität Wien
Event-type: Vortrag
Participants: Univ.-Prof. Mag. Dr. Wilfried Ellmeier, Institut für Immunologie, MedUni Wien; Ao. Univ.-Prof. Dr. Clemens Scheinecker, Universitätsklinik für Innere Medizin III, MedUni Wien/AKH Wien; Univ.-Prof. DI Dr. Hannes Stockinger, Institut für Hygiene und Angewandte Immunologie, MedUni Wien

This is the second part of the talk on the immune system. Prof. Stockinger was speaking about the possibility of B and T-lymphocytes to produce a much greater antigen receptor variability than that which would be possible by germline determination.

Recombination of gene segments

The secret of recombination was discovered by Susumu Tonegawa (who won the Nobel Prize in medicine in 1987 for this). He was the first to discover that genes can be recombined from gene segments. As such, it is possible, for example, for T-lymphocytes 1 to take V-segment 70 (gene segment – we have 70 V) and J-segment 2 (of which we have 61) and the result is a corresponding antigen receptor (which is, for example, effective against polio). By way of analogy, the B-lymphocytes 2, akin to a random generator, take a segment from V and J and as a result there is a completely different antigen receptor. Through the combination of different gene segments, it is possible for our B and T-lymphocytes to produce around 10,000 different antigen receptors. The gene segments, however, have also to be connected and this (so-called connection diversity) occurs as a result of a random selection of alkali. As such there is an almost infinite possibilty to produce recognition structures (the antigen receptors). For B-lymphocyte 3 it is, for example, possible to take cell 1 V-segment 70 and J-segment 2 but to produce a completely different antigen receptor due to another connection than cell 1.

This process is irreversible and can only take place once in the lifetime of a B or T-lymphocyte – thereafter this antigen receptor (B-lymphocyte with corresponding antibodies) is shown (“expressed”) on the surface. As such, the body has antigen receptors and antibodies against a wide variety of diseases (e.g. tick-borne encephalitis, polio or measles).

If a sickness is appraoching …

If there is a lack of antigen receptors for a certain bacterium, this can grow uncontrollably and one becomes sick.

This would be treated therapeutically, e.g. with antibiotics (this leads to a slowing down of the bacterial growth) and a B-lymphocyte or T-lymphocyte would possibly form a corresponding antigen receptor for this bacterium.

In the case of existing antigen receptors against a bacterium, induction via dendritic cells would lead to a growth of a B-lymphocyte/T-lymphocyte. And now the race begins between the growth of one’s own immune cells and the bacterium. The course is also dependent on the intensity of the infection (in this context: do not forget the significance of washing your hands!).

As a result one either does not become ill at all (so-called “silent infection”) or one becomes ill and is healthy again after one week.

This is due to the generation time of the B and T-lymphocytes (which amounts to six hours i.e. after six hours they split up after induction). At this rate, there are already one million immune cells on day five, and on day eight, around four billion cells.

This is the secret of an immune system in a restricted body – an immune cell with the specifity for every pathogen is in the body, the number of which, however, only rises in case of need (contact with the corresponding antigen).

Memory cells

During this increase, memory cells are also produced. After the bacterium has been killed, most of the immune cells also have to disappear again as space has to be created.

The remaining cells are the memory cells which multiply phenomenally when they come into contact again with the pathogen – we do not become sick.

This is the “predictable immunity” – in the course of life, we adapt to pathogens so that we are protected. These can be read in the framework of the antibody titer. This knowledge is necessary in medicine for the principle of vaccination. Here weakened or parts of pathogens are used in the body to develop memory cells.

As such, the body is able to produce a defence structure against every pathogen. The problem, however, is that the body can also turn against components that the body naturally produces or nutritional components – in the case of an attack from components naturally produced by the body, one speaks of an auto-immune disease, in the case of an attack by a harmless nutritional component, one speaks of an allergy.

Control of the system

As such, the system has to be strictly controlled in order not to trigger an immune response against harmless components or components produced by the body itself.

For the T-lymphocytes, this occurs in the thymus. The progenitor cell comes from the bone marrow, wanders to the thymus, grows there and begins to express its own antigen receptors. Those cells whose receptors are directed against components produced by the body or against harmless components die (“aptoptosis”). Only 2-3 % of all T-lymphocytes are ultimately able to wander from the thymus into the blood – this is, however, not directed against itself. Dysfunctions include, e.g. auto-immune disorders (here the body’s own tissue is attacked as not one’s own) or cancer (modified tissue is tolerated as one’s own).

How can the body differentiate between dangerous and harmless? It is thought that this occurs in the gastrointestinal tract.

However, in fact the immune system has a very hard time in differentiating these. This is shown by the fact that 25 % of the population suffer from allergies and 20 % from infections (here, the danger is erroneously tolerated). While infections can be attacked with antibiotics, it is in the meantime also possible to recongnise allergy antigens.

In this field, the personnel at the Medical University in Vienna are global leaders.

If it is known which allergy antigens there are, it is also possible to recognise certain cells with special antigen receptors and to eliminate them therapeutically. There are already excellent therapy programmes which will subsequently be presented by Prof. Scheinecker.

Therapeutic possibilites in the case of auto-immune disorders

Prof. Clemens Scheinecker spoke about the therapuetic possibilities in the case of a pathogenic immune system. As already mentioned, when the body turns against itself, auto-immune disorders result. Paul Ehrlich was one of the first to recognise that the immune system can also make us sick and referred to this disorder as “horror autotoxicus”.

In the case of auto-immune disorders, there is an infection process which is analogous to the response of an external pathogen.

A well-known drug which has been used for a long time in this context is cortisone. This is an endogenic hormone of the adrenal glands which was discovered in 1935 and first used in 1948 with phenomenal success. This is still considered a milestone in pharmacological history. Nevertheless, the side-effects can be very unpleasant, in particular if taken over a longer period of time.

Other drugs can also interfere with the immune system and these take effect when cells divide quickly. The drugs slow down the cell division and are effective in the case of infection cells due to the high rate at which they divide cells. The problem is that other cells in the human body also divide quickly, among others, the cells of the gastrointestinal tract, mucosal cells and blood cells. These cells are also adversely affected by these immunosuppressive drugs.

Currently, the strongest known immunosuppressive is cyclophosphamide, which is also used in chemotherapy. This drug can also cause extreme, undesirable side-effects.

Based on basic immunological research, other drugs have been developed which help to better target diseases, known as “targeted therapies”. Here it is not the entire system which is disabled but rather single steps are targeted.

These drugs were developed around 20 years ago – the so-called “biologicals”. These can disable the inflammatory messengers (“cytokines”, see article 1), block the activating of immune cells, eliminate entire populations of cells (e.g. the B-cell population) from the system or block the signal paths within cells.

It is important to stress that these drugs were studied in animal trials in order to subsequently be used in therapy for humans (“from bench to bedside”). Of course the biologicals also have side-effects which, however, are typically not at intensive as those from the older drugs (there are, however, problems in particular in the case of cardiovascular diseases). Among the ten bestselling drugs worldwide, four are biologicals (especially in the rheumatology/hematology field). But the high therapy costs should not be ignored.

Summarising, according to Prof. Scheinecker, the restoration of a balance of the immune system between immunity and immunological tolerance is always paramount.

This extremely fascinating event was attended by a large audience who also had the opportunity to ask questions. This highlights – despite the complicated nature of the subject – the great significance of and interest in immunology in daily life.

Our immune system

Credits

Title	Author	License
das Podium	Johanna Bickel	CC BY-SA 4.0
Prof. Scheinecker spricht über die Nebenwirkungen von Biologika	Johanna Bickel	CC BY-SA 4.0
Prof. Stockinger	Johanna Bickel	CC BY-SA 4.0
Self healing and Self destruction Part 2	Johanna Bickel	CC BY-SA 4.0