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Licence to attack the brain

Researchers from Göttingen and Erlangen study T-cell training in the lung

In patients with multiple sclerosis, immune cells cross the blood-brain barrier which normally blocks the blood circulation from the central nervous system, causing considerable damage to the nervous tissue. Scientists from the medical departments at Göttingen and Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have now demonstrated that the cells are trained to cross the barrier in the lung. The team of researchers observed a change in the lungs which reprogrammed T-cells into ‘walkers’. In the long run, the research results, which have been published in the international journal ‘Nature’, may contribute to the development of more effective forms of therapy.

As in all autoimmune diseases, in multiple sclerosis (MS), parts of the immune system turn against the body – in this case the nervous tissue – where the T-cells cause inflammation. The gravest damage caused by T-cells is paralysiss and paraethesia. T-cells form part of the immune system of every healthy person but in approximately 0.1 % of the entire population, they can cause pathologic processes in the brain. Normally, a tight barrier of blood vessels blocks the nervous system from the rest of the body and thus virtually blocks off all immune cells circulating in the blood.

Nevertheless, as previous studies have proven, pre-activated T-cells can enter the brain. Until recently, it had been unclear where the T-cells are activated in the body and which characteristics they need to cross the blood-brain barrier without difficulty. The answer to this question has now been given by a team of researchers under the supervision of Prof. Dr. Alexander Flügel, Director of the Department for Neuroimmunology and Head of the Institute for Multiple Sclerosis Research in Göttingen with contributions being made by FAU’s Institute for Anatomy (Chair Prof. Dr. Friedrich Paulsen).

According to the researchers’ findings, activated T-cells do not enter the brain immediately but rather ‘learn’ how to do so. They stop cell division, reduce protein production and become more agile. Antennae-like receptors develop on the surface of the T-cells surface facilitating orientation and helping them dock onto cell structures. Ninjurin 1 – a receptor so far unknown for T-cells – is particularly well-suited for helping the T-cells cling to the inside of brain vessels. Once they have reached the brain tissue, the seemingly harmless cells return to their destructive nature.

The lungs: training centre and depot
The lungs are the first stage in the cells’ training programme for greater agility. As soon as activated T-cells from the blood enter the tissue, they are gradually re-programmed. With increasing speed, they move through vessels and respiratory tracts, pass the ambient lymph nodes and the spleen, re-enter the blood circulation and finally reach the central nervous system. Strangely enough, the cells do not only move along the outside of the bronchi but also climb through the inside of the respiratory tracts, where the air circulates. The researchers found that in living lung tissue, the T-cells use the bronchi as a superhighway.

The lungs are a perfect niche for T-cells (Source: umg/imsf göttingen)

The lungs are a perfect niche for T-cells. Left: Image of a lung explant with dual-photon microscopy. Auto-aggressive T-cells (white arrows) accumulate in lymphatic structures (yellow arrow) and move inside and outside the bronchi (Br.). Some of them move through the alveoli (Al.). Centre: temporal projection over 10 minutes. Red dots: stopping T-cells, yellow lines: paths of T-cells. Right: 3D reconstruction (Source: umg/imsf göttingen).

Moreover, the researchers discovered T-memory cells, which are stored in the lung on a long-term basis as in a depot. Local stimuli can provoke autoaggressive characteristics and send the cells to the brain where they cause an MS-like disease. MS may therefore occur when the bronchi are infected or irritated by other causes such as smoking. A similar, even though less drastic role may be played by the lungs when activated, re-programmed T-cells cause diseases in other parts of the organ system such as the bowels or the urogenital tract.

According to the study, a considerable number of genes which evidentially make MS patients more vulnerable also cause the T-cells to ‘walk’. These findings will be of benefit to future research in developing new courses of therapy.

Original publication: T cells become licensed in the lung to enter the central nervous system, Nature (2012) 488: 675679) DOI: 10.1038.nm.2629.

Further information:
Prof. Dr. Cassandra Flügel-Koch
Cassandra.Fluegel-Koch@anatomie2.med.uni-erlangen.de

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