Research: Entry of Cells into the CNS

Arima et al. Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell. 2012;148:447-57

Although it is believed that neural activation can affect immune responses, very little is known about the neuroimmune interactions involved, especially the regulators of immune traffic across the blood-brain barrier, which occurs in neuroimmune diseases such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis, we show that disease causing white blood cells T cells access the central nervous system via the fifth lumbar spinal cord. This location is defined by IL-6 amplifier-dependent upregulation of the chemokine CCL20 (Macrophage Inflammatory Protein-3) in associated blood vessels at the top of the spinal cord, which in turn depends on gravity-induced activation of sensory neurons by the soleus muscle in the leg. Impairing soleus muscle contraction by tail suspension is sufficient to reduce localized chemokine expression and block entry of pathogenic T cells at the fifth lumbar cord, suggesting that regional neuroimmune interactions may offer therapeutic targets for a variety of neurological diseases.

The study reports on how the white blood cells can enter the central nervous system and involves the expression of a chemical that attracts cells via activation of an immune hormone called interleukin 17 via another immune hormone called interleukin 6 that acts on interleukin 6 receptors in blood vessel cells that triggers more interleukin 6 to be released in an amplifying loop that results in the expression of a chemoattractant chemical called CCL20 that attracts T cells to attach and migrate through the blood vessel.

Therefore blockade of IL-17 (IL-17 receptor), IL-6 (IL-6 receptor) or CCL-20 (CCR6 = CCL-20 receptor) may have some benefit to halt this process.

This has been sort of shown for some of these targets in MS models and some of these aspects are currrently being examined in MS. Blockade or the white cell recruitment pathway is the mechanism of action of Tysabri

This study links this initial recruitment to the spinal cord, whereas others had tried to link this initial lesion into the brain. In the animal model used the lesions in the brain occur after the spinal cord lesions had developed suggesting that spinal cord lesions were earlier. These studies imply that these locations are the gateways through which white blood cells flow.

However if you look at affected tissues once lesions start the gates appear all over the CNS, but lesion location can be very different in MS. The interesting thing that this study suggests that nerve activity can trigger this cascade to be initiated in certain locations.

In this study they implicate a muscle group that deals with posture. If true then it would have implications concerning activating muscle groups and the development of lesions in MS. Surely if this were the case that similar muscles in the front legs would activate the same pathway as the backlegs, surely they feel the effects of gravity, and the results remains to replicated This would be easy. The way this Japanese group did the experiments was to remove gravitational effects off the hindlegs and and while the results appear compelling they used an experimental design that is somewhat disturbing and involved suspending mice by their tails so they could only weight-bear on their front legs and not their back legs. They did this for weeks………Yuck. How would you feel going to the toilet and sleeping upside down? Just because you can does not mean you should!

So what are the implications for MS, well probably little, except pointing further to targets for treatment of MS. But if neural activity really does dictate lesion locations then it really would be important. However, as we all have sterotyped motor behaviours, one would think that lesion locations would be very, very similar between all MSers and you would all have the same symptoms…… they are not and you do not.

Cell is one of the best journals in the world. If the referees of this paper had paid attention to or actually read our guidelines for reporting EAE studies then at the very least the correct statistics may have been used, without out proper statistics are the right conclusions drawn?….. Another example of bad refereeing, perhaps too much attention was paid to reading the fancy science, whilst forgetting about the basics.

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