Research: Cell Trafficking

Odoardi F, Sie C, Streyl K, Ulaganathan VK, Schläger C, Lodygin D, Heckelsmiller K, Nietfeld W, Ellwart J, Klinkert WE, Lottaz C, Nosov M, Brinkmann V, Spang R, Lehrach H, Vingron M, Wekerle H, Flügel-Koch C, Flügel A.T cells become licensed in the lung to enter the central nervous system.
Nature. 2012 Aug 22. doi: 10.1038/nature11337. [Epub ahead of print]

The blood-brain barrier (BBB) and the environment of the central nervous system (CNS) guard the nervous tissue from peripheral immune cells. In the autoimmune disease multiple sclerosis, myelin-reactive T-cell blasts are thought to transgress the BBB and create a pro-inflammatory environment in the CNS, thereby making possible a second autoimmune attack that starts from the leptomeningeal vessels and progresses into the parenchyma. Using a Lewis rat model of experimental autoimmune encephalomyelitis, we show here that contrary to the expectations of this concept, T-cell blasts do not efficiently enter the CNS and are not required to prepare the BBB for immune-cell recruitment. Instead, intravenously transferred T-cell blasts gain the capacity to enter the CNS after residing transiently within the lung tissues. Inside the lung tissues, they move along and within the airways to bronchus-associated lymphoid tissues and lung-draining mediastinal lymph nodes before they enter the blood circulation from where they reach the CNS. Effector T cells transferred directly into the airways showed a similar migratory pattern and retained their full pathogenicity. On their way the T cells fundamentally reprogrammed their gene-expression profile, characterized by downregulation of their activation program and upregulation of cellular locomotion molecules together with chemokine and adhesion receptors. The adhesion receptors include ninjurin 1, which participates in T-cell intravascular crawling on cerebral blood vessels. We detected that the lung constitutes a niche not only for activated T cells but also for resting myelin-reactive memory T cells. After local stimulation in the lung, these cells strongly proliferate and, after assuming migratory properties, enter the CNS and induce paralytic disease. The lung could therefore contribute to the activation of potentially autoaggressive T cells and their transition to a migratory mode as a prerequisite to entering their target tissues and inducing autoimmune disease.

Conventional theory is that white blood cells must be activated to gain entry into the CNS and this then activates the blood vessels to produce a second wave of white blood cells in their thousands that do the damage.  Thirty years ago members of this group reported that they can get into the brain within twenty four hours but in animals (did they forget this?) but when you transfer disease causing cells it takes a few days before disease develops. In the past this group have looked also at disease-causing cells with a trackable marker and have suggested that these cells spend some time in the spleen before they go into the brain to cause disease. 

This new report however suggests that they spend time in the lungs and this could be a reservoir for white blood cells rather than the lymph glands that are specialised in generating immune function. In the lung the cells are expanded and change their surface markers-coat so that they can get into the brain.

This is surprising, but will have little application as MSers are not going to seek lung transplants. I wonder why such cell expansion has not been reported before as there must have been thousands of studies looking in the lungs of animals with ongoing immune responses. Anyway the study is was it is. However the lungs are a filtering organ and this is the first organ that many of the cells injected into the veins will encounter and so cell clumps and dead cells will get hoovered up by the lungs. Are these really the cells that will ultimately cause disease?.

This seems an overly complicated process. The immune system can make so many copies of themselves that once in tissues where they have no function it is probably easier to let them die and make new ones rather than have them leave the tissues travel through the lymphatics and back to the blood so that they can circulate into the brain. I bet the triggering event is very difficult to see as it may be triggered by a single cell or very few cells so it could be like looking for a needle in a haystack. I would make the lungs a place where the immune response is more likely to be quelled than stimulated and inhalation of myelin has been shown experimentally to control autoimmunity not generate it.

Relapses are often triggered following chest infections is this linked to this story?

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