Stroke (cerebral ischemia) is the third most common cause of death in the United States. Cerebral ischemia is caused by the lack of blood and oxygen to areas of the brain due to thrombosis (blockage) or bursting of blood vessels. Consequently, brain cells can die leading to irreversible brain damage. This damage can be severe or minor, depending on the blockage and the area damaged. Although loss of brain function is a major concern, other complications succeeding cerebral ischemia can be deadly. In fact, patients who experience a stroke are more likely to die from infection after day one than any other stroke related complications. Infections are very common due to a physiological suppression of the immune system. So why not administer immunotherapy with IFNγ to increase an immune response? This option does seem like the best strategy, but what if there is a proactive reason for immunodepression after a stroke.
If the immune system is being inhibited after a stroke, logically you could guess that the body is preemptively getting ready for an auto-immune response. Interestingly, a study was set up to test this theory. With a mouse model, this study detected increased numbers of myelin oligodendrocyte glycoprotein (MOG) specific T-cells after cerebrial ischemia. This means that T cells had an antigenic determinant for cells that partake in the myelinization of nerves. Three experiments tested the effects of this autoimmune phenotype.
1. Transgenic mice for these autoimmune T-cells developed autoimmune encephalitis, which is multiple sclerosis for mice.
2. Transferred MOG specific T-cells into naïve mice, which also developed autoimmune encephalitis.
3. Transferred splenocytes from mice (post cerebrial ischemia) into healthy mice. After inducing cerebrial ischemia, the mice experienced a worse outcome. To test this, naïve splenocytes were transferred into healthy mice without any difference in the outcome of the subsequent stroke.
This could explain immunodepression as a result of an auto-pathogenic expression in our immune system following a stroke. If this is so, how could we use these findings to decrease infection? An antibiotic therapy would most likely prove to be better than an administration of IFNγ to prevent infection, but wouldn’t prevent against viral infections. Thoughts?
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Perhaps more important than figuring out how to reverse immunodepression after a stroke, is understanding exactly HOW and WHY the immune system is depressed in the first place. Do we really want to reverse the immunodepression? What if it is some sort of compensatory or protective mechanism? And if we do want to reverse it, we probably need to understand how it got there to begin with (ie. signaling pathways, etc).
ReplyDeleteThe review cited here actually hints at this immunodepression being an adaptive response that protects the now damaged central nervous system from being attacked by the immune system, especially given that tissues forming the blood-brain barrier may be damaged after a stroke. Perhaps our bodies figured out that it was better to protect the CNS and risk other infections than vice-versa.
Out lab is currently researching the correlation of Varicella zoster virus(VZV) and stroke. We have shown the after the adventitial fibroblasts are infected with the virus, an inflammatory response is triggered. The spread of the virus from the adventitial fibroblast to the smooth muscle cell is most likely a direct infection. We speculate that the release of cytokines and chemokines call in the inflammatory cells, which in turn may be the driving force of the intima layer thickening from the inflammatory cells releasing their own cytokines and chemokines. The cerebral artery then occludes and results in stroke. Thought I'd just share our research as an interesting tidbit.
ReplyDeleteAmandaW7630: The study cited did show this autoimmune response as a possible reason for the immunodepression. And this does demonstrate that if not depressed there could be more detrimental effects to the brain (so you are completely right). However, this doesn't change the fact that people are dying from infections and more research should be done to find a way to protect the body without triggering these auto-specific T cells from attacking the CNS.
ReplyDeleteAlexc7630: Thats very interesting. So it seems this case deals with an infection leads to a stroke rather a stroke leading to an infection. Very cool!
CoryG - I completely agree that this research needs to be continued and certainly hope I didn't suggest otherwise. I was simply intrigued by the idea of the immunodepression being an adaptive response and urging that we try to understand how and why that response came about in our research. As you said in the original post, boosting the entire immune response with IFN-gamma may not be the best strategy, especially given the reason behind the immunodepression in the first place.
ReplyDeleteI think it is also important to note that a study of SCID mice shows reduced total and cortex infarct volume compared to wild type mice during middle cerebral artery occlusion (Hurn et al. 'T- and B-cell deficient mice with experimental stroke have reduced lesion size and inflammation'. Journal of Cerebral Blood Flow and Metabolism (2007) 27, 1798-1805.) This might give evidence to support a positive effect of the stroke-induced immunodepression for the individual. It is possible that immunodepression helps protect the penumbral areas of the infarct. However, this study was performed on mice and only looked at 22 hours after middle cerebral occlusion. Mortality was also constant between SCID and WT mice.
ReplyDeleteThats a good point. Possibly, the immunodepression could be a negative feedback mechanism that the body initiates due to inflammatory induced brain damaged. An interesting point on the SCID study was that some cytokines, including IFN gamma, were shown to be secreted independent of T and B cells. It would be interesting to find out if the secretion of IFN gamma is suppressed in SCID mice after the 22 hour period. This could tell us whether the immunodepression is dependent upon T and B cells.
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