Myelin

December 7, 2010 at 12:01pm

Myelin, the insulating sheath around all of our nerves,  is damaged by an auto-immune reaction in stroke, spinal cord injury, neurovascular disease, dementia, and carbon monoxide poisoning.  

This is a fact.

MS is not unique.  The immune system has the same reaction in situations where there is oxidative stress.

Here's some of the research: 

Long term immunologic consequences of experimental stroke and mucosal tolerance
Background
An inflammatory insult following middle cerebral artery occlusion (MCAO) is associated with a predisposition to develop a deleterious autoimmune response to the brain antigen myelin basic protein (MBP)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2816867/

The "autoimmune" reaction of t-cells in spinal cord injury ( SCI) 

Previously, we demonstrated that CNS-reactive T cells are activated in SCI [29,30]. Other groups have shown activation of myelin basic protein (MBP)-reactive T cells after experimental and clinical nerve trauma [31,32]. Clinical studies that show increased frequencies of MBP-reactive T cells in SCI and stroke patients provide further evidence of an association between CNS trauma and the activation of CNS-autoreactive T cells.

http://recovery.tamu.edu/journal%20club%20articles/Popovich03.pdf

Myelin basic protein antigens in carbon monoxide poisoning 

We hypothesized that acute CO-mediated oxidative stress causes alterations in MBP and that immune responses to the modified protein precipitate delayed neurological dysfunction.

These findings provide insight into the pathophysiology of brain injury due to CO poisoning. Biochemical and immunological studies indicate that MBP undergoes charge and antigenic alterations. A causal relationship between lipid peroxidation and MBP modifications is supported by colocalization of MDA-adducts.

http://www.pnas.org/content/101/37/13660.full 

In every single one of these instances, antigens (attackers) to myelin basic protein (MBP reactive t-cells) go after the myelin and destroy it. This is considered an "auto-immune" response.

But in stroke, vascular disease, spinal injury, dementia and CO poisoning, the real culprit, ischemia (injury due to low oxygen) and a break in the blood brain barrier is known.  

-No one calls a stroke an "auto immune disease."

The autoimmune response in stroke

December 4, 2010 at 9:06pm

We are often told that MS is an autoimmune disease, as evidenced by the seemingly unprovoked immune activity against myelin.  But what we are not told is that this same process happens in the brains of those who have strokes and cerebrovascular disease.

In fact, in stroke survivors there is actual more immune response to myelin than there is in people with MS. 

A new paper from 2010--- Post-ischemic immune response to stroke

Here is a link to the full paper.

http://stroke.ahajournals.org/content/41/10_suppl_1/S75.full

"To date, there has been little interest in exploring the possibility that autoimmune responses to brain antigens might affect outcome from stroke. There are, however, studies that document the fact immune responses to brain antigens do occur following stroke.

For instance, lymphocytes from stroke survivors show more activity against MBP than the lymphocytes from patients with multiple sclerosis.18,19 

In addition, myelin-reactive T cells are found in higher numbers among patients with cerebrovascular disease.20 These data thus provide evidence that a cellular immune response to brain antigens occurs following stroke.

Furthermore, there are increased titers of antibodies to brain antigens, including neurofilaments and portions of N-methyl-D-aspartate receptor, following stroke, indicating that there is also the development of a humoral response to these antigens.21,22 The immune response to CNS antigens after stroke is likely just an epiphenomena of stroke given that cerebral ischemic injury to the blood–brain barrier allows for the systemic immune system to come into contact with the antigens that are normally sequestered from it. Nonetheless, it is possible that this response leads to "collateral damage"; whether these immune responses affect outcome from stroke is largely an unanswered question."

---Why has there been "little interest" in studying the autoimmune response of the body to stroke?   Why have we been told that myelin antigens are found only in the cerebral spinal fluid of those with MS?   These antigens are found in higher levels following a stroke.

"Furthermore, although immunosuppressive strategies might decrease the risk of developing a Th1 (and possibly Th17?) response after stroke, such interventions might increase the risk infection, a risk that is already high in the poststroke period. On the other hand, strategies to enhance the immune response to prevent infection in the poststroke period might increase the risk of developing a detrimental Th1 (and possibly Th17?) immune response to brain, and, as already discussed, these responses might predispose to worse functional outcome from stroke. It is also in the realm of possibility that the development of immune responses to brain antigens, be they cellular or humoral, may have longer-lasting effects. For instance, it is appreciated that stroke is a potent risk factor for dementia, and it could be that autoimmune responses to brain contribute to cognitive decline and even the progression of white matter disease.42 Future clinical studies will need to address the contribution of the postischemic immune response to these long-term outcomes.

In summary, the nature of the postischemic immune response affects outcome from stroke (Figure). Modulation of this response may be a viable approach to improving outcome in stroke, but there are potential dangers associated with immunomodulation. A more complete understanding of the endogenous immune response following stroke is needed to safely manipulate this response in the poststroke period."

Sadly, we know all too well about the potential dangers of brain viruses (like PML) associated with immunomodulation.  Interesting that it is considered too dangerous to give these treatments to those with stroke....but for those with MS, it is an "acceptable risk."  Perhaps we need to understand the disease mechanism of MS first.

Joan

MS as a Cerebrovascular Disease

December 4, 2010 at 5:42pm

Since the beginning of my journey with Jeff's MS diagnosis in 2007, I've been told by neurologists that MS is an auto-immune disease and this can be measured by Myelin Basic Protein (MBP) autoreactive t-cells found in cerebral spinal fluid (CSF) , and that this is exclusive to MS, and this is part of the target for immuno-modulating therapies.  

But what if these MBP auto-reactive T-cells are NOT really exclusive to MS?   Guess what?  They're not.

Here is a study where the CSF of patients with cerebrovascular disease is tested. And those with MS and CVD have the same range of MBP reactive T-cells in the CSF. This leads the researchers to posit that this immune reaction is secondary to damage in the CNS. Which makes me wonder....is the CSF of stroke patients and those with hypoxia or ischemic events regularly tested? And if so, are these people told they have an immune system disease? Why has the research of MS as a cerebrovascular disease been so fraught with controversy? 

Myelin antigen reactive T cells in cerebrovascular diseases

 W.Z.WANG,T.OLSSON,V.KOSTULAS,B.HOJEBERG,H.P.EKRE&H.LINK

Department of Neurology, Karolinska Institutet, Huddinge Hospital, Stockholm, Sweden 

INTRODUCTION In acute ischaemic cerebrovascular diseases (CVD), mononuclear cells appear in the brain parenchyma within 1-2 days and increase in number over the ensuing 5-30 days[1].Also in cerebrospinal fluid (CSF), elevated numbers of mononuclear cells may be detected. These cells are considered to mainly represent monocytes-macrophages, but there are no detailed studies on their lineage with,e.g.,antibodies to different cell surface markers. Oligoclonal IgG bands are present in the CSF while missing in corresponding serum, in about 10% of patients with CVD [2,3].A local B cell response directed to neurotropic viruses,as in patients with multiple sclerosis, has been reported in those patients with CVD who displayed oligoclonal IgG bands in CSF [4].Taken together,these observations indicate that patients with acute CVD may display an intrathecal immune response. 

The strong increases in numbers of MBP, MBP peptide and PLP reactive T cells in blood, and of MBP reactive T cells in CSF, which we here report in our patients with Cerebro Vascular Disease, are in the same range as we have previously observed in MS [10,11].Thus, both diseases are accompanied by an expanded pool of myelin autoreactive T cells and they may well be secondary to damage to the central nervous system.

Here is the full paper in PDF form.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1554378/pdf/clinexpimmunol00048-0161.pdf

It's really dense, but it is worth the read.

If these autoreactive t-cells are found in people that have strokes or cerebrovascular disease, and are NOT exclusive to MS,  how on God's green earth can we say that MS is auto-immune?

It's not.  I believe MS is a disease of the vascular system which creates a secondary reaction by the immune system.  I believe Dr. Zamboni discovered the engine in MS---and it is CCSVI.  

more ahead,

Joan