MBP autoreactive T-cells not exclusive to MS

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MBP autoreactive T-cells not exclusive to MS

Postby cheerleader » Sat Dec 04, 2010 6:25 pm

Since the beginning of my learning curve, I've been told (on here and by neurologists) that MS can be measured by MBP autoreactive t-cells found in CSF, and that this is exclusive to MS. And this is part of the target for immuno-modulating therapies. But is it really exclusive to MS?

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 complete paper, in pdf form
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Postby cheerleader » Sun Dec 05, 2010 11:10 am

Here is a new paper from 2010 which references the paper above. It further defines the auto-immune reaction of the body after stroke, and suggests immune modulation to improve stroke outcome-
http://stroke.ahajournals.org/cgi/conte ... uppl_1/S75

Modulation of the Postischemic Immune Response to Improve Stroke Outcome

Kyra J. Becker, MD
From the University of Washington School of Medicine, Seattle, Wash.
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-Daspartate 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.

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."


Again, the question is-if stroke and cerebrovascular disease have so many similarities in immune reaction after break in BBB, why is the study of MS as a cerebrovascular disease so fraught with controversy?
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Re: MB autoreactive T-cells not exclusive to MS

Postby NHE » Sun Dec 05, 2010 7:26 pm

Hi Cheer,
Thanks for posting these interesting papers!

NHE
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Postby CuriousRobot » Sun Dec 05, 2010 9:35 pm

Awesome research.
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Postby rainer » Sun Dec 05, 2010 10:05 pm

Again, the question is-if stroke and cerebrovascular disease have so many similarities in immune reaction after break in BBB, why is the study of MS as a cerebrovascular disease so fraught with controversy?


Interesting research and an angle that deserves more play but... "why is it fraught with controversy" is disingenuous and smacks of victimization. Your own research shows that vascular studies weren't always so controversial. So what's changed?
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Postby cheerleader » Mon Dec 06, 2010 8:00 am

Long term immunologic consequences of experimental stroke and mucosal tolerance
J Michael Gee,1 Dannielle Zierath,1 Jessica Hadwin,1 Anna Savos,1 Angela Kalil,1 Matthew Thullbery,1 and Kyra J Becker1
1Department of Neurology, University of Washington School of Medicine Seattle Washington, USA

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). Induction of immunologic tolerance to brain antigens prior to MCAO prevents this deleterious autoimmune response and is associated with better functional outcome early after stroke. In this study, we sought to determine the long term immunologic consequences of experimental stroke and induction of mucosal tolerance.

There is a complex interplay between the central nervous system (CNS) and the systemic immune system; the immune response appears to contribute to ischemic brain injury and cerebral ischemia affects the systemic immune response. Immediately after experimental stroke, peripheral blood lymphocytes and splenocytes become activated and are capable of secreting massive amounts of pro-inflammatory cytokines [1]. In concert with this systemic response, there is inflammation within the injured brain, and strategies that limit the inflammatory response within the brain improve outcome from experimental stroke [2]. Modulation of the immune response following stroke, however, has yet to translate into clinical benefit.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2816867/
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Postby cheerleader » Mon Dec 06, 2010 10:59 am

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

http://recovery.tamu.edu/journal%20club ... vich03.pdf

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 [33 – 35].

The extent to which these T cells participate in tissue injury after SCI remains controversial. However, using Lewis rats and transgenic mice enriched in MBP-reactive T cells, we have demonstrated that CNS-reactive T cells can exacerbate axonal injury, demyelination and functional loss after SCI, thereby revealing their destructive potential [29,30].

We are just beginning to appreciate that cells and mediators of the immune system can have divergent effects on neuronal and glial survival after SCI. Consequently, we must proceed with caution and acknowledge the infancy of this research area; otherwise, we risk damaging spared tissues that patients might learn to use either spontaneously or through rehabilitation therapy.



So, we have ischemic stroke, nerve injury and spinal cord injury all showing myelin reactive t cells--the autoimmune reaction- in CSF after the event.
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Postby cheerleader » Mon Dec 06, 2010 4:22 pm

And finally---
Myelin basic protein antigens in carbon monoxide poisoning

Inflammatory responses play an important role in the pathogenesis of many brain disorders, including excito-toxicity (17, ). Therefore, we evaluated immunological responses in brain after CO poisoning. We focused our attention on myelin basic protein (MBP), because it is the major myelin protein of central nervous system (∼30%). Others have shown that chemical modifications of MBP can alter three-dimensional structure, enhancing protease attack, and influence antibody recognition (19–21). A highly encephalitogenic agent, MBP causes an autoimmune disorder when injected into animals, and it may play a role in CNS inflammation after transient focal ischemia (22, 23). Anionic isoforms of MBP occur in a number of neurodegenerative diseases (24–26). 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 with MBP on tissue sections and results with the ELISA. MALDI-TOF and tandem MS analyses confirm that the antibodies detected MBP, although the CO-mediated chemical alterations were not identified.

Finally, CO-poisoned rats exhibited impaired learning in maze studies that did not occur in rats rendered immunologically tolerant to MBP. This result supports a causal relationship between CO-mediated oxidative stress, structural MBP changes, immunological responses, and learning dysfunction. Activated microglia can mediate cognitive dysfunction by impairing neurogenesis and by causing neuronal necrosis or apoptosis (37, ). Necrosis and apoptosis have been reported after CO poisoning (5–7). It is notable that motor deficits and gross demyelination were not observed in the CO-poisoned rats. Clearly, the immunological responses after CO poisoning differ from experimental allergic encephalomyelitis, which arises after injection of adjuvant and MBP chemical extracts (23).


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

Postby ppicklee » Mon Dec 06, 2010 6:24 pm

Good research. Where do you get this stuff?? I will need to spend some time reading these items (PDF format is easiest for me) before I pipe in with my two cents worth. :-)
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Postby cheerleader » Tue Dec 07, 2010 10:08 pm

Perhaps these autoimmune responses, which occur in a variety of injurious situations, are actually protective, and there for a reason.

Protective autoimmunity in acute and chronic CNS disorders

Participation of the immune system is of critical importance for processes of maintenance and recovery from injuries and disorders of the central nervous system (CNS). Such participation can be viewed as the body’s own mechanism of repair, which can be boosted for therapeutic purposes. We have shown that the innate immune response (involving macrophages), if well-controlled, can promote the post-traumatic process of healing in CNS axons.

The adaptive immune response (involving T cells) has long been viewed as an immune activity evoked with the purpose of enabling the organism to defend itself against invading pathogens such as bacteria and viruses. Accordingly, it was believed that an adaptive immune response would not be evoked unless the pathogen is recognized as non-self. Our rodent studies of the crush-injured optic nerve, the contused spinal cord, and retinal gangion cell damage induced by glutamate toxicity suggest that CNS insults stimulate the recruitment of autoreactive T cells (directed against myelin-associated proteins and peptides), and that these T cells have a protective effect in that they help reduce the neuronal losses resulting from secondary degeneration after the insult.


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for more information, check out "protective autoimmunity"
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Postby malden » Wed Dec 08, 2010 6:54 am

According to:

Genain CP, Lee-Parritz D, Nguyen MH, Massacesi L, Joshi N, Ferrante R, Hoffman K, Moseley M, Letvin NL, Hauser SL.
Department of Neurology, University of California, San Francisco 94143.


In healthy primates, circulating autoreactive T cells mediate autoimmune disease.
http://www.ncbi.nlm.nih.gov/pubmed/7521889

Abstract:
A T cell response against myelin basic protein (MBP) is thought to contribute to the central nervous system (CNS) inflammation that occurs in the human demyelinating disease multiple sclerosis. To test whether MBP-reactive T cells that are normally retrieved from the circulation are capable of inducing CNS disease, MBP-reactive T cell clones were isolated from the peripheral blood of healthy, unimmunized Callithrix jacchus (C. jacchus) marmosets. This primate species is characterized by a natural chimerism of bone marrow elements between siblings that should make possible adoptive transfer of MBP-reactive T cells. We report that MBP-reactive T cell clones efficiently and reproducibly transfer CNS inflammatory disease between members of C. jacchus chimeric sets. The demyelination that is characteristic of experimental allergic encephalomyelitis induced in C. jacchus by immunization against human white matter did not occur after adoptive transfer of the MBP-reactive clones. It was noteworthy that encephalitogenic T cell clones were diverse in terms of their recognition of different epitopes of MBP, distinguishing the response in C. jacchus from that in some inbred rodents in which restricted recognition of MBP occurs. These findings are the first direct evidence that natural populations of circulating T cells directed against a CNS antigen can mediate an inflammatory autoimmune disease.


No veins involved at all.
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Postby fernando » Wed Dec 08, 2010 8:48 am

Malden wrote:According to:

Genain CP, Lee-Parritz D, Nguyen MH, Massacesi L, Joshi N, Ferrante R, Hoffman K, Moseley M, Letvin NL, Hauser SL.
Department of Neurology, University of California, San Francisco 94143.


In healthy primates, circulating autoreactive T cells mediate autoimmune disease.
http://www.ncbi.nlm.nih.gov/pubmed/7521889

Abstract:
A T cell response against myelin basic protein (MBP) is thought to contribute to the central nervous system (CNS) inflammation that occurs in the human demyelinating disease multiple sclerosis. To test whether MBP-reactive T cells that are normally retrieved from the circulation are capable of inducing CNS disease, MBP-reactive T cell clones were isolated from the peripheral blood of healthy, unimmunized Callithrix jacchus (C. jacchus) marmosets. This primate species is characterized by a natural chimerism of bone marrow elements between siblings that should make possible adoptive transfer of MBP-reactive T cells. We report that MBP-reactive T cell clones efficiently and reproducibly transfer CNS inflammatory disease between members of C. jacchus chimeric sets. The demyelination that is characteristic of experimental allergic encephalomyelitis induced in C. jacchus by immunization against human white matter did not occur after adoptive transfer of the MBP-reactive clones. It was noteworthy that encephalitogenic T cell clones were diverse in terms of their recognition of different epitopes of MBP, distinguishing the response in C. jacchus from that in some inbred rodents in which restricted recognition of MBP occurs. These findings are the first direct evidence that natural populations of circulating T cells directed against a CNS antigen can mediate an inflammatory autoimmune disease.


No veins involved at all.


Malden,

Exactly, autoreactive T-cells are not exclusive of MS. That's what cheer has tried to express since the first post in this thread.
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Postby cheerleader » Wed Dec 08, 2010 9:33 am

Thank you for posting that study, Malden. You're right, this thread is not about veins. It is about t-cells which target myelin basic protein. These t-cells are found in many more circumstances than just MS.

In cerebrovascular disease, stroke, carbon monoxide poisoning, spinal cord injury, and dementia--we see MBP antigens are activated after the vascular injury. There is an auto-immune reaction to a variety of cerebrovascular insults. The question is, why?

New research states that these antigens are actually "protective autoimmunity"

CNS insults stimulate the recruitment of autoreactive T cells (directed against myelin-associated proteins and peptides), and that these T cells have a protective effect in that they help reduce the neuronal losses resulting from secondary degeneration after the insult.


MBP t-cells reduce neuronal losses after a cerebrovascular injury.
The Weizmann Institute in Israel has been conducting research for the past ten years--in relation to their work with copaxone. Here's a good paper for those interested, "Protective Autoimmunity is a Physiological Response to CNS Trauma"
http://neuro.cjb.net/cgi/reprint/21/11/3740

and another from this year...
Abstract
The influence of the immune system was originally thought to be harmful regarding injuries and infarctions of the brain. Recently, there has been increasing evidence for the protective, positive effects of cells of the immune system on brain tissue. From an evolutionary biology standpoint, this hypothesis is more compelling than viewing the immune system only as a harmful influence. Herein we emphasize how physiological activation of immune cells following tissue damage and/or by infarcts of brain tissue can lead to an activation of T-lymphocytes. These activated T-lymphocytes are then regarded to perform several protective effects.

http://www.jni-journal.com/article/S016 ... 4/abstract



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