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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.

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?

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.

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.

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).

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.

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.

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:


No veins involved at all.

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.

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.