Inflammation vs. neurodegeneration

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Postby dignan » Mon Apr 06, 2009 12:30 pm

Bob, I didn't notice that the full article is freely available. Thanks for the link.
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Postby Lyon » Mon Apr 06, 2009 3:32 pm

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Postby dignan » Sat Aug 15, 2009 11:04 am

Remember that 4 lesion-type theory from Lucchinetti et al? Other groups are having a hard time replicating their findings.


MS: is it one disease?
Barnett MH, Parratt JD, Pollard JD, Prineas JW.

Institute of Clinical Neurosciences, University of Sydney, New South Wales, Australia. mbarnett@mail.usyd.edu.au

Neuropathological studies of early multiple sclerosis (MS) tissue have shaped prevailing views of the pathogenesis of the disease. The hallmark of the acute MS lesion, inflammatory demyelination, has been largely accepted as evidence of a macrophage-mediated attack on normal myelin, driven by perivascular and parenchymal autoreactive CD4+ Th1 cells primed in the periphery by an unknown self or foreign antigen(s).

Predicated largely upon comparisons with experimental allergic encephalomyelitis, this paradigm has, in recent years, been recognized as a simplification of the events that constitute and perhaps presage lesion formation in the human disease; and the importance of the innate immune cells of the central nervous system, humoral factors, cytotoxic CD8+ T-cells and regulatory T-cells has been emphasized.

An influential series of publications by one group, based on histopathological examination of actively demyelinating lesions in selected autopsy and biopsy MS tissue, defined four early lesion subtypes. In a given individual, these subtypes were reported to be mutually exclusive, suggesting that disparate pathogenetic pathways separate patients with clinically indistinguishable syndromes.

This schema, which has considerable therapeutic implications, has not been independently verified and has recently been questioned by the finding of a uniform pre-phagocytic pathology and overlap of lesion subtypes in individual patients with typical relapsing and remitting disease. The latter findings would suggest that the heterogeneous features observed in active MS lesions sampled at different time-points are a reflection of the evolution of a single pathophysiological process, perhaps modified in part by genetic factors in individual cases.

For the full, free paper:
http://www.msforum.net/journal/download/20091657.pdf
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Postby Lyon » Sat Aug 15, 2009 5:11 pm

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Postby CureOrBust » Sat Aug 15, 2009 5:54 pm

...The neuropathology of early relapsing MS is unmistakable...
Huh?

I have to admit, after 10+y of the wrong diagnosis, I walked into Prof Pollards office and the guy's first guess was a re-diagnosis of MS. DOH!
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Postby dignan » Sun Aug 16, 2009 12:22 pm

Reading this paper makes me think that this group's suggestion in an earlier paper still looks like a good guess about the pathogenesis of MS -- i.e. that it all starts with some unknown entity (possibly a virus or virus-related) attacking oligodendrocytes. Here is the relevant section of this latest paper:


Oligodendrocyte Death Underpins the Pathology of Evolving MS Lesions
A variable and unexplained reduction in the number of oligodendrocytes is present in most active MS lesions that arise de novo in previously unaffected white matter. Within weeks of onset of lesion-associated symptoms, a brisk regenerative response results in the appearance of oligodendrocyte precursors, chains of proliferating CNPase positive oligodendrocytes and thin remyelinating sheaths. Oligodendrocyte loss may therefore be obscured by either florid inflammatory demyelination or striking oligodendrocyte regeneration, and has been largely overlooked as a potential pathomechanism in MS.

In a study of autopsy MS tissue, we described pathological changes that precede myelin phagocytosis in intact white matter at sites correlating with the symptoms of patients who had died during or shortly after a clinical relapse. Such prephagocytic lesions were defined by: a) fields of apoptotic oligodendrocytes in the absence of a significant macrophage infiltrate; b) pronounced local microglial activation; and c) myelin pallor (on luxol fast bluestained sections), but no overt structural myelin pathology. Parenchymal T-cells are almost absent in prephagocytic zones, are present in only modest numbers in regions of active phagocytosis and reach maximum densities in recently demyelinated, postphagocytic tissue packed with lipid-laden macrophages (Henderson et al., unpublished data).

The observation of oligodendrocyte loss prior to inflammatory demyelination or lymphocyte infiltration in nascent MS lesions suggests a novel pathogenesis, namely that macrophage activity is largely scavenger in nature and is directed toward dead, rather than normal, myelin sheaths in response to the expression of phagocytic ligands such as phosphatidylserine on their external surface. In this paradigm, tissue injury is amplified by the subsequent recruitment of a systemic Th1 immune response to the CNS by either: a) self antigen(s) unmasked during death of the oligodendrocyte/myelin complex; or b) foreign antigen that also initiates the apoptotic sequence. The presence of myeloid DC-like cells expressing the chemokine receptor CCR7 in active MS lesions, and of CD68+ cells containing myelin degradation products in the cervical lymph nodes of MS patients, indirectly support the notion that antigen-presenting cells migrate from the evolving lesion to the cervical lymph nodes, where they can regulate the differentiation of naïve T-cells into effector and central memory T-lymphocytes that are capable of entering the CNS and amplifying tissue injury. Favourable Phase II trials of fingolimod, a sphingosine-1-phosphate receptor agonist that prevents the egress of lymphocytes from secondary lymphoid organs, are not inconsistent with this hypothesis.

While we have observed prephagocytic pathology in available tissue blocks from only a proportion of autopsy cases of early relapsing MS, patients rarely succumb to acute relapse in MS and rapid shifts in lesion pathology are likely to obscure transient cellular changes such as apoptosis within hours to days. Typical actively demyelinating lesions are present in contiguous white matter and elsewhere in the neuraxis in all cases exhibiting prephagocytic pathology examined to date. We therefore propose that lesion stage explains much of the pathological heterogeneity observed in newly forming MS plaques; and that death of the oligodendrocyte/myelin complex is the first in a uniform sequence of events that underpins active lesion pathology in typical relapsing disease.

This hypothesis is illustrated in Figure 1. An alternative explanation for the proximity of active phagocytic and prephagocytic pathologies is that the latter is a secondary phenomenon. While consistent with the conventional paradigm of MS pathogenesis, the low prephagocytic/phagocytic lesion ratio in individual patients with early relapsing MS weakens this interpretation.

The factors that trigger oligodendrocyte apoptosis in newly forming MS lesions are speculative, and have been reviewed in detail elsewhere. There is circumstantial evidence supporting the role of microgliaderived proinflammatory cytokines; and comparison with the pathological changes observed in white matter ischaemia implicates oxidative stress and excitotoxicity as potential patho-mechanisms.36 Whilst these factors may constitute ‘pieces’ of the molecular puzzle, they are also general accompaniments of microglial/macrophage activity and do not constitute a framework for the aetiology of MS. A foreign antigen that induces both oligodendrocyte injury and inflammatory cell recruitment would obviate the need to identify an auto-antigen in MS and has re-emerged as a serious aetiological candidate. The epidemiological data supporting a specific viral cause of MS have been recently reviewed by Lipton et al.
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Postby cheerleader » Sun Aug 16, 2009 12:58 pm

...and comparison with the pathological changes observed in white matter ischaemia implicates oxidative stress and excitotoxicity as potential patho-mechanisms.


Stroke or reduced blood flow are not considered autoimmune, yet the immune system is activated in a similar way as MS.
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Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby Lyon » Sun Aug 16, 2009 1:00 pm

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Postby Terry » Sun Aug 16, 2009 1:23 pm

Hey Bob,
This seems a good time to ask. Where do I find info on Faroe Island/MS that includes timeframes? I always just find an overview, but I'd like to see more detail.
Terry
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Postby Lyon » Sun Aug 16, 2009 1:34 pm

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Postby Terry » Sun Aug 16, 2009 1:51 pm

Beautiful!

Thanks!
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Postby dignan » Sun Aug 16, 2009 1:52 pm

Cheer, this group is definitely arguing against the prevailing autoimmune view. The rest of the paragraph you quote suggests they like the idea of a "foreign antigen" as it provides the simplest explanation of the process.
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Postby cheerleader » Sun Aug 16, 2009 3:17 pm

dignan wrote:Cheer, this group is definitely arguing against the prevailing autoimmune view. The rest of the paragraph you quote suggests they like the idea of a "foreign antigen" as it provides the simplest explanation of the process.


Oh, I got that they are against autoimmune, dig...Prineas and Barnett are Marie's favs :)
If the damage looks like ischemia, why can't it be ischemia? (No need for an "unknown foreign antigen" in the CCSVI scenario...which would be an even simpler explanation.)
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby dignan » Sun Aug 16, 2009 6:58 pm

Cheer, good question. Prineas et al say, "they are also general accompaniments of microglial/macrophage activity and do not constitute a framework for the aetiology of MS. " They could be saying this knowing what Zamboni is doing and they are not convinced, or it could be that they wrote this paper before some of the more recent Zamboni and Simka papers were published.
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Postby finn » Mon Aug 17, 2009 8:51 am

Lyon wrote:...and Finn from the grave!

"The rumors of my death have been greatly exaggerated".

It's great that dignan's posts have kept this thread alive. Now at least it's clear that Prineas et al are questioning both autoimmunity and Lucchinetti's theory. Interesting.

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"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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