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A piece of research after Bromley's heart...



Cause of nerve fiber damage in multiple sclerosis identified

UC Irvine -- Researchers have identified how the body's own immune system contributes to the nerve fiber damage caused by multiple sclerosis, a finding that can potentially aid earlier diagnosis and improved treatment for this chronic disease.

The study reveals how immune system B-cells damage axons during MS attacks by inhibiting energy production in these nerve fiber cells, ultimately causing them to degenerate and die. Study results appear in the Oct. 15 issue of the Journal of Immunology.

B-cell-axon activity is an emerging area of MS research, one that is changing how scientists and clinicians can look at this disease. In this study, Dr. Yufen Qin and fellow researchers from UC Irvine's School of Medicine analyzed spinal fluid and tissue samples from MS patients to identify substances that stimulate a B-cell immune response. They noted an increased level of B-cell antibodies on lesions and in spinal fluid bound to two specific enzymes -- GAPDH and TPI.

These two enzymes are essential for efficient energy production. The researchers believe that the binding of these antibodies to these enzymes -- GAPDH, in particular -- may lower the amounts of ATP -- the chemical fuel for cells -- available in cells, which eventually can lead to axon cell degeneration and death. In addition to the energy-production function, GAPDH is involved with a number of genetic activities, such as RNA translocation, DNA replication and DNA repair.

Other recent studies have shown that binding of inhibitors to GAPDH and TPI causes decreased ATP production in neurons, followed by progressive neuronal degeneration and death. Moreover, patients with TPI deficiency can develop progressive neurological disorders.

"This research is exciting and potentially important for future treatments because it identifies new antibodies associated with MS that can be targeted with emerging therapies," said Qin, an assistant professor of neurology. "Significantly, these are the first antibodies to be identified with axon activity, which is a new area researchers are exploring in the pathology of MS."

MS is a chronic central nervous system disease that can cause blurred vision, poor coordination, slurred speech, numbness, acute fatigue and, in its most extreme form, blindness and paralysis. Some 400,000 Americans have this disease. Its causes are unknown, and symptoms are unpredictable and vary greatly in severity.

Much MS research is focused on an autoimmune process in which T-cells attack and damage myelin, the fatty insulating tissue of axons. These T-cells do not attack axons themselves; the process of demyelination interrupts electrical impulses that run through these nerve fibers, thus causing MS symptoms. Demyelination has been considered the central feature of MS.

Recently, however, Qin has been among a group of researchers who have discovered that B-cells too are involved with the autoimmune response to MS. Instead of targeting myelin, these B-cells attack axons directly. Axons are the long, slender fibers of a neuron that serve as the primary transmission lines of the nervous system, and as bundles they help make up nerves.

Research at UCI and elsewhere has shown that myelin grows back if the T-cell autoimmune response is turned off, and drugs exist or are in development to block demyelination. Axons, in turn, repair very slowly, which implies that B-cell attacks on axons may have a significant impact on the chronic central nervous system damage caused by MS.

"Since this area of research is in its early stage, it's important to understand the process by which these B-cell responses happen," Qin said. "Hopefully, by identifying these two crucial enzymes, it will lead to a greater understanding of MS and lead to more effective treatments for people who live with this disease."

http://www.physorg.com/news80230112.html

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This seems to confirm the theories that there are 2 processes going on, on the one hand the inflammation and demyelination (T-cells) and on the other hand the axonal damage (becoming clear now that it is coming from the B-cells).

In this light there is the publication of Prineas where he stated that the axonal damage migth happen even before the inflammation.

If studies keep on appearing in this direction, there seems to be a serious reshift in the understanding of MS in the direction of axonal damage and hopefully something good will come out of it for the persons with MS.

Thanks for posting this Dignan.

I think we are seeing a shift in thinking. This disease is much more that bored T cells waking up one morning and deciding to eat some myelin. And there is now some doubt that MBP is the target.

Thankfully, there are some treatments that deplete B cells - Rituximab for one, and Campath which nukes both T cells and B cells. Of course it's important to get in early before too much irreversible damage is done (this is when repair / regeneration strategies are needed).

If B cells are proved to be involved this would help explain the different mechanisms that are seen - inflammation (T cells?) and neuro-degeneration (B cells?).

Let's hope the research into B cells really pays dividends!

Ian

This is the research we all need. Now we are waiting to know whom or what are the causes that move to B cells to destroy the axon. And so on…

Thanks Dignan.

okay time to start looking into b cell chemistry and what turns em off, it they're so turned on by axons! let's start checkin pubmed... have to leave for school soon so can't now, but will later!!

I'm entering the 2006 Jimmylegs World B-Cell Challenge...

I start with an oldie, but a goodie...


Multiple sclerosis and high incidence of a B lymphocyte antigen.

Terasaki PI, Park MS, Opelz G, Ting A.

Multiple sclerosis patients were tested for six new antigens present on human B lymphocytes. The group 4 specificity occurred in 83.9% of the 56 patients as compared to 32.5 percent in 72 healthy controls (P less than .003). The antiserums defining the five other B lymphocyte specificities reacted at a lower frequency to B cells from multiple sclerosis patients, showing that increased reactivity to group 4 antiserum was specific. Linkage of a hypothesized multiple sclerosis susceptibility gene with certain haplotypes of HLA-A3, HLA-B7 HLA-DW2, and the new B group 4 can be inferred.

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Left the date of that study for last: September 1976...so the involvement of B cells in MS has been studied for a long time...

I like this abstract because it shows one bright spark was proposing that a B cell abnormality caused MS (or played a major role) back in 1985...



B-cell abnormalities in multiple sclerosis. A hypothesis.

Roos RP.
Arch Neurol. 1985 Jan;42(1):73-5.

Quantitative and qualitative (oligoclonal band) immunoglobulin abnormalities are one of the hallmarks of multiple sclerosis. The usual explanations offered for these abnormalities include persistent antigenic stimulation, "nonsense" antibody, immunodysregulation, and nonspecific polyclonal stimulation. We propose that an intrinsic B-cell abnormality leads to the immunoglobulin disturbances--perhaps in association with one of the aforementioned mechanisms. Genetic translocations and abnormalities in the normal B cell developmental immunoglobulin rearrangements could produce a selective advantage for certain B cells or enhance transcription causing clonal proliferation with the subsequent production of oligoclonal immunoglobulin bands. Cytogenetic and molecular hybridization studies of the B cell may help answer these issues.

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I like this one because we've all seen Bromely prattling on about EBV and B cells, and this abstract from 2003 nicely sums up the underlying theory behind said prattling...



Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases.

Trends Immunol. 2003 Nov;24(11):584-8.
Pender MP.
Department of Medicine, The University of Queensland, Clinical Sciences Building, Royal Brisbane Hospital, 4029, Herston, Queensland, Australia. m.hawes@mailbox.uq.edu.au

I hypothesize that human chronic autoimmune diseases are based on infection of autoreactive B lymphocytes by Epstein-Barr virus (EBV), in the following proposed scenario. During primary infection, autoreactive B cells are infected by EBV, proliferate and become latently infected memory B cells, which are resistant to the apoptosis that occurs during normal B-cell homeostasis because they express virus-encoded anti-apoptotic molecules. Genetic susceptibility to the effects of B-cell infection by EBV leads to an increased number of latently infected autoreactive memory B cells, which lodge in organs where their target antigen is expressed, and act there as antigen-presenting cells. When CD4(+) T cells that recognize antigens within the target organ are activated in lymphoid organs by cross-reactivity with infectious agents, they migrate to the target organ but fail to undergo activation-induced apoptosis because they receive a co-stimulatory survival signal from the infected B cells. The autoreactive T cells proliferate and produce cytokines, which recruit other inflammatory cells, with resultant target organ damage and chronic autoimmune disease.

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And last but not least, this one is good because it's as if some magical MS researchers looked into their crystal balls back in December 2003 and foresaw our ThisIsMS discussions of October 2006 and decided to address some of our concerns...



B-cell immunity in MS.

Int MS J. 2003 Dec;10(4):110-20.
Qin Y, Duquette P.
Department of Neurology, University of California, Irvine, CA, USA.

T-cell-mediated immunity has dominated studies of multiple sclerosis (MS) pathogenesis, mainly due to detection of activated T-cells in MS lesions, and analogies with the animal model experimental allergic encephalomyelitis. The prevailing aetiological hypothesis is that MS is a multifactorial disorder, affecting individuals predisposed by a combination of susceptibility genes and environmental factors. Plaque formation is attributed to immune mechanisms, triggered by an autoimmune attack directed against antigens in the myelin membrane. This article reviews the roles of components of the immune response in MS including B-cells, the complement cascade, antibodies and genes. Evidence suggests that B-cell clonal expansion in cerebrospinal fluid and plaques of MS patients indicate an ongoing, antigen-driven response in the central nervous system. That MS is an autoimmune disease remains inconclusive, but the assumption is that humoral immunity plays a role in lesion formation and perpetuation, or is involved in tissue-repair mechanisms. The paradigm of MS as a T-cell disease must be revisited, as B-cells are involved during the initial and later disease stages, and evidence is mounting for a 'degenerative process', in addition to (and possibly even preceding) inflammation.

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Dignan wrote:And last but not least, this one is good because it's as if some magical MS researchers looked into their crystal balls back in December 2003 and foresaw our ThisIsMS discussions of October 2006 and decided to address some of our concerns...

B-cell immunity in MS.
Int MS J. 2003 Dec;10(4):110-20.
Qin Y, Duquette P.
Department of Neurology, University of California, Irvine, CA, USA.

For anyone who's interested, that article is freely available from
http://www.msforumonline.net/journal/do ... 310110.pdf

NHE

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Very interesting. I mentioned B-cells in the 102 post. They are part of the Humoral system and that's STRIKING because .. Humoral system has been believed to be a positive for those with MS v/s the cell-mediated immune system which has ben cited as the culprit. This is VERY interesting. Potentially revolutionary.

Perhaps this is why Novantrone works -short abstract

That's an abstract from the annual meeting of the American Acadamy of Neurologists - 2006. I'd also say, be careful. There's also stuff out there, even a time lapse photos that say that it's the CD8+ cells that chew on the myelin.

I want to know more about this cellular communication thing. I'd like to have info to revisit the Glyconutrient's issue. napay