New discovery about autoimmune relapses

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New discovery about autoimmune relapses

Postby dignan » Sun Dec 03, 2006 6:37 pm

Interesting discovery about the role of osteopontin in relapses.



Molecule linked to autoimmune disease relapses identified at Stanford

Dec 3/06 -- STANFORD, Calif. -- The ebb and flow of such autoimmune diseases as multiple sclerosis, lupus and rheumatoid arthritis has long been a perplexing mystery. But new findings from the Stanford University School of Medicine bring scientists closer to solving the puzzle, identifying a molecule that appears to play a central role in relapses.

The study, to be published in the Dec. 3 advance online edition of Nature Immunology, lays the groundwork for a way to determine when a relapse is about to occur, and could eventually lead to a treatment to prevent relapses. "Right now, there is no good blood test to evaluate when a person is going to have a flare-up," said senior author Larry Steinman, MD, professor of neurology and neurological sciences. "If we had one, we might be able to give them prophylactic preventive medication."

The current study had its genesis five years ago: In a paper published in 2001 in the journal Science, Steinman found that a protein called osteopontin was abundant in multiple sclerosis-affected brain tissue, but not in normal tissue. Since then, other groups have confirmed that osteopontin is elevated just prior to and during a relapse of the disease in M.S. patients.

Although the protein had been known to play a role in bone growth, it was unclear why it would be associated with multiple sclerosis, which results when the immune system attacks the protective myelin sheath surrounding nerve cells.

To explore this question, Eun Mi Hur, PhD, who was then a graduate student in Steinman's lab, began using a mouse model of multiple sclerosis (experimental autoimmune encephalomyletis, or EAE) to investigate how osteopontin could cause these flare-ups. She and Steinman gave osteopontin to mice that had already experienced paralysis, similar to that of an M.S. patient, and found that the mice then experienced a relapse of the disease.

The researchers also found that the relapse would occur sometimes in an area of the brain other than the site of the original attack. For example, after receiving the osteopontin, some animals that had previously suffered paralysis became blind from a condition called optic neuritis. One feature of multiple sclerosis is that the flare-ups can affect different parts of the nervous system at different times.

"When I saw that all mice with EAE relapsed and died from the disease after about a month of osteopontin administration, I was surprised," said Hur, the study's first author who is now a postdoctoral scholar at Caltech. "I got a strong belief that a high level of osteopontin in patients' blood and tissue is a major contributor of the relapse and progression of the disease."

Through the mouse studies and molecular characterizations, Hur and Steinman showed that osteopontin - produced by immune cells and brain cells themselves - promotes the survival of the T cells that carry out the damaging attack on myelin; by increasing the number of these T cells, osteopontin increases their destructive potential. These results could be applicable to many other autoimmune diseases, including rheumatoid arthritis, type-1 diabetes and lupus.

Indeed, the effect of osteopontin may severely alter the way the immune system works. Normally, after the immune system does its job - eradicating a microbe, for instance - the response is then dialed down. If this didn't happen, the immune response would go on indefinitely. Imagine a cold or an attack of poison oak that would last forever.

One of the ways that the immune response is muffled is that the activated T cells die in a process known as apoptosis. That is precisely what osteopontin seems to prevent. Osteopontin lets the T cells linger in the blood, ready to attack again. "We don't know exactly what triggers that new attack but the cells certainly are around and ready to do it," said Steinman. So scientists now face the challenge of figuring out how and why osteopontin is produced. "We're back to the chicken-and-the-egg problem," said Steinman. "We know the egg, so why did the chicken lay it" That is a trickier problem to work out."

Even without knowing the answer to that question, there is one inviting practical use of their observations: Osteopontin could be used as a marker of an impending relapse. What's more, if the protein could be blocked, it might thwart the relapse from ever occurring. Steinman's lab is working to develop antibodies to inactivate the protein's effect. "It's still a long road between saying we want to do it and getting the antibodies, getting it approved by the FDA and getting it tested," said Steinman, "but we are determined to do that."

Still, Steinman offered a caveat. Researchers may find that blocking osteopontin has undesirable side effects. The protein may serve other purposes in addition to promoting survival of immune cells. It could also be vital to the body's ability to produce myelin, a function that could cause severe problems if disrupted. "Like a lot of important biological molecules, osteopontin has a Janus-like quality - a bad side and a good side," Steinman said. "We're going to be extremely lucky if we give the antibody opposing osteopontin and derive just the good side: We stop the autoimmune attack but don't interfere with the survival of other cells."

Further study will determine whether thwarting osteopontin's effect yields new types of treatments for autoimmune diseases, but regardless, it is likely to lead to discoveries in a host of areas. "I think osteopontin will turn out to be important in a lot of processes, spanning autoimmunity to stem cells," said Steinman. "It's probably going to turn out to be a very basic growth factor."

http://www.eurekalert.org/pub_releases/ ... 120106.php
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Postby Lyon » Sun Dec 03, 2006 7:16 pm

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Postby CureOrBust » Mon Dec 04, 2006 12:12 am

yeah it did.
The current study had its genesis five years ago: In a paper published in 2001 in the journal Science, Steinman found that a protein called osteopontin was abundant in multiple sclerosis-affected brain tissue, but not in normal tissue. Since then, other groups have confirmed that osteopontin is elevated just prior to and during a relapse of the disease in M.S. patients.
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Postby Lyon » Mon Dec 04, 2006 1:15 pm

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Postby BioDocFL » Mon Dec 04, 2006 2:48 pm

What is interesting about this is that osteopontin is stimulated by the estrogen receptor. The question that would follow is: Is there more estrogen receptor being expressed for some reason or is the receptor being stabilized longer when bound to the promoter of the osteopontin gene (chromosome 4)? There are other possibilities of course, such as reduction in the turnover of the osteopontin mRNA and/or protein. Osteopontin does seem to have a lot of potential interactions if you do a Google Scholar search on it.

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Postby bromley » Tue Dec 05, 2006 1:42 am

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Postby Chris55 » Tue Dec 05, 2006 7:53 am

Just read that statins lower osteopontin. Perhaps this is why they are having positive results using the statin-lowering drugs for MS.
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Postby dignan » Tue Dec 05, 2006 9:33 am

Here's the Pubmed abstract...



Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells.

Nat Immunol. 2006 Dec 3;
Hur EM, Youssef S, Haws ME, Zhang SY, Sobel RA, Steinman L.
Interdepartmental Program in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA. [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.

Relapses and disease exacerbations are vexing features of multiple sclerosis. Osteopontin (Opn), which is expressed in multiple sclerosis lesions, is increased in patients' plasma during relapses.

Here, in models of multiple sclerosis including relapsing, progressive and multifocal experimental autoimmune encephalomyelitis (EAE), Opn triggered recurrent relapses, promoted worsening paralysis and induced neurological deficits, including optic neuritis. Increased inflammation followed Opn administration, whereas its absence resulted in more cell death of brain-infiltrating lymphocytes. Opn promoted the survival of activated T cells by inhibiting the transcription factor Foxo3a, by activating the transcription factor NF-kappaB through induction of phosphorylation of the kinase IKKbeta and by altering expression of the proapoptotic proteins Bim, Bak and Bax. Those mechanisms collectively suppressed the death of myelin-reactive T cells, linking Opn to the relapses and insidious progression characterizing multiple sclerosis.

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