Re: What if......

[Guest guest]

What if monkeys flew out my.....

I'm going to have to take a closer look at this paper. I couldn't

find any papers saying that CRYAB is an extracellular signaling

molecule. If CRYAB is just another intracellular protein to which

autoantibodies are generated, then I don't see how the

autoantibodies would be pathogenic (I'm not talking here about the

generation of immune complexes that deposit in organs like the

kidneys; that's a secondary, and uninteresting effect) unless they

are cross-reacting to another extracellular protein (i.e., it's

highly unlikely that antibodies can enter a cell and produce

pathology that way). Maybe the CRYAB antibodies cross-react with

some other protein and the " antiinflammatory " effect of CRYAB

injections simply reflects the ability of CRYAB to bind up all the

antibodies, thereby preventing the binding of those antibodies to

the putative other protein. That story would be less tidy than the

one I thought (and still sort of think) these authors are trying to

tell.

Matt

>

> has pointed out a number of times that autoantibodies are

> common, and are not generated only in patients experiencing

> autoimmune diseases.

>

> Various proteins are capable of putting the brakes on

inflammation.

> IL-10 is the obvious example, but there are others. So what if

the

> autoantibody that some people generate happens to neutralize one

of

> these " brakes " ? The inflammation might persist unabated, and

might

> perpetuate the production of the original offending autoantibody.

>

> Today's offering by Nature suggests that this indeed happens with

MS:

>

> http://tinyurl.com/yofjda

>

> They present data indicating that MS patients, but not control

> patients, produce antibody against CRYAB, a molecule that inhibits

> inflammation. They present other data, in mice, indicating the

> negative impact that this has.

>

> If true, this is spectacular.

>

> Matt

>

[Guest guest]

This does seem huge, Matt! "...Thus, the immune response against a negative regulator of inflammation, CRYAB, in multiple sclerosis, would exacerbate inflammation and demyelination. This can be countered by giving CRYAB itself for therapy of ongoing disease." http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=ShowDetailView & TermToSearch=17568699 & ordinalpos=1 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum But if CRYAB

triggers the inflammatory immune response in the first place, is this suggesting that if administered in large enough amounts, it will effectively overpower that response? Do you think this would have applications for non MS patients with chronic inflammation like most of us, even if we're not experiencing demyelination? Can we get hold of CRYAB and try it somehow? penny Full Abstract: Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Ousman SS, Tomooka BH, van Noort JM, Wawrousek EF, O'conner K, Hafler DA, Sobel RA, WH, Steinman L. Department of Neurology and Neurological Sciences, Stanford University. alphaB-crystallin (CRYAB) is the most abundant gene transcript present in early active multiple sclerosis lesions, whereas such transcripts are absent in normal brain tissue. This crystallin has anti-apoptotic and neuroprotective functions. CRYAB is the major target of CD4(+) T-cell immunity to the myelin sheath from multiple sclerosis brain. The pathophysiological implications of this immune response were investigated here. We demonstrate that CRYAB is a potent negative regulator acting as a brake on several inflammatory pathways in both the immune system and central nervous system (CNS). Cryab(-/-) mice showed worse experimental autoimmune encephalomyelitis (EAE) at the acute and progressive phases, with higher Th1 and Th17 cytokine secretion from T cells and macrophages, and more intense CNS inflammation, compared with their wild-type counterparts. Furthermore, Cryab(-/-) astrocytes showed more cleaved caspase-3 and more TUNEL staining, indicating an

anti-apoptotic function of Cryab. Antibody to CRYAB was detected in cerebrospinal fluid from multiple sclerosis patients and in sera from mice with EAE. Administration of recombinant CRYAB ameliorated EAE. Thus, the immune response against a negative regulator of inflammation, CRYAB, in multiple sclerosis, would exacerbate inflammation and demyelination. This can be countered by giving CRYAB itself for therapy of ongoing disease. PMID: 17568699 [PubMed - as supplied by publisher] phagelod <mpalmer@...> wrote: has pointed out a number of times that autoantibodies are common, and are not generated only in patients experiencing autoimmune diseases.Various proteins are capable of putting the brakes on inflammation. IL-10 is the obvious example, but there are others. So what if the autoantibody that some people generate happens to neutralize one of these "brakes"? The inflammation might persist unabated, and might perpetuate the production of the original offending autoantibody.Today's offering by Nature suggests that this indeed happens with MS:http://tinyurl.com/yofjdaThey present data indicating that MS patients, but not control patients, produce antibody against CRYAB, a molecule that inhibits inflammation. They present other data, in mice, indicating the negative impact that this has.If

true, this is spectacular.Matt

[Guest guest]

"...What if monkeys flew out my....." Lol! But I'm still interested in the anti-inflammatory role CRYAB might have (I'm just scared that not taking enough would just make things worse). I'd like to find some antiinflammatory alternative. Otherwise, Benicar's starting to look good to me again because of these frequent migraines that have come back. And I really don't want to go there as I feel that the Benicar definitely did something to my leg muscles that I've slowly recovered from and don't want to revisit. But its anti-inflammatory effects were so remarkable for me. It's strange that a an ARB for blood pressure, vasoconstriction and/or vasodilation all seem to have some kind of role in these headaches. a, how soon after stopping the Benicar, did

the headache begin? pennyphagelod <mpalmer@...> wrote: What if monkeys flew out my.....I'm going to have to take a closer look at this paper. I couldn't find any papers saying that CRYAB is an extracellular signaling molecule. If CRYAB is just another intracellular protein to which autoantibodies are generated, then I don't see how the autoantibodies would be pathogenic (I'm not talking here about the generation of immune complexes that deposit in organs like

the kidneys; that's a secondary, and uninteresting effect) unless they are cross-reacting to another extracellular protein (i.e., it's highly unlikely that antibodies can enter a cell and produce pathology that way). Maybe the CRYAB antibodies cross-react with some other protein and the "antiinflammatory" effect of CRYAB injections simply reflects the ability of CRYAB to bind up all the antibodies, thereby preventing the binding of those antibodies to the putative other protein. That story would be less tidy than the one I thought (and still sort of think) these authors are trying to tell.Matt>> has pointed out a number of times that autoantibodies are > common, and are not generated only in patients experiencing >

autoimmune diseases.> > Various proteins are capable of putting the brakes on inflammation. > IL-10 is the obvious example, but there are others. So what if the > autoantibody that some people generate happens to neutralize one of > these "brakes"? The inflammation might persist unabated, and might > perpetuate the production of the original offending autoantibody.> > Today's offering by Nature suggests that this indeed happens with MS:> > http://tinyurl.com/yofjda> > They present data indicating that MS patients, but not control > patients, produce antibody against CRYAB, a molecule that inhibits > inflammation. They present other data, in mice, indicating the > negative impact that this has.> > If true, this is spectacular.> >

Matt>

[Guest guest]

There's one sentence in the full text of that paper that deals with

mechanism. They don't know why CRYAB would work, but they give

brief speculations. They suggest that the intravenously injected

CRYAB might enter the CNS and then cross the cell membrane into the

cell where it could then mediate an anti-inflammatory effect. This

seems like a tall tale to me. They also suggest that CRYAB might

neutralize the anti-CRYAB autoantibodies, which I think is the more

likely scenario. But it looks to me like CRYAB is an INTRAcellular

protein. So how would autoantibody enter the cell in order to bind

CRYAB? It seems to me that the most likely explaination is that the

anti-CRYAB autoantibodies are cross-reacting with some unidentified

EXTRAcellular protein and that is what mediates disease whereas the

binding of CRYAB itself by these antibodies is not mediating

disease. But that takes all the elegance out of this paper. What

looked beautiful about this paper at first was the idea that the

immune system might be neutralizing an anti-inflammatory protein.

This would go along way towards accounting for " autoimmunity "

itself. Alas, I don't think this paper has moved us one step closer

to understanding this Big Question (i.e., why would the immune

system become autoaggressive for protracted periods?).

CRYAB is not available commercially, and I doubt that intravenously

injected CRYAB has a general anti-inflammatory effect anyway. I

think that if this works at all, it works by complexing anti-CRYAB

antibody and that might be therapeutic only for MS (if that).

Matt

>

>

> But I'm still interested in the anti-inflammatory role CRYAB

might have (I'm just scared that not taking enough would just make

things worse).

>

> I'd like to find some antiinflammatory alternative. Otherwise,

Benicar's starting to look good to me again because of these

frequent migraines that have come back. And I really don't want to

go there as I feel that the Benicar definitely did something to my

leg muscles that I've slowly recovered from and don't want to

revisit. But its anti-inflammatory effects were so remarkable for

me.

>

> penny

>

[Guest guest]

It's been at least 2 years since I ws taking Benicar. I also had leg

muscle weakness on Benicar. My good GP put me on low dose Cozaar. I

can't say it has had any effect. She didn't use Benicar since, even

at high dose, it never lowered my blood pressure at all, and we were

seeing spikes and then dips in my blood pressure currently. Also, I

sometimes have severe drops in blood sugar levels now, like down in

the 40s, but no high blood sugar levels. I do think the headache is

worse when the blood sugar levels are severely low, since eating

something does seem to help. I am not saying that is the cause. You

don't get a dilated pupil and double vision in one eye, nor do you

get vestibular nerve damage and vertigo from occasional low blood

sugar.

a

>

> " ...What if monkeys flew out my..... "

>

> Lol!

>

> But I'm still interested in the anti-inflammatory role CRYAB

might have (I'm just scared that not taking enough would just make

things worse).

>

> I'd like to find some antiinflammatory alternative. Otherwise,

Benicar's starting to look good to me again because of these frequent

migraines that have come back. And I really don't want to go there as

I feel that the Benicar definitely did something to my leg muscles

that I've slowly recovered from and don't want to revisit. But its

anti-inflammatory effects were so remarkable for me.

>

> It's strange that a an ARB for blood pressure, vasoconstriction

and/or vasodilation all seem to have some kind of role in these

headaches.

>

> a, how soon after stopping the Benicar, did the headache

begin?

>

> penny

>

> phagelod <mpalmer@...> wrote:

> What if monkeys flew out my.....

>

> I'm going to have to take a closer look at this paper. I couldn't

> find any papers saying that CRYAB is an extracellular signaling

> molecule. If CRYAB is just another intracellular protein to which

> autoantibodies are generated, then I don't see how the

> autoantibodies would be pathogenic (I'm not talking here about the

> generation of immune complexes that deposit in organs like the

> kidneys; that's a secondary, and uninteresting effect) unless they

> are cross-reacting to another extracellular protein (i.e., it's

> highly unlikely that antibodies can enter a cell and produce

> pathology that way). Maybe the CRYAB antibodies cross-react with

> some other protein and the " antiinflammatory " effect of CRYAB

> injections simply reflects the ability of CRYAB to bind up all the

> antibodies, thereby preventing the binding of those antibodies to

> the putative other protein. That story would be less tidy than the

> one I thought (and still sort of think) these authors are trying to

> tell.

>

> Matt

>

>

> >

> > has pointed out a number of times that autoantibodies are

> > common, and are not generated only in patients experiencing

> > autoimmune diseases.

> >

> > Various proteins are capable of putting the brakes on

> inflammation.

> > IL-10 is the obvious example, but there are others. So what if

> the

> > autoantibody that some people generate happens to neutralize one

> of

> > these " brakes " ? The inflammation might persist unabated, and

> might

> > perpetuate the production of the original offending autoantibody.

> >

> > Today's offering by Nature suggests that this indeed happens with

> MS:

> >

> > http://tinyurl.com/yofjda

> >

> > They present data indicating that MS patients, but not control

> > patients, produce antibody against CRYAB, a molecule that

inhibits

> > inflammation. They present other data, in mice, indicating the

> > negative impact that this has.

> >

> > If true, this is spectacular.

> >

> > Matt

> >

>

[Guest guest]

Product Overview - MBP8298

Product Information

MBP8298 is a synthetic peptide that consists of 17 amino acids linked

in a sequence identical to that of a portion of human myelin basic

protein (MBP). MBP8298 has been developed for the treatment of

multiple sclerosis (MS), and is based on over 26 years of research.

MS is generally considered an autoimmune disease, caused by immune

attack against normal components of the central nervous system. The

specificity of the immune attack at the molecular level is determined

in each case by the HLA type of the individual patient, and HLA type

is known to be one factor that contributes to susceptibility to MS.

The MBP8298 synthetic peptide is a molecular replicate of the site of

attack that is dominant in MS patients with HLA haplotypes DR-2 or DR-

4. These HLA types are found in 65-75% of all MS patients.

The apparent mechanism of action of MBP8298 is the induction or

restoration of immunological tolerance with respect to ongoing immune

attack at this molecular site. High doses of antigen delivered

periodically by the intravenous route are expected to suppress immune

responses to the administered substance. The potential benefit of

MBP8298 for any individual patient is therefore expected to be

related to the extent to which his or her disease process is

dominated by autoimmune attack at the site represented by this

synthetic peptide .

The results of phase II and long-term follow-up treatment of MS

patients with MBP8298, recently published in the European Journal of

Neurology (EJN), showed that MBP8298 safely delayed median time to

disease progression for five years in progressive MS patients with

HLA-DR2 or HLA-DR4 immune response genes.

[Guest guest]

I looked up the abstract (PMID 16879301). Its statistics are very

dubious. Their main analysis " at 24 months showed no significant

difference between MBP8298 and placebo-treatments " . They then picked out

a subgroup of HLA subtypes for which it did work (to P=0.01). That

P-value probably doesn't include Bonferroni correction (the correction

you're supposed to apply when picking and choosing your subgroups), so

this could be pure randomness.

They then went on to treat this subgroup for 3 more years, and got

reduced rates of progression, compared to placebo, at a P-value of 0.004.

But when you pick out a subgroup that is doing better, it's not a

surprise that it continues to do better, even if the reason isn't what

you think it is.

In any case, the idea that antibodies to myelin basic protein are the

basic driver of MS was given a very big whack by a paper by Prineas and

Barnett that came out after they started the MPB8298 trial. That paper

examined MS lesions in the process of forming, and found that the first

event was the mass apoptosis of oligodendrocytes, which maintain the

myelin; the subsequent loss of myelin is just cleanup.

And that's not even getting into the evidence (which is very good) that

most MS is caused by an infection with chlamydia pneumoniae.

On Sat, Jun 16, 2007 at 06:22:09PM -0000, pjeanneus wrote:

>Product Overview - MBP8298

>

>Product Information

>

>MBP8298 is a synthetic peptide that consists of 17 amino acids linked

>in a sequence identical to that of a portion of human myelin basic

>protein (MBP). MBP8298 has been developed for the treatment of

>multiple sclerosis (MS), and is based on over 26 years of research.

>

>MS is generally considered an autoimmune disease, caused by immune

>attack against normal components of the central nervous system. The

>specificity of the immune attack at the molecular level is determined

>in each case by the HLA type of the individual patient, and HLA type

>is known to be one factor that contributes to susceptibility to MS.

>The MBP8298 synthetic peptide is a molecular replicate of the site of

>attack that is dominant in MS patients with HLA haplotypes DR-2 or DR-

>4. These HLA types are found in 65-75% of all MS patients.

>

>The apparent mechanism of action of MBP8298 is the induction or

>restoration of immunological tolerance with respect to ongoing immune

>attack at this molecular site. High doses of antigen delivered

>periodically by the intravenous route are expected to suppress immune

>responses to the administered substance. The potential benefit of

>MBP8298 for any individual patient is therefore expected to be

>related to the extent to which his or her disease process is

>dominated by autoimmune attack at the site represented by this

>synthetic peptide .

>

>The results of phase II and long-term follow-up treatment of MS

>patients with MBP8298, recently published in the European Journal of

>Neurology (EJN), showed that MBP8298 safely delayed median time to

>disease progression for five years in progressive MS patients with

>HLA-DR2 or HLA-DR4 immune response genes.

[Guest guest]

Norman, I also believe that MS is an infectious disease. However,

that doesn't mean that a large portion of MS patients with those two

genotypes won't benifit from this new drug. In some ways this is like

the debate between Yasko and Rich V and those of us who believe

various infections underlie cfs. While we want the infections

treated, there certainly is a place for treating the fallout and

basing this on genotypes who can't fight the assault on the body.

After all, some folks get the same infections and are able to fight

them off with just a few weeks to months of antibiotics.

a

>

> I looked up the abstract (PMID 16879301). Its statistics are very

> dubious. Their main analysis " at 24 months showed no significant

> difference between MBP8298 and placebo-treatments " . They then

picked out

> a subgroup of HLA subtypes for which it did work (to P=0.01). That

> P-value probably doesn't include Bonferroni correction (the

correction

> you're supposed to apply when picking and choosing your subgroups),

so

> this could be pure randomness.

>

> They then went on to treat this subgroup for 3 more years, and got

> reduced rates of progression, compared to placebo, at a P-value of

0.004.

> But when you pick out a subgroup that is doing better, it's not a

> surprise that it continues to do better, even if the reason isn't

what

> you think it is.

>

> In any case, the idea that antibodies to myelin basic protein are

the

> basic driver of MS was given a very big whack by a paper by Prineas

and

> Barnett that came out after they started the MPB8298 trial. That

paper

> examined MS lesions in the process of forming, and found that the

first

> event was the mass apoptosis of oligodendrocytes, which maintain the

> myelin; the subsequent loss of myelin is just cleanup.

>

> And that's not even getting into the evidence (which is very good)

that

> most MS is caused by an infection with chlamydia pneumoniae.

>

>

> On Sat, Jun 16, 2007 at 06:22:09PM -0000, pjeanneus wrote:

> >Product Overview - MBP8298

> >

> >Product Information

> >

> >MBP8298 is a synthetic peptide that consists of 17 amino acids

linked

> >in a sequence identical to that of a portion of human myelin basic

> >protein (MBP). MBP8298 has been developed for the treatment of

> >multiple sclerosis (MS), and is based on over 26 years of

research.

> >

> >MS is generally considered an autoimmune disease, caused by immune

> >attack against normal components of the central nervous system.

The

> >specificity of the immune attack at the molecular level is

determined

> >in each case by the HLA type of the individual patient, and HLA

type

> >is known to be one factor that contributes to susceptibility to

MS.

> >The MBP8298 synthetic peptide is a molecular replicate of the site

of

> >attack that is dominant in MS patients with HLA haplotypes DR-2 or

DR-

> >4. These HLA types are found in 65-75% of all MS patients.

> >

> >The apparent mechanism of action of MBP8298 is the induction or

> >restoration of immunological tolerance with respect to ongoing

immune

> >attack at this molecular site. High doses of antigen delivered

> >periodically by the intravenous route are expected to suppress

immune

> >responses to the administered substance. The potential benefit of

> >MBP8298 for any individual patient is therefore expected to be

> >related to the extent to which his or her disease process is

> >dominated by autoimmune attack at the site represented by this

> >synthetic peptide .

> >

> >The results of phase II and long-term follow-up treatment of MS

> >patients with MBP8298, recently published in the European Journal

of

> >Neurology (EJN), showed that MBP8298 safely delayed median time to

> >disease progression for five years in progressive MS patients with

> >HLA-DR2 or HLA-DR4 immune response genes.

>

[Guest guest]

This is an interesting post as I was discussing inflammation with my

cousin who has MS. He felt that stability in the cycle was important.

Cycling of inflammation was a big factor in the disease process-

according to him.we also discovered that the pacific islanders where

less likely to get MS with the people in a cold scottish climate the

most likely.I felt that the constant dipping into the ocean, which in

it's own way tames inflammation may have been a big player in there

inflammatory process, not to mention there availability to eat only

fresh produce which on it's own wouldn't fuel inflammation like the

additives in our foods may.

tony

> has pointed out a number of times that

autoantibodies are

> common, and are not generated only in patients experiencing

> autoimmune diseases.

>

> Various proteins are capable of putting the brakes on inflammation.

> IL-10 is the obvious example, but there are others. So what if the

> autoantibody that some people generate happens to neutralize one of

> these " brakes " ? The inflammation might persist unabated, and might

> perpetuate the production of the original offending autoantibody.

>

> Today's offering by Nature suggests that this indeed happens with

MS:

>

> http://tinyurl.com/yofjda

>

> They present data indicating that MS patients, but not control

> patients, produce antibody against CRYAB, a molecule that inhibits

> inflammation. They present other data, in mice, indicating the

> negative impact that this has.

>

> If true, this is spectacular.

>

> Matt

>

[Guest guest]

> There's one sentence in the full text of that paper that deals with

> mechanism. They don't know why CRYAB would work, but they give

> brief speculations. They suggest that the intravenously injected

> CRYAB might enter the CNS and then cross the cell membrane into the

> cell where it could then mediate an anti-inflammatory effect. This

> seems like a tall tale to me.

Here's some data for another HSP. Though, I admit, the fact that they

are both HSPs doesn't mean much.

" In contrast to E. coli, where Hsp60 was localized exclusively in the

cytoplasm, in L. pneumophila Hsp60 was predominantly associated with

the cell envelope "

" Putative secretion of Hsp60 by L. pneumophila was further indicated

by the accumulation of Hsp60 in the endosomal space, between

replicating intracellular bacteria. "

http://jb.asm.org/cgi/content/abstract/180/3/505

Presumably the possibility of artifacts by cross-reaction with human

HSPs was addressed, but I didn't read the paper. The mode of

exocystosis of HSP60 was not determined... could be cell lysis,

secretion system apparatus, whatever... or could it be that HSP60 can

cross membranes unaided?

> They also suggest that CRYAB might

> neutralize the anti-CRYAB autoantibodies, which I think is the more

> likely scenario. But it looks to me like CRYAB is an INTRAcellular

> protein. So how would autoantibody enter the cell in order to bind

> CRYAB?

Yaakov Naparstek and Chaim Putterman are the guys I'd go to for info

on cell-penetrating antibodies. There are multiple results in that

field, but I haven't read. The notion is even mentioned briefly in

Dubois' Lupus 2002 (courteousy of one of the above guys), so it seems

to be palatable enough to the editors of that very mainstream book.

HSPs are often abundant - in aggregate, they form something like 5% of

cytoplasmic protein mass. And these authors say " alphaB-crystallin

(CRYAB) is the most abundant gene transcript present in early active

multiple sclerosis lesions. " So if a pathogenic effect were to proceed

from antagonisation of CRYAB, it seems like a lot of Ab would be needed.