Coolest paper on how T-cells cross BBB

[Buster]

I just ran across another paper that now has the B-cells crossing the BBB.

 

The paper from Nature that started this thread shows that T-cells are attracted to weaknesses in the BBB and recruit other T-cells there.

We've been wondering if antibodies to strep (i.e., 24.3.1) then cross at this point and interfere with neuronal tissue

Now this paper indicates that if the breach is wide enough, B-cells can cross and if responsive to neuronal tissue, can activate antibodies on the brain side

 

I have no idea if this applies in the PANDAS case, but this would explain the rapid onset -- because a B cell on the Brain side of the BBB that happened to be there with an activated T-cell would propogate a whole bunch of antibodies all at once.

 

http://www.jimmunol.org/cgi/reprint/170/9/4497

 

I'm looking for followups to this work ....

 

Buster

 

Determinants of Human B Cell Migration Across Brain Endothelial Cells

Andrea Alter et al

Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and

disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction

with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that

regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We

found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly

inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously

reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN--

inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor

expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural

inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR

comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells

revealed distinct profiles of expression of these molecules in the different cell subsets.

Our results provide insights into the

molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and

unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell

migration, such as anti-VLA-4 Abs, may impact on B cell trafficking

. The Journal of Immunology, 2003, 170: 4497–4505.

 

Without a doubt, one of the coolest papers I've seen recently -- and I've read a bunch. It explains and documents (with movies) how T-cells can cross the blood-brain barrier. This should have huge impact on MS, SC and frankly on PANDAS too.

 

 

http://www.nature.com/nature/journal/v462/...ature08478.html

 

Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions

Nature 462, 94-98 (5 November 2009) | doi:10.1038/nature08478;

[peglem]

Well, this gives me an ominous feeling. Overreacting too soon to not enough info probably. But the thought of Bcells churning out antibodies in my childs brain...gives me a feeling of dread! And if that is happening, how do you stop the little boogers? Which leads me to ask....

When you get IVIG or PEX, is it better to have the BBB opened or closed?

 

AND

 

I know MS is different, as it involves tissue destruction, but if this is happening in PANDAS, how likely is it that the neuronal receptors that are being activated and/or blocked by the antibodies are stimulating the immune system to produce those antibodies?

 

I think I liked life better before I heard about this.

[Buster]

peglem,

 

First, sorry, last thing I wanted to do was add more weight to the worries we all feel. Let me go with the good stuff first:

 

1. There is no evidence of any permanent damage in PANDAS -- no demyelination, no plaque, no ....

2. The studies seem to indicate it is interference and not aptosis occuring (i.e., the antibodies are acting like neurotransmitters and not like antibodies)

3. The antibodies seem to have a half-life of 4 weeks (as best as I can figure out -- still searching)

4. PEX, IVIG, pred, and antibiotics all seem to work

 

And yes, I too am not thrilled by the prospect of the antibodies being in the brain, but I'm sort of stuck figuring out how they get there. Without that piece explained, I'm not sure whether this one time treatment will hold or not -- was it an immune failure, a genetic pre-disposition, a BBB failure or all three.

 

I've been struggling with how would so many antibodies cross into the brain -- I mean you need a fair amount to compete with dopamine receptors on neurons. Well, this would be an explanation... not sure it is "the" explanation....

 

I'm happy to label these types of posts as "WACKY THEORY" posts if that helps lower the concern level -- this is definitely not science yet -- it's speculation.

 

Buster

 

 

 

Well, this gives me an ominous feeling. Overreacting too soon to not enough info probably. But the thought of Bcells churning out antibodies in my childs brain...gives me a feeling of dread! And if that is happening, how do you stop the little boogers? Which leads me to ask....

When you get IVIG or PEX, is it better to have the BBB opened or closed?

 

AND

 

I know MS is different, as it involves tissue destruction, but if this is happening in PANDAS, how likely is it that the neuronal receptors that are being activated and/or blocked by the antibodies are stimulating the immune system to produce those antibodies?

 

I think I liked life better before I heard about this.

[peglem]

Oh, sorry Buster...not trying to quash anything...I AM interested in the research and better to know for sure. Just is scary sometimes. But I suppose if my daughter can force herself to let me drink from a coffee cup (these trigger anxiety for her!), than I can bloody well over look my comparatively small worries to find out what is going on. It was just my knee-jerk reaction! I'm fine, really.

 

But, that other question....Best to try to close BBB before PEX/IVIG, or would open be better in that case? I'm not looking for a fersure answer here. I don't think anybody knows. But, you probably know more about what's going on here than anybody and I'd really like to hear you speculate on that.

 

And please, continue sharing research, no matter what-that's very important.

[Buster]

Best to try to close BBB before PEX/IVIG, or would open be better in that case? I'm not looking for a fersure answer here. I don't think anybody knows. But, you probably know more about what's going on here than anybody and I'd really like to hear you speculate on that.

 

I don't think it matters. If anything IVIG will help close the BBB if it is open by being so anti-inflammatory. There really is unlikely to be any significant flow across the BBB. I do think that it's worth considering a pred-burst before IVIG... I have no great reason why except that it's the protocol that Dr. K uses and, well, seems to work. Can't give you a paper on it, but I think the antibiotics, then if that doesn't work, pred, then if that has effect, IVIG or PEX, then continued prophylaxis -- seems the right course.

[peglem]

Best to try to close BBB before PEX/IVIG, or would open be better in that case? I'm not looking for a fersure answer here. I don't think anybody knows. But, you probably know more about what's going on here than anybody and I'd really like to hear you speculate on that.

 

I don't think it matters. If anything IVIG will help close the BBB if it is open by being so anti-inflammatory. There really is unlikely to be any significant flow across the BBB. I do think that it's worth considering a pred-burst before IVIG... I have no great reason why except that it's the protocol that Dr. K uses and, well, seems to work. Can't give you a paper on it, but I think the antibiotics, then if that doesn't work, pred, then if that has effect, IVIG or PEX, then continued prophylaxis -- seems the right course.

Thanks, I really respect your opinion!

[sf_mom]

Buster,

 

Back to the fact that they've had great success with Steroids and IVIG with Kawasaki's. I understood this to be a simultaneous treatment.... BUT again this is based on my memory of long conversations with Dr. K. My memory could be a little foggy.

 

-Wendy

 

Best to try to close BBB before PEX/IVIG, or would open be better in that case? I'm not looking for a fersure answer here. I don't think anybody knows. But, you probably know more about what's going on here than anybody and I'd really like to hear you speculate on that.

 

I don't think it matters. If anything IVIG will help close the BBB if it is open by being so anti-inflammatory. There really is unlikely to be any significant flow across the BBB. I do think that it's worth considering a pred-burst before IVIG... I have no great reason why except that it's the protocol that Dr. K uses and, well, seems to work. Can't give you a paper on it, but I think the antibiotics, then if that doesn't work, pred, then if that has effect, IVIG or PEX, then continued prophylaxis -- seems the right course.

[Buster]

Just ran into an interesting paper at http://www.ncbi.nlm.nih.gov/pubmed/8649201 that indicates why ibuprofen might help prevent T-cell migration into the brain and thereby help close the BBB. Essentially, Ibuprofen helps remove the "footholds" known as ICAM-1 (intercellular adhesion molecule-1) on the inner surface of the blood vessels so the T-cells can't move upstream.

 

Buster

 

 

What's different about the vessels of the CNS that allows the T cells to start sticking?

From the paper it seems like LFA-1 (lymphocyte function-associated antigen 1) was implicated in recruiting the T-cells to the site. LFA-1 is produced by Eicosanoids and by Leukocytes that are on the "brain" side of the BBB. The endothelial cells then seem to present "footholds" known as ICAM-1 (intercellular adhesion molecule-1) on the inner surface of the bloood vessel (see fig22b ), and then the T-cell seems to squeeze through similar to the leukocytes (see fig22c).

 

My guess (no data/reference yet) is there is some chemical near the site of the macrophage on the brain side that has high concentration of the chemical near where the T-cell should push through.

 

If these aggressive T cells are actually able to creep against the current, it occurs to me that the bbb isn't really as "open" as I had imagined. It's the capabilty of the "possesed" T cell that's really the trouble maker?

I think it is still the permeability of the BBB. It is true that certain antibodies and MS medication seems to stop the creeping behavior and limit the ability of the T-cells to creep with the ICAM-1.

 

What would happen if they added a little NAG to these T cells, if it has such "stunning" results against autoimmunity...would they stick, creep and invade? One of the concerns of using NAG was an "open," bbb regarding treatment of MS.

I can't speak to NAG, but NAC seems to be studied and seems to down regulate the LFA-1

 

Are the phagocytes somehow signaling the T cells, hence their determination? It didn't really sound like there was an abnormal population of phagocytes in the area where the crossing took place?

I agree and think it likely that it is a chemical getting across the BBB that "attracts" the T-cells to use the ICAM-1 to try to find the source. I keep thinking of it like one of those tom and jerry movies where the scent draws them toward the source.

 

Buster

[kim]

Buster,

 

I have been looking at curcumin/turmeric for the same purpose. My youngest son cannot tolerate ibuprofen at all (stomach issue) and my oldest has taken more of it than i'd like and is currently having a lot of reflux. He has an appt with gastro this month. Not sure where we're going with that, as he does have a prescription for generic Prilosec, but I don't want him on that long term either. sorry OT. Anyway, I came across something regarding glucosamine and ICAM-1 in relationship to Uveitis too, altho the dose looks undoable to me. Going to see if there is anything regarding N acetylglu. when I get a chance.

 

Was wondeing if you read this? Looks like some interesting stuff here i just don't know what it means or if it's relevant. Was going to struggle a little with it later, but thought this might give you something to do in your spare time

 

http://www.jbc.org/content/279/34/35201.full.pdf

 

Intercellular adhesion molecule-1 (ICAM-1) occurs as

both a membrane and a soluble, secreted glycoprotein

(sICAM-1). ICAM-1 on endothelial cells mediates leukocyte

adhesion by binding to leukocyte function associated

antigen-1 (LFA-1) and macrophage antigen-1 (Mac-1). Recombinant

mouse sICAM-1 induces the production of

macrophage inflammatory protein-2 (MIP-2) in mouse astrocytes

by a novel LFA-1- and Mac-1-independent mechanism.

Here we showed that N-glycan structures of sICAM-

1 influence its ability to induce MIP-2 production.

 

 

http://www.agrawal.org/PDF/Curcumin-Season-Bw1.pdf

 

Page 352 downregulates VCAM1 ICAM1

 

http://www.jbc.org/content/277/43/40594.abstract.

JAK-STAT Signaling Mediates Gangliosides-induced Inflammatory Responses in Brain Microglial Cells

 

Neuronal cell membranes are particularly rich in gangliosides, which play important roles in brain physiology and pathology. Previously, we reported that gangliosides could act as microglial activators and are thus likely to participate in many neuronal diseases.

 

http://www.jimmunol.org/cgi/content/full/171/11/6072

 

J Immunol. 2003 Dec 1;171(11):6072-9.

 

Curcumin suppresses Janus kinase-STAT inflammatory signaling through

activation of Src homology 2 domain-containing tyrosine phosphatase 2

in brain microglia.

 

http://www.iovs.org/cgi/content/abstract/iovs.08-1784v1

 

Glucosamine Inhibits Endotoxin-Induced Uveitis in Lewis Rats

 

Conclusions. GS suppresses EIU in rats by blockading the NF-B-dependent signaling pathway and the subsequent production of ICAM-1 and proinflammatory mediators. This study has extended our previous observation that GS is a potentially important compound for reducing ICAM-1-mediated inflammatory effects in the eye.

[kim]

this was a very good paper for anyone interested in this subject. It really helped to clarify why so many things that I read seem contradictory.

 

The first article regarding TH17 was what led me to the 2nd.

 

 

http://www3.interscience.wiley.com/journal...=1&SRETRY=0

 

Abstract

The T help 1 (Th1) and Th2 cell classification have provided the framework for understanding CD4+ T cell biology and the interplay between innate and adaptive immunity for almost two decades. Recent studies have defined a previously unknown arm of the CD4+ T cell effector response, the Th17 lineage, which promises to change our understanding of immune regulation, immune pathogenesis and host defense. The factors that specify differentiation of IL-17 producing effector T cells from naïve T cell precursors are being rapidly discovered and are providing insights into mechanisms by which signals from cells of the innate immune system guide alternative pathways of Th1, Th2, or Th17 development. In this review, we will focus on recent studies that have identified new subsets of Th cells, new insights regarding the induced generation and differentiation mechanisms of Th17 cells and immune regulatory effects. J. Cell. Physiol. 211: 273-278, 2007. © 2007 Wiley-Liss, Inc.

 

 

http://medicine1.bjmu.edu.cn/department/im...E6%96%99/41.pdf

 

excerpt

 

Support for the pathogenic role of TH17 cells in autoimmunity

and infectious disease

Komiyama and colleagues showed that EAE could still occur in IL-17

knockout mice but that disease progression was severely attenuated44.

Adoptive transfer of EAE from myelin-reactive T cells in IL-17−/− mice

was severely attenuated. One can interpret these experiments to mean

that IL-17 may not be critical for initiation of disease and that there

might still be a critical role for TH1 T cells in disease initiation. TH1

cells, by secreting γ-IFN, may make the vascular endothelium at the site

of inflammation more adherent to intravascular lymphocytes (Fig. 2).

γ-IFN and TNF secreted by TH1 cells play a key role in the induction

of vascular cellular adhesion molecule-1 (VCAM-1). VCAM-1 binds

lymphocytes with α4 integrin, and this step is a critical tipping point

in the pathophysiology of several experimental autoimmune diseases,

including EAE, type 1 diabetes mellitus in the NOD mouse, and collagen

arthritis45–47. Blockade of α4 integrin has led to the most effective therapy

to date for MS (refs. 45,46) and has been shown to be effective in the

treatment of rheumatoid arthritis and Crohn disease. One might argue

that initiation of VCAM-1 is a direct consequence of TH1 interaction

with the vascular endothelium. Following the state of increased vascular

adherence, induced via TH1 T cells, TH17 T cells can gain access to tissues

and produce autoimmune damage. IL-6 increases expression of intercellular

adhesion molecule-1 (ICAM-1), the receptor for leukocyte function

associated antigen-1 (LFA-1) on activated T cells43.