SWEET WHEY Makes CENTs OR Whats uP with CD70?
randall
While looking at autoimmune news today I found this story on CD70.
It has some cd70 and LPS info and how lps turns cd70 on.
I thought, I haven't seen much on CD70 and what it means for us?
Let's see. I'll google the p newsgroup.
Alrighty then, not a whole lot there.....
But some critical points are made regarding it.
Here's what initially sPurred me on to CD70:
You knock out cd70 and autoimmune conditions like rheumatoid
arthritis, lupus and Crohn's disease are
all controlled by SGN-70 and it some how blocks CD70.
Well this is news to me.
BIG NEWs...
Cute huh? SGN-70 helps control CD70.
Where does CD70 come from? I'll expand on it further down.
First look at pubmed.
This looks key.
http://www.ncbi.nlm.nih.gov/pubmed/15857939?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Lipopolysaccharide (lps) stimulation converts vigorously washed
dendritic cells (DCs) to nonexhausted DCs expressing CD70 and evoking
long-lasting type 1 T cell responses. (aka- TH1)
Iwamoto S, Ishida M, Takahashi K, Takeda K, ____Miyazaki A.____
Department of Biochemistry, School of Medicine, Showa University,
1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
iwas...@med.showa-u.ac.jp
A great variety of in vitro culture protocols for human monocyte-
derived dendritic cells (mo-DCs) has been used to generate DCs
suitable for use in immunotherapy. It is thought that activated DCs
undergo one-way differentiation into "exhausted" DCs. In the present
study, we contrived an in vitro method for facilitating expression of
CD70 by mature DCs. This was achieved by vigorous washing of mo-DCs
before exposure to lipopolysaccharide (LPS). Unexpectedly, these
mature DCs retain expression of some interleukin (IL)-12 family
members after extended periods and maintain their ability to stimulate
type 1 T cell responses. In contrast, DCs exposed to IL-4 before LPS
stimulation or LPS-stimulated DCs not exposed to washing stress before
activation failed to express CD70 and did differentiate into exhausted
DCs. It is interesting that DCs expressing CD70 (CD70+ DCs) induced
interferon-gamma production from purified, allogeneic CD8+ T cells
through a direct CD27-CD70 interaction. This is evidence for a pathway
resulting in generation of CD8 T effectors by B7-independent
mechanisms. These data suggest that exposure of immature DCs to LPS
stimulation contributes to their terminal differentiation into CD70+
DCs, which have potent ability to prolong type 1 T cell responses
through alternative pathways.
PMID: 15857939
So let me see.
If your gut leaks like crazy and we NOW KNOW it's leaking cell wall of
endotoxins (LPS), found
in the flora of microbes in the Gi tract, then the more you leak the
more severe
your PSORIASIS.
LPS creates -----> TNF.
Is that right?
How does this LPS stuff screw up your immunity?
This last author, ___Miyazaki___ seems in the last abstract to be on
track.
Here's a more recent one from Dr. Miyazaki.
TNF-alpha drives human CD14+ monocytes to differentiate into CD70+
dendritic cells evoking Th1 and Th17 responses.
Iwamoto S, Iwai S, Tsujiyama K, Kurahashi C, Takeshita K, Naoe M,
Masunaga A, Ogawa Y, Oguchi K, ____Miyazaki A.____
Department of Biochemistry, School of Medicine, Showa University,
Tokyo, Japan. iwas...@med.showa-u.ac.jp
Many mechanisms involving TNF-alpha, Th1 responses, and Th17 responses
are implicated in chronic inflammatory autoimmune disease. Recently,
the clinical impact of anti-TNF therapy on disease progression has
resulted in re-evaluation of the central role of this cytokine and
engendered novel concept of TNF-dependent immunity. However, the
overall relationship of TNF-alpha to pathogenesis is unclear. Here, we
demonstrate a TNF-dependent differentiation pathway of dendritic cells
(DC) evoking Th1 and Th17 responses. CD14(+) monocytes cultured in the
presence of TNF-alpha and GM-CSF converted to CD14(+) CD1a(low)
adherent cells with little capacity to stimulate T cells. On
stimulation by LPS, however, they produced high levels of TNF-alpha,
matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either
into mature DC or activated macrophages (M phi). The mature DC
(CD83(+) CD70(+) HLA-DR (high) CD14(low)) expressed high levels of
mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce
IFN-gamma and TNF-alpha, and stimulated resting CD4 T cells to secret
IL-17. Intriguingly, TNF-alpha added to the monocyte culture medium
determined the magnitude of LPS-induced maturation and the functions
of the derived DC. In contrast, the M phi (CD14(high)CD70(+)CD83(-)HLA-
DR(-)) produced large amounts of MMP-9 and TNF-alpha without exogenous
TNF stimulation. These results suggest that the TNF priming of
monocytes controls Th1 and Th17 responses induced by mature DC, but
not inflammation induced by activated M phi. Therefore, additional
stimulation of monocytes with TNF-alpha may facilitate TNF-dependent
adaptive immunity together with GM-CSF-stimulated M phi-mediated
innate immunity.
PMID: 17641010
[this abstract has been posted three times to the p ng- July 31 2007,
Aug 30 2007 & Jun 12 2008]
See:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=17641010&qt_g=Search+this+group
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CD14 recognizes LPS... check it out.
http://en.wikipedia.org/wiki/CD14
Cluster of differentiation 14 also known as CD14 is a human gene.[1]
[2]
The protein encoded by this gene is a component of the innate immune
system. CD14 exists in two forms. It is either anchored into the
membrane by a a glycosylphosphatidylinositol tail (mCD14) or it
appears in a soluble form (sCD14). Soluble CD14 appears either after
shedding of mCD14 (48 KDa) or is directly secreted from intracellular
vesicles (56 KDa).[3]
CD14 takes its name from its inclusion in the cluster of
differentiation group of cell surface marker proteins.
CD14 was the first described pattern recognition receptor.
Function
CD14 acts as a co-receptor (along with the Toll-like receptor TLR 4
and MD-2) for the detection of bacterial lipopolysaccharide (LPS).[4]
[5] CD14 can only bind LPS in the presence of lipopolysaccharide-
binding protein (LBP). Although LPS is considered it's main ligand
CD14 also recognizes other pathogen associated molecular patterns.
Here's the image:
http://en.wikipedia.org/wiki/Image:Toll-like_receptor_pathways_revised.jpg
Tissue distribution
CD14 is expressed mainly by macrophages and (at 10 times lesser
extent) by neutrophil granulocytes. A soluble form sCD14 is secreted
by the liver and monocytes and is sufficient in low concentrations to
confer LPS-responsiveness to cells which otherwise do not express
CD14.
Differentiation
CD14+ are monocytes that can differentiate into a host of different
cells. (A '+' sign refers to the presence of the CD14 protein on a
cell. )
One type of cell is the dendritic cell, where differentiation is
encouraged by cytokines. Examples of cytokines that will cause
dendritic cell differentiation includes GM-CSF and IL-4.
<sniP>
===================================
I've had a gut hunch about P since I was able to nearly clear my skin
by uPregulation of lacti loving bacteria that create a slighly acidic
condition in the Gi tract. IOWs the garden inside of me was haPPy
and my skin followed suit.
So?
Well, that lead me to the conclusion that P would be cured in the gut
somehow.
And i've skewed my Th1 skewed investigations in that direction. :)
And it's paid off in sPades over the last decade.
While the REAL scientists were busy telling me what had and
was haPPening in me I was verifying their research with my own.
This next abstract tells how Th17 can be upregulated via the lamina
propria tissue.
http://en.wikipedia.org/wiki/Lamina_propria [btw- it's in the Gi
tract]
What's key here?
Ligands?
http://en.wikipedia.org/wiki/Ligand
What about MAN sugars?
You've posted on that one:
http://en.wikipedia.org/wiki/Sialic_acid
http://www.glycoforum.gr.jp/science/word/evolution/ES-A03E.html
Hey!
We're going to far off the mark.
Lets stick with cluster of differentiation (CD's) today.
http://en.wikipedia.org/wiki/Cluster_of_differentiation
The cluster of differentiation (cluster of designation) (often
abbreviated as CD) is a protocol used for the identification and
investigation of cell surface molecules present on leukocytes. CD
molecules can act in numerous ways, often acting as receptors or
ligands (the molecule that activates a receptor) important to the
cell. A signal cascade is usually initiated, altering the behavior of
the cell (see cell signaling). Some CD proteins do not play a role in
cell signaling, but have other functions, such as cell adhesion. There
are approximately 250 different proteins
<sniP>
So?
Plain old cell surface markers?
And whats sPecial with CD70 then?
OK.. let's get on with CD70.
CD70 on the docket today so to sPeak.
ATP drives lamina propria T(H)17 cell differentiation.
Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M,
Yagita H, Ishii N, Evans R, Honda K, Takeda K.
Laboratory of Immune Regulation, Graduate School of Medicine, Osaka
University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Interleukin (IL)-17-producing CD4(+) T lymphocytes (T(H)17 cells)
constitute a subset of T-helper cells involved in host defence and
several immune disorders. An intriguing feature of T(H)17 cells is
their selective and constitutive presence in the intestinal ___lamina
propria.___ Here we show that adenosine 5'-triphosphate (ATP) that can
be derived from commensal bacteria activates a unique subset of lamina
propria cells, CD70(high)CD11c(low) cells, leading to the
differentiation of T(H)17 cells. Germ-free mice exhibit much lower
concentrations of luminal ATP, accompanied by fewer lamina propria
T(H)17 cells, compared to specific-pathogen-free mice. Systemic or
rectal administration of ATP into these germ-free mice results in a
marked increase in the number of lamina propria T(H)17 cells. A
CD70(high)CD11c(low) subset of the lamina propria cells expresses
T(H)17-prone molecules, such as IL-6, IL-23p19 and transforming-growth-
factor-beta-activating integrin-alphaV and -beta8, in response to ATP
stimulation, and preferentially induces T(H)17 differentiation of co-
cultured naive CD4(+) T cells. The critical role of ATP is further
underscored by the observation that administration of ATP exacerbates
a T-cell-mediated colitis model with enhanced T(H)17 differentiation.
These observations highlight the importance of commensal bacteria and
ATP for T(H)17 differentiation in health and disease, and offer an
explanation of why T(H)17 cells specifically present in the intestinal
lamina propria.
PMID: 18716618
Amazing! CD70, LPS and TH17 are all intimately connected. Do they keep
the
TREGs turned off? And indirectly P turned on?
Let investigate.
CD70
http://en.wikipedia.org/wiki/CD70
CD70 (Cluster of Differentiation 70) is a ligand for CD27.
http://en.wikipedia.org/wiki/CD27
CD27 is a tumor necrosis factor receptor.
The protein encoded by this gene is a member of the TNF-receptor
superfamily. This receptor is required for generation and long-term
maintenance of T cell immunity. It binds to ligand CD70, and plays a
key role in regulating B-cell activation and immunoglobulin synthesis.
This receptor transduces signals that lead to the activation of NF-κB
and MAPK8/JNK. Adaptor proteins TRAF2 and TRAF5 have been shown to
mediate the signaling process of this receptor. CD27-binding protein
(SIVA), a proapoptotic protein, can bind to this receptor and is
thought to play an important role in the apoptosis induced by this
receptor.[1]
<sniP>
Well?
We know we have to much TNF or there would be no need for biological
drugs.
And since blocking or disabling TNF in some fashion with biologicals,
then the ligands
or receptors must be working pretty damn skiPPy. :(
http://en.wikipedia.org/wiki/Tumor_necrosis_factor_receptor
A tumor necrosis factor receptor (TNFR), or death receptor, is a
cytokine receptor that binds tumor necrosis factors (TNF).
Because "TNF" is often used to describe TNF alpha, "TNFR" is often
used to describe the receptors that bind to TNF alpha - namely, CD120.
However, there several other members of this family that bind to the
other TNFs.[1][2]
<sniP>
======================================
Going back to the OLD days (1997) for CD70
http://www.ncbi.nlm.nih.gov/pubmed/9143940?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
CD70 expression on T-cell subpopulations: study of normal individuals
and patients with chronic immune activation.
Brugnoni D, Airò P, Marino R, Notarangelo LD, van Lier RA, Cattaneo R.
Clinical Immunology Service, Spedali Civili/University of Brescia,
Italy.
CD70, the ligand of CD27, is a member of the TNF family, which
includes molecules essential in the regulation of lymphocyte growth
and survival. It is absent on resting lymphocytes but can be induced
in vitro with activating stimuli. To extend information about its
expression by different T-cell subpopulations, and its regulation in
normal and pathologic conditions, highly purified T-cell
subpopulations were studied: CD70 expression depended both on the
activating stimulus and on the T-cell subset analyzed. PMA + Ionomycin
induced CD70 on the large majority of CD8+ cells, but only on a
minority of CD4+ cells (P < 0.002), and among these, preferentially on
the CD45R0+ subset compared with the CD45RA+. The presence of CD4+
lymphocytes in cell cultures containing mixtures of T-cell subsets
inhibited CD70 expression on CD8+ cells. On the contrary, stimulation
with allogeneic cells induced CD70 expression also on CD4+ cells.
Moreover, CD70 was found to be expressed by chronically in vivo
activated T-cells, in conditions characterized by allogeneic and
autoimmune reactions. These data suggest a possible role of CD70 in
the pathogenesis of immune dysregulation; interestingly, this role may
not be simply restricted to bind to, and signal through, CD27, since
cross-linking of CD70 enhances the proliferative response induced by
the stimuli used to elicit its expression.
PMID: 9143940
Makes one think.
We know guys were working on AOAH already ten years before 1997 and
they aimed their research at LPS and endotoxins.
That same doc is still working on AOAH.
Dr. Mundford may have a simple way to clear systemic wide LPS
(endogenous endotoxins)
released from a leaky gut. See zot or zonulin in the P NG. Or
permeable or loose junctions etc.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Munford%20RS%22[Author]&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus
Does make me think that working on these pathways without simply
eliminating the LPS is PURe stuPidity.
Hence, my method to change & rearrange gut flora makes the MOST sense.
For me anyway. And you should you go for it and find it cheaP and the
ultimate way to health. :)
Unfortunately BIG PHARpMA is looking for LARGE bucks and not small
cents.
Which is what sweet whey costs. Cents...
Once again...
Taking some asPect of the inflammatory psoriasis pathway and
completely
understanding ALL the ramifications.
Is this CLEAR yet?
The damn leaking LPS is being GAMED by you know who to
make mega-bucks $$$$...
Block the LPS and no need to block or worry about CD70 and the
whole enchilada of autoimmunity.
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randall... what's not to like? Besides P plaque of course...