THE Ultimate Key to T Cell Stimulation ( A REAL Turn ON)
randall
HOW does one turn on a T cell receptor?
Would that be a th1 or th2?
OK, either one, turn it on.
I don't mean a bottle or jug of red wine. LOL
But the resveratrol therewith may actually stop genetic inflammation.
<g>
If this next person, Dr. Saito has it figured out, then it's a
miracle.
I for one have looked intently at LPS (endogenous endotoxin) for a
long time.
And since the smarty pooh scientists haven't nailed it, then i'm uP
for anything.
http://www.nanowerk.com/news/newsid=9184.php
Posted: February 6, 2009
Immune cell activation under the microscope
(Nanowerk News)
T cells are central to an organism's defense against invading
pathogens. But scientists have long puzzled over how they are
activated and regulated after pathogen recognition. Now a team of
researchers, led by Takashi Saito from the RIKEN Research Center for
Allergy and Immunology in Yokohama, has succeeded in imaging molecular
events that are crucial for these processes ("Spatiotemporal
Regulation of T Cell Costimulation by TCR-CD28 Microclusters and
Protein Kinase C Translocation").
TCR-CD28 (94 hits on pubmed)
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=TCR-CD28&log$=activity
Full activation and differentiation of T cells requires a primary
signal from T cell receptors (TCRs) upon interaction with an antigen-
presenting cell (APC), and a second, distinct signal transmitted
through 'costimulatory' receptors.
The receptor CD28 plays a predominant role in T cell costimulation.
CD28-mediated signals augment many T cell functions, such as cytokine
production and cell proliferation.
Modulation of these costimulatory signals has been applied in clinical
trials by increasing tumor immunity and reducing autoimmune diseases.
But the precise roles of molecules implicated in CD28-mediated
costimulatory signals and their relationship with TCR signals require
clarification.
-----------------
jpg:
http://www.nanowerk.com/news/id9184.jpg
An immunological synapse showing the central supramolecular activation
cluster containing both T cell receptors (red) and PKC? (green).
-------------------
Antigen-specific T cells 'communicate' with APCs through an
'immunological synapse', which forms at their interface and contains a
central (c-) and a peripheral (p-) supramolecular activation cluster
(SMAC).
At initial activation, TCRs form microclusters, which contain
receptors, kinases, and adaptor proteins to induce activation signals
at the interface between a T cell and an APC. These microclusters
translocate to the center of the interface, resulting in cSMAC
formation.
The role of microcluster translocation in T cell signaling has been
unclear, and the concept that they function as signaling centers for T
cell activation has raised questions as to how CD28-mediated
costimulation is regulated.
Using sophisticated fluorescence microscopy techniques to study CD28-
mediated costimulation at the molecular level, Saito and colleagues
have found that the accumulation of microclusters at cSMAC is
important for T cell costimulation. CD28 is initially recruited
together with TCRs to microclusters. PKC?--a protein kinase acting
downstream of CD28--is also recruited to microclusters by association
with CD28, thereby resulting in the initial activation of T cells.
CD28 also plays a role in retaining PKC? at a spatially unique
subregion of cSMAC, leading to sustained signals for T cell
activation. "Thus, costimulation is mediated by the generation of a
unique costimulatory compartment in the cSMAC via the dynamic
regulation of microcluster translocation," say the researchers.
Establishing the underlying mechanisms should lead to new treatments
for autoimmune diseases, such as rheumatoid arthritis and
______psoriasis,______ as well as the prevention of graft versus host
disease in transplantation, more effective vaccinations, and augmented
anti-tumor immunity.
Source: RIKEN
--------------
TCR's
http://en.wikipedia.org/wiki/T_cell_receptor
PKC
http://en.wikipedia.org/wiki/Protein_kinase_C
Protein kinase C ('PKC', EC 2.7.11.13) is a family of protein kinases
consisting of ~10 isozymes.[1] They are divided into three
subfamilies, based on their second messenger requirements:
conventional (or classical), novel, and atypical.[2] Conventional (c)
PKCs contain the isoforms α, βI, βII, and γ. These require Ca2+,
diacylglycerol (DAG), and a phospholipid such as phosphatidylcholine
for activation. Novel (n)PKCs include the δ, ε, η, and θ isoforms, and
require DAG, but do not require Ca2+ for activation. Thus,
conventional and novel PKCs are activated through the same signal
transduction pathway as phospholipase C. On the other hand, atypical
(a)PKCs (including protein kinase Mζ and ι / λ isoforms) require
neither Ca2+ nor diacylglycerol for activation. The term "protein
kinase C" usually refers to the entire family of isoforms.
<sniP>
To:
http://en.wikipedia.org/wiki/Serine/threonine-specific_protein_kinase
&
http://en.wikipedia.org/wiki/Antigen-presenting_cell
And C-smac
http://en.wikipedia.org/wiki/Immunological_synapse
In immunology, an immunological synapse is the interface between an
antigen-presenting cell and a lymphocyte. It was first discovered by
Abraham Kupfer at the National Jewish Center in Denver and the term
was coined by Michael Dustin at NYU who studied it in further detail.
Key molecules in the synapse are the T cell receptor and its
counterpart the major histocompatibility complex (MHC). Also important
are LFA-1, ICAM-1, CD28, and CD80/CD86. The structure is composed of
concentric rings, the C-SMAC, the P-SMAC, and the D-SMAC each
containing a peculiar mix of molecules.
And ever uPward.
-----------------------------
Their abstract:
http://www.ncbi.nlm.nih.gov/pubmed/18848472?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Spatiotemporal regulation of T cell costimulation by TCR-CD28
microclusters and protein kinase C theta translocation.
Yokosuka T, Kobayashi W, Sakata-Sogawa K, Takamatsu M, Hashimoto-Tane
A, Dustin ML, Tokunaga M, Saito T.
Laboratory for Cell Signaling, RIKEN Research Center for Allergy and
Immunology, Tsurumi-ku, Yokohama 230-0045, Japan.
T cell activation is mediated by microclusters (MCs) containing T cell
receptors (TCRs), kinases, and adaptors. Although TCR MCs translocate
to form a central supramolecular activation cluster (cSMAC) of the
immunological synapse at the interface of a T cell and an antigen-
presenting cell, the role of MC translocation in T cell signaling
remains unclear. Here, we found that the accumulation of MCs at cSMAC
was important for T cell costimulation. Costimulatory receptor CD28
was initially recruited coordinately with TCR to MCs, and its signals
were mediated through the assembly with the kinase PKCtheta. The
accumulation of MCs at the cSMAC was accompanied by the segregation of
CD28 from the TCR, which resulted in the translocation of both CD28
and PKCtheta to a spatially unique subregion of cSMAC. Thus,
costimulation is mediated by the generation of a unique costimulatory
compartment in the cSMAC via the dynamic regulation of MC
translocation.
PMID: 18848472
Is Dr T.. Saito on steroids or what? 5,609 hits for HIM on pubmed?
Yikes... robo abstraction MAN , but if he's so freaking smart where's
the CURE. LOL
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=%22Saito+T%22[Author]&log$=activity
Must be more then ONE of these saito's?
You guess? LOL
Duh these abstracts go back to the stone age. LOL <w>
--------------------
34 hits for CD28 + psoria* on pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=psoria*+AND+cd28&log$=activity
And 110 hits for cd28 + LPS
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=CD28+lps&log$=activity
When do I find time?
Crap a zoid already.
I'm taking on Sjorgens as a key to P.
How am I suPPose to find time?
Don't know or care. Just do it.
OK, stop bugging me. You ME thingy.
===============================
randall... what will I do without LPS? Punt?
randall
>
> 34 hits for CD28 + psoria* on pubmed:http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&...
>
>
> randall... what will I do without LPS? Punt?
And I take it in the end zone and run for 100 + yards
and end up right back where i've COME from.
See: [and how much do you bet by taking resveratrol it would
attenuate it?]
Immune dysfunction in patients with functional gastrointestinal
disorders.
Kindt S, van Oudenhove L, Broekaert D, Kasran A, Ceuppens JL, Bossuyt
X, Fischler B, Tack J.
Department of Gastroenterological Research, K.U.Leuven, Leuven,
Belgium.
There is increasing evidence for involvement of the immune system in
functional gastrointestinal disorder (FGID), including onset after
acute gastrointestinal infections, genotypes resulting in altered
cytokine expression and abnormal presence of immune cells. Our aim was
to assess cellular and humoral immune responses in (i) FGIDs, compared
to healthy subjects and (ii) acute vs unspecified onset FGIDs.
Lymphocytic [interleukin (IL)-5, IL-10, IL-13 and interferon gamma
(IFN-gamma)] and monocytic [IL-10, IL-12, tumour necrosis factor (TNF)-
alpha] cytokine production was characterized at baseline and after
stimulation with phytohemagglutinine and anti-CD28 or
lipopolysaccharide (LPS) in controls (n = 32), irritable bowel
syndrome (IBS) (n = 30), functional dyspepsia (FD) (n = 23) and non-
cardiac chest pain (NCCP) (n = 15). Serum IL-6 and IL-10
concentrations were compared, and the immunophenotype was assessed
using fluorescent-activated cell sorter. Findings were compared for
acute vs unspecified onset FGID. Compared to controls, stimulated
lymphocyte expression of IL-5 and IL-13 was enhanced in IBS, FD and
NCCP (all P < 0.05). Conversely, the stimulated monocytic IL-12 and
lymphocytic IL-10 expression were reduced in IBS and FD, while IFN-
gamma expression was also reduced in FD patients. Except for an
increase in the numbers of CD3(+)CD45RA(+)CD45RO(+) cells, no distinct
cellular profile was detected. Patients with a presumed acute onset of
their symptoms had higher serum IL-10 levels and more CD3(+)CD45RA(+)
CD45RO(+) cells, while TNF-alpha levels following stimulation with LPS
were higher in FD patients reporting an acute onset. A shift towards a
Th2 cytokine profile is present in FGID, while the cellular
immunophenotype remains largely unchanged. Further research is
indicated and could provide new therapeutic strategies for these
disorders.
PMID: 19126184
WELL duh, the LPS makes TNF and IFN worse for Th1 conditions like
asthma and Psoriasis.
I"m gonna watch TV and TRY to stop thinking now. LOL
randall...cept I need to start reviewing Ai Sjorgen's now.
randall
> On Feb 5, 7:59 pm, randall <ranhu...@aol.com> wrote:
>
The last one was a GUT deal for Ai.
And this NEXT one is what exactly?
An integrated classification of pediatric inflammatory diseases, based
on the concepts of autoinflammation and the immunological disease
continuum.
McGonagle D, Aziz A, Dickie LJ, McDermott MF.
Section of Musculoskeletal Disease, University of Leeds, Leeds, LS9
7TF, UK.
Historically pediatric inflammatory diseases were viewed as autoimmune
but developments in genetics of monogenic disease have supported our
proposal that "inflammation against self" be viewed as an
immunological disease continuum, with genetic disorders of adaptive
and innate immunity at either end. Innate immune-mediated diseases may
be associated with significant tissue destruction without evident
adaptive immune responses and are designated as autoinflammatory due
to distinct immunopathologic features. However, the majority of
pediatric inflammatory disorders are situated along this IDC. Innate
immunity has been demonstrated in polygenic autoimmune disorders,
particularly Crohn's disease. A genetic overlap exists between Crohn's
diseases and some major histocompatibility complex class I-associated
diseases, including ___psoriasis;___ these diseases appear to
represent a true intermediate between autoinflammation and
autoimmunity. Conversely, classical autoimmune diseases, with
autoantibody and MHC class II associations, including celiac disease,
and rheumatoid arthritis (RA), have adaptive immune genetic
associations, including ___CTLA4 and PTPN22.___ This proposed
classification is clinically relevant, since innate immune-mediated
disorders may respond to cytokine antagonism whereas autoimmune-
mediated diseases respond better to anti-T and B cell therapies.
Furthermore, the etiopathogenesis of poorly defined "autoimmune"
diseases, such as juvenile idiopathic arthritis, may be inferred to
have substantial innate immune involvement, based on response to IL-1
antagonism.
PMID: 19190531
Hey! CTLA-4 was BIG in the FUN GAL post yesterday (FEB4/2009)
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/msg/eac397159da9ceef
17 hits for PTPN22
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=+PTPN22&start=0&scoring=d&
284 hits on PTPN22 -- on pubmed
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=+PTPN22&start=0&scoring=d&
12 hits for PTPN22 + psoria* -- on pubmed
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=ptpn22+psoria*&log$=activity
You do need to go way way down in that post to hit CTLA4 material.
The first one in these 12 hits is right above and the next one is a
krueger, bowcock thing from oct/2008
Further Genetic Evidence for Three Psoriasis-Risk Genes: ADAM33,
CDKAL1, and PTPN22.
Li Y, Liao W, Chang M, Schrodi SJ, Bui N, Catanese JJ, Poon A,
Matsunami N, Callis-Duffin KP, Leppert MF, __Bowcock__ AM, Kwok PY,
____Krueger GG___, Begovich AB.
1Celera, Alameda, California, USA.
Predisposition to psoriasis is known to be affected by genetic
variation in HLA-C, IL12B, and IL23R, and although other psoriasis-
associated variants have been identified, incontrovertible statistical
evidence for these markers has not yet been obtained. To help resolve
this issue, we tested 15 single-nucleotide polymorphisms (SNPs) from 7
putative psoriasis-risk genes in 1,448 psoriasis patients and 1,385
control subjects; 3 SNPs, rs597980 in ADAM33, rs6908425 in CDKAL1 and
rs3789604 in PTPN22, were significant with the same risk allele as in
prior reports (one-sided P<0.05, false discovery rate<0.15). These
three markers were tested in a fourth sample set (599 cases and 299
controls); one marker, rs597980, replicated (one-sided P<0.05) and the
other two had odds ratios with the same directionality as in the
original sample sets. Mantel-Haenszel meta-analyses of all available
case-control data, including those published by other groups, showed
that these three markers were highly significant (rs597980: P=0.0057
(2,025 cases and 1,597 controls), rs6908425: P=1.57 x 10(-5) (3,206
cases and 4,529 controls), and rs3789604: P=3.45 x 10(-5) (2,823 cases
and 4,066 controls)). These data increase the likelihood that ADAM33,
CDKAL1, and PTPN22 are true psoriasis-risk genes.Journal of
Investigative Dermatology advance online publication, 16 October 2008;
doi:10.1038/jid.2008.297.
PMID: 18923449
--------------------
Ctla-4 in the P NG: (56 hits)
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=ctla-4&start=0&scoring=d&
CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic
tolerance.
Friedline RH, Brown DS, Nguyen H, Kornfeld H, Lee J, Zhang Y, Appleby
M, Der SD, Kang J, Chambers CA.
Department of Pathology, 2 Department of Medicine, Graduate Program in
Immunology and Virology, University of Massachusetts Medical School,
Worcester, MA 01655.
Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in
negatively regulating T cell responses and has also been implicated in
the development and function of natural ___FOXP3(+)___ regulatory T
cells. CTLA-4-deficient mice develop fatal, early onset
lymphoproliferative disease. However, chimeric mice containing both
CTLA-4-deficient and -sufficient bone marrow (BM)-derived cells do not
develop disease, indicating that CTLA-4 can act in trans to maintain T
cell self-tolerance. Using genetically mixed blastocyst and BM
chimaeras as well as in vivo T cell transfer systems, we demonstrate
that in vivo regulation of Ctla4(-/-) T cells in trans by CTLA-4-
sufficient T cells is a reversible process that requires the
persistent presence of FOXP3(+) regulatory T cells with a diverse TCR
repertoire. Based on gene expression studies, the regulatory T cells
do not appear to act directly on T cells, suggesting they may instead
modulate the stimulatory activities of antigen-presenting cells. These
results demonstrate that CTLA-4 is absolutely required for FOXP3(+)
regulatory T cell function in vivo.
PMID: 19188497
So with weak CTLA-4 all YOU really needs is good old bone marrow.
Can we eat it in the diet?
Give me five lbs. of bone marrow today, Mister Butcher.
I'm famished and flaring like John Updike today.
OK, Mister Psor Head coming right up....
The cure for not enough CTLA-4
What other conditions can BENEFIT?
Try HIV/AiDs
http://en.wikipedia.org/wiki/CTLA-4
[...]
Clinical significance
Mutations in this gene have been associated with insulin-dependent
diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, celiac
disease, systemic lupus erythematosus, thyroid-associated orbitopathy,
and other autoimmune diseases.
The comparatively higher binding affinity of CTLA4 has made it a
potential therapy for autoimmune diseases. It plays a role in the
initial immune response to and infection of immune cells by HIV, along
with the CD-1 pathway and others. Fusion proteins of CTLA4 and
antibodies (CTLA4-Ig) have been used in clinical trials for rheumatoid
arthritis.[4] The fusion protein CTLA4-Ig is commercially available as
Orencia (abatacept). A second generation form of CTLA4-Ig known as
belatacept is currently being tested in trials. Both of these
compounds are expected to find wide use in organ transplantation.
Conversely, there is increasing interest in the possible therapeutic
benefits of blocking CTLA4 (using antibodies against CTLA such as
Ipilimumab) as a means of inhibiting immune system tolerance to
tumours and thereby providing a potentially useful immunotherapy
strategy for patients with cancer.
Polymorphisms of the CTLA-4 gene are associated with autoimmune
diseases such as autoimmune thyroid disease and multiple sclerosis,
though this association is often weak. In Systemic Lupus Erythematosus
(SLE), the splice variant sCTLA-4 is found to be aberrantly produced
and found in the serum of patients with active SLE.
------------------------
CTLA-4 is a drug of sorts already:
http://en.wikipedia.org/wiki/Abatacept
Abatacept (marketed as Orencia) is a fusion protein composed of an
immunoglobulin fused to the extracellular domain of CTLA-4, a molecule
capable of binding B7. Abatacept is a selective costimulation
modulator as it inhibits the costimulation of T cells. It was
developed by Bristol-Myers-Squibb and is licensed in the United States
for the treatment of rheumatoid arthritis in the case of inadequate
response to anti-TNFα therapy.
<sniP>
http://www.emaxhealth.com/2/23/28695/saving-insulin-producing-cells.html
[...]
In autoimmune disorders, certain triggers in the immune system are
overactive and can cause the immune system to become destructive.
Doctors now know this is one of the mechanisms involved in the
destruction of insulin-producing cells (beta cells) in type 1
diabetes.
Abatacept, or CTLA-4 immunoglobulin (Ig), is already approved to quell
the autoimmune disorder rheumatoid arthritis in children. CTLA4-Ig
binds to a crucial trigger in the T cells of the immune system. The
hope is by continually tying up the triggers through regular infusions
of Abatacept, the immune system will be quieted and insulin-producing
beta cells will be spared.
"If you can preserve some of the indigenous production of insulin, it
is much easier to control blood sugar levels and prevent some of the
long-term and devastating effects of the disease than if you try to
control blood sugars in a completely artificial manner,"
<sniP>
=====================================
randall
JRStern
wrote:
>CTLA-4 is a drug of sorts already:
>
>http://en.wikipedia.org/wiki/Abatacept
>
>Abatacept (marketed as Orencia) is a fusion protein composed of an
>immunoglobulin fused to the extracellular domain of CTLA-4, a molecule
>capable of binding B7. Abatacept is a selective costimulation
>modulator as it inhibits the costimulation of T cells. It was
>developed by Bristol-Myers-Squibb and is licensed in the United States
>for the treatment of rheumatoid arthritis in the case of inadequate
>response to anti-TNFá therapy.
So why should it not be used in combination with TNF blockers?
J.
randall
> On Thu, 5 Feb 2009 21:17:29 -0800 (PST), randall <ranhu...@aol.com>
J,
I would suspect off label usage of cept's and mAb's may push the
Practicality envelope?
http://en.wikipedia.org/wiki/Off-label_use
And why raise your rates?
http://en.wikipedia.org/wiki/Malpractice_insurance
Not exactly a sertraline situation, if you get my drift. Still
even that could prompt a lawsuit with much less at risk?
I otoh would approve of a low dosage trial after a review of the
caveats.
Then again that's just me.
And low dose monkey business may cut two ways?
http://en.wikipedia.org/wiki/Pragmatism
randall...