Endocrine-Immune Mechanisms
manfred
The End of AIDS. Part One
This essay is reposted from our subscription blog in the public
interest.
The following article, published in the 1994 edition of Discover
Magazine, changed my life. I am an immunologist whose primary research
interest is the effect of glucosteroids (hydrocortisone,
dexamethasone, prednisone) on the immune system. After reading this
article, I began to quietly cry. Finally, I knew what was driving the
terminal phase of AIDS.
The article speaks for itself.
http://discovermagazine.com/1994/jun/adeadlymasquerad387
This woman was two days, max, away from dying of advanced AIDS. The
physicians gave her a hormone replacement dose, probably of
prednisone, and she walked out of the hospital three days later. In
one month she had gained 25 pounds. Six months later she remained
healthy and was back at work.
A hormone replacement dose is a small dose given to people who show
signs of adrenal insufficiency. A pharmacological dose is used to
treat serious inflammatory diseases. However, these high doses can
only be taken for a short period of time.
A physician at the University of Pittsburgh has argued for years that
a hormone replacement dose of glucosteroids can largely prevent shock
and death. A pharmacological dose makes the situation worse, because
the body senses the high concentration of hormone and blocks its
ability to bind the glucosteroid receptor. This is a normal feedback
response. This physician has been attacked for years by the medical
whores who are paid consultants for the pharmaceutical industry. They
want to sell expensive drugs to treat shock.
The following study shows that low glucosteroid doses inhibited
inflammation and organ failure in shock, while high doses did
nothing.
Shock basically refers to vascular collapse. When your blood pressure
drops too low, you die. Inflammatory hormones such as TNF, tumor
necrosis factor, are responsible for shock and death. Low doses of
glucosteroids inhibit the synthesis of TNF, but high doses do not.
In the next essay, I will present current evidence that TNF, its
receptors and other death hormones such as FAS are responsible for the
progression from HIV infection to actual AIDS. This inflammatory
response can be controlled or corrected by low dose glucosteroid
therapy and/or zinc sulfate supplementation. I know it sounds too good
to be true, but it is true.
Ms Kaye walked out of hospital because the low dose glucosteroid dose
she was given terminated the inflammatory response that was killing
her.
I gave a short talk over ten years ago to some AIDS doctors from UCSF
in San Francisco. It was in the evening and everyone was tired and
hungry. When I mentioned that low dose glucosteroid therapy could
block the terminal phase of AIDS by inhibiting the inflammatory
hormones driving the disease, no one responded. Except one woman
physician who was listening intensively. She gave prednisone to an
AIDS patients for some inflammatory problem and he disappeared. When
she asked one of his friends about his wheareabouts, she was told that
he was "off climbing mountains somewhere".
Touche.
Stay tuned...
Grouppe Kurosawa, Medicine in the Public Interest
manfred
This essay is reposted in from our subscription blog in the public
interest.
In part one of this series, I presented evidence that low doses of
glucosteroids can inhibit inflammatory responses on a long term basis,
while high pharmacological doses can only do so temporarily.
Acute, in contrast to chronic, inflammatory responses are absolutely
necessary to activate the immune system against pathogens. Since
glucosteroid concentrations also increase during stress, the body must
protect itself from an inappropriate glucosteroid mediated
immunosuppression.
There are two glucosteroid cellular receptors. The alpha receptor
activates glucosteroid controlled genes, while the beta receptor
blocks glucosteroid signaling. Inflammatory hormones, such as TNF,
induce resistance to glucosteroids by activating the beta receptor.
On the other hand, the synthesis and release of TNF and other
inflammatory mediators, primarily released from tissue macrophages, is
inhibited by the glucosteroid inhibition of NF-kappaB and other
signaling pathways.
It is obvious that glucosteroids and TNF have a crosstalk relationship
in modulating each other's actions in the body.
It is important to understand that an HIV infection is not AIDS. AIDS
refers to the final terminal phase of the disease. Many people live
with serious HIV infections for many years without ever developing
AIDS.
Twenty years ago, a Japanese group published a review article
suggesting that AIDS was a TNF driven disease. Today, scientists are
finally beginning to take this suggestion seriously.
Last year a review article was published entitled "Is HIV infection a
TNF receptor signaling-driven disease?"
The answer appears to be yes.
The viral protein NEF and TNF both promote the synthesis of HIV in
viral reservoirs such as monocytes and macrophages. The viral membrane
protein gp120, binding the CD4/chemokine receptors, increases further
TNF synthesis, which promotes additonal viral synthesis. This is
called a feed forward cycle.
If this cycle proceeds unabated, the final phase of HIV infections,
AIDS, will eventually develop.
Lets consider the evidence.
The membrane receptors for FAS and TNF, over expressed on macrophages,
and their ligands are well known to be able to kill normal CD4 T
cells. This is a characteristic feature of HIV infections.
It is VERY clear that viral proteins can induce the synthesis of all
three death receptors (TNF, FAS and TRAIL) in monocytes/macrophages.
The excessive expression of these receptors and their activators on
monocytes drives the progression of HIV infections into AIDS by
causing additional inflammation while simultaneously killing non-
infected CD4 T cells.
It is also very clear that the presence of TNF and soluble forms of
its receptors parallels the severity of HIV infection and the
progression towards AIDS by chronic immune activation. Again, chronic
immune activation is characteristic of HIV infections.
As the level of TNF and other pro-inflammatory mediators increase in
HIV infections, glucosteroid sensitivity will decrease. As in the case
of Ms Kaye, hydrocortisone levels in the blood may be normal but the
body has become resistant to the hormone. As far as I am concerned,
this is the fundamental "trigger" that initiates progression towards
AIDS.
Glucosteroids maintain the integrity of the body. Symptoms of
glucosteroid insufficiency include muscle weakness, anorexia,
diarrhea, mental confusion, abdominal pain, weight loss and extreme
susceptibility to infections. Every one of these symptoms is
associated with AIDS.
As foolish as this sounds, I believe that even advanced AIDS can be
reversed. This doesn't mean that the HIV virus is going away. It will
never completely go away. But people can live with the HIV virus IF
and only IF the progession towards AIDS can be blocked. And it can.
First and foremost, hormone replacement doses of glucosteroids, such
as methylprednisolone, should be given. This is critical in order to
inhibit the synthesis of pro-inflammatory hormones and restore
homeostatis in the body.
Second, a soluble form of zinc, zinc sulfate, should be given. Zinc is
extremely anti-inflammatory and will downregulate the expression of
the TNF and FAS membrane receptors. Zinc is also a powerful activator
of the entire immune system via its ability to control the activity of
a host of proteins that contain "zinc fingers".
Third, oxidative stress promotes the synthesis of TNF, etc. The
glutathione mimic n-acetylcysteine should be used to reduce oxidative
stress.
I will be discussing the role of zinc in controlling HIV infections in
the next essay.
manfred
read:
An effective veterinary model may offer therapuetic promise for human
conditions: cortisol and thyroid hormones
JXStern
I don't quite know what to say. This would explain how someone with
AIDS could still suffer from psoriasis - excess TNF. Can a simple
blood test measure TNF levels?
Would Enbrel possibly help with AIDS - if anything beyond a little
prednisone is even needed? I'm sure Amgen would be happy if it did!
J.
manfred
> Manfred,
>
> I don't quite know what to say. This would explain how someone with
> AIDS could still suffer from psoriasis - excess TNF. Can a simple
> blood test measure TNF levels?
>
> Would Enbrel possibly help with AIDS - if anything beyond a little
> prednisone is even needed? I'm sure Amgen would be happy if it did!
>
> J.
Just so happens, this article just showed up:
http://www.sciencedaily.com/releases/2008/07/080717193027.htm
ScienceDaily (July 17, 2008) — Drugs that have helped treat millions
of rheumatoid arthritis sufferers may hold the key to many more
medical conditions, including atherosclerosis -- a leading cause of
heart disease -- says the researcher who jointly invented and
developed them.
Professor Marc Feldmann will tell scientists attending the 2008
Congress of European Pharmacological Societies (EPHAR) -- hosted by
the British Pharmacological Society -- that drugs he and colleagues
helped develop have already proved successful against other autoimmune
diseases.
The drugs target proteins called cytokines, which are protein
messaging molecules released by immune cells to alert the immune and
other systems that the body is under attack from a pathogen and to
initiate a protective counter-response against the infection.
"In autoimmune diseases, such as arthritis, we discovered that
cytokines are over-produced causing the immune system to fight itself,
resulting in inflammation and tissue destruction," said Professor
Feldmann, from Imperial College London, who is speaking at the EPHAR
2008 conference at The University of Manchester the week of July 18.
"We further found that by blocking just one cytokine -- Tumor Necrosis
Factor (TNF) alpha -- we were able to block all the cytokines involved
in the inflammation, with remarkable clinical results."
The team's research led to the development of three anti-TNF alpha
drugs -- infliximab, etanercept and adalimumab -- which have had a
dramatic effect on the symptoms of rheumatoid arthritis patients,
protecting the joints from further deterioration in the vast majority
of cases.
Blocking TNF alpha has had further success in treating several more
chronic inflammatory conditions, including Crohn's disease, psoriasis,
psoriatic arthritis, ankylosing spondylitis and ulcerative colitis.
But Professor Feldmann, Head of the Kennedy Institute of Rheumatology,
believes similar drugs have the potential to treat many other medical
conditions and will also tell the conference about his work on
atherosclerosis, a disease affecting the arterial blood vessels,
commonly known as 'hardening of the arteries', with his colleague Dr
Claudia Monaco.
Their work, which has won a number of awards, has resulted in the
emergence of a new branch of medicine -- anti-cytokine therapy -- and
research elsewhere has showed promise in yet more conditions,
including the potentially fatal acute alcoholic hepatitis.
Professor Feldmann said: "During the conference I will be discussing
the potential therapeutic targets in tissue affected by
atherosclerosis, which is caused by a chronic inflammatory response in
the walls of the arteries, in large part, caused by an excessive
immune response to cholesterol.
"I will also discuss whether it is possible -- even likely -- that
cytokines play a critical role in all diseases involving multiple
biological processes, thus providing therapeutic targets for all unmet
medical needs."
randall
> On Jul 18, 8:17 pm, JXStern <JXSternChange...@gte.net> wrote:
>
> > Manfred,
>
> > I don't quite know what to say. This would explain how someone with
> > AIDS could still suffer from psoriasis - excess TNF. Can a simple
> > blood test measure TNF levels?
>
> > Would Enbrel possibly help with AIDS - if anything beyond a little
> > prednisone is even needed? I'm sure Amgen would be happy if it did!
>
> > J.
>
> Just so happens, this article just showed up:
>
> http://www.sciencedaily.com/releases/2008/07/080717193027.htm
>
> ScienceDaily (July 17, 2008) — Drugs that have helped treat millions
> of rheumatoid arthritis sufferers may hold the key to many more
> medical conditions, including atherosclerosis -- a leading cause of
> heart disease -- says the researcher who jointly invented and
> developed them.
>
We should give Marc a HERO designation for his
ancient work on TNF?. LOL
http://www.hydrabiosciences.com/images/pic_prog_biopic_mfeldmann.jpg
Thanks for posting it Manfred.
Shall we add in more recent relevant links?
http://www.sciencedaily.com/releases/2008/07/080717134612.htm
How Cells Die Determines Whether Immune System Mounts Response
ScienceDaily (July 17, 2008) — Every moment we live, cells in our
bodies are dying. One type of cell death activates an immune response
while another type doesn't. Now researchers at Washington University
School of Medicine in St. Louis and St. Jude's Children's Research
Hospital in Memphis have figured out how some dying cells signal the
immune system. They say the finding eventually could have important
implications in the treatment of autoimmune diseases and cancer.
The researchers have found that a molecule, called high mobility group
box-1 protein (HMGB1), which cells release when they die, seems to
determine whether the immune system is alerted. But what happens to
HMGB1 after it's made and whether the immune system ever gets the
signal depends on how the cell dies.
"Cells die in two general ways: apoptosis, or programmed cell death,
and necrosis, which results from injuries and infections," says Thomas
A. Ferguson, Ph.D., a senior investigator on the study and professor
of ophthalmology and visual sciences at Washington University. "In
general, we don't want the immune system to respond to apoptosis, but
we do want an immune response following necrosis because necrotic
death can be a sign of infection. Necrotic cells release components to
stimulate the immune system, and one is the HMGB1molecule."
Apoptosis normally is a healthy process that occurs all the time, so
it shouldn't activate an immune response, according to co-senior
investigator Douglas R. Green, Ph.D. the Peter C. Doherty Endowed
Professor of Immunology at St. Jude's.
"Apoptosis is an orderly death that occurs during development and
tissue turnover, and it's an important process that allows us to
replace old, worn-out cells with fresh, new ones," says Green. "We
don't need the immune system paying attention as our cells die through
apoptosis. When it does react to apoptosis, we can develop
autoimmunity, as in diabetes, arthritis and other autoimmune diseases
in which the immune system will attack the 'self.'"
The researchers say scientists had believed that necrotic cells
released HMGB1 whereas apoptotic cells did not. The problem is that
experiments in Ferguson's laboratory and elsewhere have found that in
some cases, apoptotic cells also release the HMGB1 protein.
"Whether they were apoptotic or necrotic, we found that dying cells
were releasing the protein, but the cells that were undergoing
apoptosis still weren't stimulating the immune system," Ferguson says.
"So our question was, 'If the molecule being released is the same, why
is it stimulating the immune system in one situation and not in
another?'"
Further experiments showed that when they die, apoptotic cells also
produce free radicals, and those reactive oxygen free radicals modify
HMGB1 to prevent it from stimulating the immune system. In necrosis,
no free radicals are produced, so HMGB1 both signals and stimulates an
immune system response.
Free radicals have been thought to be bad for us, but in the case of
cell death, they have the beneficial effect of preventing the immune
system from attacking and destroying healthy cells. The finding may
have important implications, both for some autoimmune processes and
for cancer treatment. The researchers believe it may be possible to
use HMGB1 to stoke up the immune system in response to cancer.
"Sometimes tumors can stimulate an immune response," says Green. "This
study suggests that when we give chemotherapy, whether dying tumor
cells make these reactive oxygen free radicals could be very important
because if we can mount an immune response to the tumor, chemotherapy
might be more successful, and we may be able to keep the cancer from
coming back."
The inverse would be true in autoimmune diseases.
"If we could oxidize the danger signals coming from dying cells in a
way similar to how apoptotic cells release free radicals to modify
HMGB1, maybe autoimmunity could be down-regulated," Ferguson says.
This research was supported by the National Eye Institute and the
National Institute of Allergy and Infectious Diseases of the
Institutes of Health, the Foundation Fighting Blindness and Research
to Prevent Blindness.
-------
Let's make this a WIKI moment:
http://en.wikipedia.org/wiki/HMGB1
High-mobility group box 1, also known as HMGB1 and Amphoterin, is a
human gene and protein that belongs to high mobility group.
http://en.wikipedia.org/wiki/High_mobility_group
[...]
Function
HMG proteins are thought to play a significant role in various human
disorders. Disruptions and rearrangements in the genes coding for some
of the HMG proteins are associated with some common benign tumors.
Antibodies to HMG proteins are found in patients suffering from
autoimmune diseases. The SRY gene on the Y Chromosome, responsible for
male sexual differentiation, contains an HMG-Box domain. Recently, a
member of the HMG family of proteins, HMGB1, has been shown to have an
extracellular activity as a chemokine, attracting neutrophils and
mononuclear inflammatory cells to the infected liver[1].
-----------------
The rube goldbergian autoinflammatory machine just keePs getting
BIGGER and BIGGER.
How BIG?
----------------------------------
http://www.medicalnewstoday.com/articles/115161.php
Scientists Identify A New Molecular Brake That Can Curb Excessive
Immune Activation
In new research published in the open access, peer-reviewed online
journal PLoS ONE, a team of scientists from NYU School of Medicine
report the identification of a molecule expressed on a special class
of T cells called regulatory T cells that appears to play a role in
allowing these cells to control immune responses.
The researchers speculate that identification of this novel molecule
as a modulator on regulatory T cells may help pave the way for new
approaches to suppress immune responses as a means to treat autoimmune
diseases, chronic inflammation during infections such as HIV, or for
preventing transplantation rejection.
The immune system is a highly organized and intricate network
consisting of nearly a dozen cell types whose primary function is to
protect the body from infectious organisms. To perform this function,
cells of the immune system are armed with powerful molecular "weapons"
that can kill or neutralize pathogens. However, as important is a
potent immune response in ridding the body of invasive pathogens, it
can also be a double-edged sword if not properly controlled, with the
potential for prolonged inflammatory responses to cause extensive
damage to "innocent bystander" host cells.
Two extensively studied cell types of the immune syste m, T and B
cells, naturally undergo a selection process during their development
that is intended to eliminate any cells that recognize self-antigens.
Such cells could otherwise have the potential to initiate autoimmune
responses, which are defined as immune cell attacks against normal
host tissues. The fact that autoimmune diseases are prevalent is
thought to reflect inherent imperfections in this selection process,
with some auto-reactive T and B cells managing to escape elimination.
Because immune responses have the potential to be harmful, there are
several built-in safety mechanisms that constantly regulate, with
exquisite sensitivity, the degree of response. A major mechanism that
ensures control of immune responses is mediated by a professional T
cell subset called regulatory T cells or Tregs. These cells are
specialized in suppressing the activation of other immune system
cells, especially T cells, thereby helping maintain a state of
tolerance to self-antigens.
Based on studies in humans as well as mice, genetic defects in Treg
cells have been shown to lead to massive autoimmune diseases and death
due to uncontrolled immune activation. Although several mechanisms
have been proposed, it still remains unclear how Tregs mediate their
suppressive function.
Now a team led by Dr. Derya Unutmaz at the New York University School
of Medicine has identified a molecule that is expressed on Tregs and
could mediate part of their potent sup pression of immune reactions.
The molecule, which is called GARP (or LRRC32), was previously
detected in other tissues including blood platelets, but no function
for the protein that it encodes had been defined.
Dr. Unutmaz's lab, using microarray analysis, found that GARP was one
of the few molecules highly expressed on activated Tregs compared to
other T cell subsets. They then genetically engineered conventional T
cells to express GARP and showed that these cells acquired partial
characteristics of suppression. In a reverse experiment, Dr. Unutmaz
and colleagues knocked down expression of GARP in genetically
reprogrammed human Tregs, which resulted in a corresponding reduction
in their capacity to inhibit T-cell activation.
If GARP is also shown to be an important regulator of immune response
in vivo, as suggested by cell culture experiments, it can be
potentially developed as a treatment approach against autoimmune
diseases or to prevent transplantation rejection. This can be
potentially achieved by enhancing the expression of GARP in either
Tregs or different cell types such as transplant tissue.
Alternatively, biological or small molecules as drugs with the
capability to mimic GARP signals may also be developed as
therapeutics.
While Tregs are critical in controlling harmful immune reactions,
there are possible scenarios in which over-regulation by these cells
may lead to insufficient response to pathogens or ineffective
vaccination. It is also conceivable that some tumor cells express GARP
to elude the immune system. Thus, in such cases blocking the function
of GARP could potentially amplify immune responses to infectious
diseases or cancers.
Dr. Unutmaz and colleagues are particularly excited that discovery of
this molecule as a novel immune suppressor enhances the toolbox
available to scientists to both explore and modulate the delicate
balance of immune system function.
Graduate student Rui Wang in Unutmaz lab was the lead author in the
characterization of GARP function. Additional authors who contributed
to this study were Qi Wan, Lina Kozhaya and Hodaka Fujii.
Funding: This study was supported by funding from National Institutes
of Health, National Institute of Allergy and Infectious Diseases grant
R01 AI065303 to Derya Unutmaz.
----------------
Unutmaz may have instant HERO status for the P'sters
http://pimm.files.wordpress.com/2007/01/photo.jpg
And for life extender's, a much larger crowd: Why a NUT for U?
aMAZing,
http://pimm.wordpress.com/2007/01/29/biosingularitys-derya-unutmaz-a-t-cell-expert-on-life-extension/
Biosingularity’s Derya Unutmaz: a T cell expert on life extension
----------------------------------------
FOXP3 oh YES.
http://www.ncbi.nlm.nih.gov/pubmed/18628982?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Identification of a regulatory T cell specific cell surface molecule
that mediates suppressive signals and induces Foxp3 expression.
Wang R, Wan Q, Kozhaya L, Fujii H, Unutmaz D.
Department of Microbiology, New York University School of Medicine,
New York, New York, United States of America.
Regulatory T (T(reg)) cells control immune activation and maintain
tolerance. How T(regs) mediate their suppressive function is unclear.
Here we identified a cell surface molecule, called GARP, (or LRRC32),
which within T cells is specifically expressed in T(regs) activated
through the T cell receptor (TCR). Ectopic expression of GARP in human
naïve T (T(N)) cells inhibited their proliferation and cytokine
secretion upon TCR activation. Remarkably, GARP over-expression in
T(N) cells induced expression of T(reg) master transcription factor
Foxp3 and endowed them with a partial suppressive function. The
extracellular but not the cytoplasmic region of GARP, was necessary
for these functions. Silencing Foxp3 in h uman T(reg) cells reduced
expression of GARP and attenuated their suppressive function. However,
GARP function was not affected when Foxp3 was downregulated in GARP-
overexpressing cells, while silencing GARP in Foxp3-overexpressing
cells reduced their suppressive activity. These findings reveal a
novel cell surface molecule-mediated regulatory mechanism, with
implications for modulating aberrant immune responses.
PMID: 18628982
=========================================================
Gosh this next one says foxp3 hatched Tregs are made in the mucosal
tissue.
How is cruiser gonna deal with that?
He does want to cure ALL disease. Will uwe give him the uridine links?
LOL
http://www.sciencedaily.com/releases/2008/07/080714155301.htm
Researchers Identify Immune Cells That Block Allergic Reactions
ScienceDaily (July 16, 2008) — When it comes to allergies, both the
problem and the solution are found within us. Our immune systems
respond to foreign substances with an arsenal of cells. Some are
programmed to "remember" invaders they've encountered in the past.
Normally, anything previously identified as harmless is allowed to
pass. Sometimes, however, the immune response goes awry, triggering an
allergic reaction.
Now, researchers at NYU Langone Medical Center have zeroed in on a
class of custom-made immune cells that block allergic reactions. These
regulatory T cells are manufactured according to instructions from a
gene called Foxp3 whenever we eat or inhale a potential allergen for
the first time, ensuring that the next time we encounter that
substance, we will not mount an allergic response.
"We don't become allergic to lots of things--we eat all kinds of
things, we breathe all kinds of things, and what prevents us from
developing allergies is that we make regulatory T cells, which
specifically recognize this allergen," says Maria A. Curotto de
Lafaille, Ph.D., research assistant professor of pathology at NYU
Langone Medical Center. "Every time we don't react to something or
don't become allergic, it's not because nothing is happening," Dr. de
Lafaille explains. "It's because something very important is
happening: We're making these cells,"
Mucosal tissue, which lines both the respiratory and digestive tracts,
has long been known as an effective barrier against allergens, which
are always protein molecules. The NYU research shows that
________Foxp3-directed regulatory T cells (Treg) are produced in the
mucosal tissue____ and remain there to prevent allergic reactions. New
ones are tailor-made every time an unknown protein is inhaled or
ingested. The inability to make Treg cells results in high
susceptibility to becoming allergic.
The NYU researchers induced allergic reactions in mice with a Foxp3
mutation that prevented formation of Treg cells. Exposure to the same
allergen--in this case egg protein--did not elicit an allergic
response in mice that were able to make Treg cells.
The formation of Foxp3-positive Treg cells occurs in response to
any0Apotential allergen, so the findings are applicable to a broad
range of allergic reactions and autoimmune diseases, says Dr. de
Lafaille. When people suffer from allergies, including life-
threatening ones such as asthma, something goes wrong in the process
by which Foxp3 signals Treg cell formation. The problem is not
necessarily a mutation in the Foxp3 gene, which is known to cause
severe autoimmune disease. Rather, something occurs, or fails to
occur, in the lungs or the gut that interferes with the production of
allergen-specific Treg cells.
The NYU researchers also determined that Treg cells control damage
from long-term inflammation. They found high concentrations of Treg
cells in inflamed lung tissue of mice without the Foxp3 defect. "The
question arose about what these cells are doing in the tissue--are
they beneficial or not?" Dr. de Lafaille says. It turns out that even
though the Treg cells did not prevent inflammation in an ongoing
allergic reaction, they kept it under control, ensuring it did not
worsen or spread to other areas of the body. "We think that over time
these regulatory T cells become more important than the inflammatory
cells and end up completely shutting off the inflammation. But it's
not overnight and it's not black and white," Dr. de Lafaille
emphasizes.
This finding provides a key to one of the most serious consequences of
asthma. In addition to breathing problems during an acute attack,
people with asthma have chronic inflammation, which can permanently
damage their lu ngs. If a means could be found to increase the number
of Treg cells in inflamed tissue, this might be prevented. Allergic
asthma, the most common and best-understood type, affects more than 10
million people in the US, many of them children. Acute asthma attacks
are responsible for nearly 4000 deaths in the United States each year.
Dr. de Lafaille and her colleagues have been investigating ways to
grow allergen-specific Treg cells in the lab and inject them into
people who cannot make their own. Her group published a paper in
Nature Medicine in February 2008 describing a method of making the
cells. "The big challenge is how to isolate the cells that will
recognize the right allergens that the person is allergic to," she
says. Another approach is to stimulate the body to manufacture the
cells itself, an area of ongoing research.
This work represents an important step in understanding the genetic
and cellular mechanisms underlying the allergic response, which may
lead to more effective therapies. Current treatment is aimed at
suppressing symptoms and reducing inflammation after an allergic
reaction has already occurred. Having identified the cell type that
must be present to prevent allergies, Dr. de Lafaille and her
colleagues are now looking for the glitch that blocks formation of
those cells.
The findings are reported in the July 18, 2008, issue of the journal
Immunity. The co-authors of the study include: Dr. de Lafaille, Nino
Kutchukhidze and Shiqian Shen, former postdoctoral stud ents in
pathology, Yi Ding, a graduate student in pathology, and Herman Yee,
M.D., Ph.D., associate professor of pathology, and Juan J. Lafaille,
Ph.D., associate professor of pathology and Medicine at NYU Langone
Medical Center.
The research was supported by grants from the National Institutes of
Health, the National Multiple Sclerosis Society, and the Sandler
Foundation.
========================================
Darn I forgot to read it....the BOX is confusing isn't it?
randall....been my experience...in general..
manfred
The End of AIDS. Part Three
This essay is reposted from our subscription blog in the public
interest.
It is estimated that 25% of the population of the world is deficient
in zinc. This deficiency is particularly prevalent in the elderly and
vegetarians. The highest dietary concentration of zinc is found in
meat.
Zinc plays many, many roles in the body by virtue of its ability to
control the activity of over 300 "zinc finger" proteins. These
proteins MUST bind zinc in order to be biologically active.
Many critically important zinc finger proteins are found in every cell
in the immune system. If zinc becomes even slightly depleted, the
immune response begins to fail. I cannot emphasize this point enough.
The following review articles provide all the necessary background
information. These articles can be read online.
The elderly suffer from a low grade inflammation that contributes to
chronic immune activation. They also suffer from mild zinc
deficiencies. When zinc supplements are provided, these defects are
corrected.
An excellent example of the importance of zinc in the immune response
is typified by the immune hormone thymulin. This hormone is found in
the thymus where it promotes the differentiation of immature T cells
into mature CD4 and CD8 T cells. Thymulin is a zinc dependent hormone.
When zinc concentrations become limiting, the CD4/CD8 ratio
decreases.
Zinc is also a powerful anti-oxidant by virtue of its ability to
increase the activity of enzymes such as catalase and superoxide
dismutase. When alcohol is chronically fed to mice, their livers over
express mRNA for TNF, its receptors, FAS ligand, and its receptors.
Zinc supplementation largely prevented the over expression of these
pro-inflammatory, pro-apoptotic immune hormones, thereby preventing
alcohol from causing cirrhosis.
Zinc is frequently diminished in HIV infected people. Low zinc is
associated with a low CD4 T cell count possibly due to the inhibition
of thymulin activity in the thymus gland.
Zinc deficiency is particularly common in IV drug users. These people
usually suffer from extreme malnutrition which naturally diminishes
zinc uptake. Vegetables contain very little zinc and "junk" or highly
processed foods contain almost none. This study confirms that zinc
deficiency is associated with declining CD4 T cell counts and reduced
survival.
Zinc supplementation increases the CD4 T cell count, and a reduced
incidence of opportunistic infections, such as candida and
pneumocystis carinii.
The maximum dose of zinc per day is 50 milligrams of elemental zinc.
This figure should not be exceeded.
randall
New players on the immune field.
http://www.genengnews.com/news/bnitem.aspx?name=38445556
Investigators Find that Mice without IL-21 Are Severely
Immunocompromised
GEN News Highlights
Our immune system depends on interleukin 21 (IL-21), according to a
team of scientists. They discovered that this molecule acts as a
growth factor for a subset of T cells called T follicular helper (TFH)
cells. The researchers say that without IL-21, the TFH cells could
neither develop nor survive.
“Without IL-21, we probably wouldn't be completely immunodeficient,
just severely compromised,” explains Cecile King, Ph.D., head of the
mucosal autoimmunity group at the Garvan Institute of Medical Research
in Sydney.
TFH cells have been identified to play a critical role in that they
communicate with and help activate B cells. These TFH cells act in
specialized areas within lymph organs, called germinal centers, where
B cells proliferate to form antibodies.
“We showed that if you take a mouse genetically deficient in IL-21 and
immunize it, you don't get TFH cells, and you don't get antibody
production,” reports Dr. King. “Conversely, if you put IL-21 receptor
sufficient, or normal, T cells into the same mouse,20where of course
the B cells remain abnormal, you recover the normal immune reaction.”
----------------------
Their abstract:
http://www.ncbi.nlm.nih.gov/pubmed/18602282?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
A Fundamental Role for Interleukin-21 in the Generation of T
Follicular Helper Cells.
Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C.
Department of Immunology, Garvan Institute of Medical Research, 384
Victoria Street, Darlinghurst, NSW 2010, Australia.
T cell help to B cells is a fundamental property of adaptive immunity,
yet only recently have many of the cellular and molecular mechanisms
of T cell help emerged. T follicular helper (Tfh) cells are the CD4(+)
T helper cells that provide cognate help to B cells for high-affinity
antibody production in germinal centers (GC). Tfh cells produce
interleukin-21 (IL-21), and we show that IL-21 was necessary for GC
formation. However, the central role of IL-21 in GC formation
reflected its20effects on Tfh cell generation rather than on B cells.
Expression of the inducible costimulator (ICOS) was necessary for
optimal production of IL-21, indicative of interplay between these two
Tfh cell-expressed molecules. Finally, we demonstrate that IL-21's
costimulatory capacity for T helper cell differentiation operated at
the level of the T cell receptor signalosome through Vav1, a sig
naling molecule that controls T cell helper function. This study
reveals a previously unappreciated role for Tfh cells in the formation
of the GC and isotype switching through a CD4(+) T cell-intrinsic
requirement for IL-21.
PMID: 18602282
Manfred you should be haPPy to see this next one. You started a VDr
and histone deacetylase thread not to long ago. How about a cocktail
with VD3, melatonin and Histone deacetylase?
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=histone+deacetylase+&qt_g=Search+this+group
http://www.ncbi.nlm.nih.gov/pubmed/18617638?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Human CD25highFoxp3pos regulatory T-cells differentiate into IL-17
producing cells.
Koenen HJ, Smeets RL, Vink PM, Rijssen EV, Boots AM, Joosten I.
Dept. of Blood transfusion and Transplantati on Immunology, Radboud
University Nijmegen Medical Centre, Nijmegen, Netherlands.
The effector T-cell lineage shows great plasticity. Th17 cells are
acknowledged to be instrumental in the response against microbial
infection, but are also associated with autoimmune inflammatory
processes. Here, we report that human regulatory T-cells
(CD4(pos)CD25(high)Foxp3(pos)CD127(neg)CD27(pos)) can differentiate
into IL-17 producing cells, when stimulated by allogeneic antigen
presenting cells, especially monocytes, in the presence of rhIL-2/
rhIL-15. These Treg derived IL-17 producing cells showed high
expression of the Th17-related transcription factor RORgammat and were
positively identified by CCR6 expression. This differentiation process
was enhanced by exogenous IL-1beta, IL-23, IL-21, while IL-6 or
TGFbeta did not affect the emergence of IL-17 producing cells. The
addition of IL-1 receptor antagonist (IL-1Ra), but not anti-IL-23
antibody, reduced IL-17 producing cell numbers. When an histone
deacetylase (HDAC) inhibitor Trichostatin A (TSA) was evaluated, we
found a profound negative effect on the emergence of IL-17 producing
cel ls from Treg, implying that Treg differentiation into IL-17
producing cells depends on histone/protein deacetylase activity. Thus,
the data suggest that epigenetic modification underlies the phenomenon
of Treg plasticity here described.
PMID: 18617638
------------------
Finally, a KICKER for starting to fully understand immunity. This
clears up
the rube goldbergian skew mechanism somewhat.
Now, can we translate that clearness to our skin?
http://www.ncbi.nlm.nih.gov/pubmed/18599325?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Generation of T Follicular Helper Cells Is Mediated by Interleukin-21
but Independent of T Helper 1, 2, or 17 Cell Lineages.
Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, Wang YH,
Watowich SS, Jetten AM, Tian Q, Dong C.
Department of Immunology, University of Texas M.D. Anderson Cancer
Center and Graduate School of Biomedical Sciences, Houston, TX 77030,
USA.
After activation, CD4(+) helper T (Th) cells differentiate into
distinct effector subsets. Although chemokine (C-X-C motif) receptor=0
A5-expressing T follicular helper (Tfh) cells are important in humoral
immunity, their developmental regulation is unclear. Here we show that
Tfh cells had a distinct gene expression profile and developed in vivo
independently of the Th1 or Th2 cell lineages. Tfh cell generation was
regulated by ICOS ligand (ICOSL) expressed on B cells and was
dependent on interleukin-21 (IL-21), IL-6, and signal transducer and
activator of transcription 3 (STAT3). However, unlike Th17 cells,
differentiation of Tfh cells did not require transforming growth
factor beta (TGF-beta) or Th17-specific orphan nuclear receptors
RORalpha and RORgamma in vivo. Finally, naive T cells activated in
vitro in the presence of IL-21 but not TGF-beta signaling
preferentially acquired Tfh g ene expression and promoted germinal-
center reactions in vivo. This study thus demonstrates that Tfh is a
distinct Th cell lineage.
PMID: 18599325
============================
http://www.ncbi.nlm.nih.gov/pubmed/18549797?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The biology of intestinal immunoglobulin A responses.
Cerutti A, Rescigno M.
Department of Pathology and Laboratory Medicine, Weill Medical College
of Cornell University, and Weill Graduate School of Medical Sciences
of Cornell University, 1300 York Aven ue, New York, NY 10065, USA.
acer...@med.cornell.edu
The gut mucosa is exposed to a large community of commensal bacteria
that are required for the processing of nutrients and the education of
the local immune system. Conversely, the gut immune system generates
innate and adaptive responses that shape the composition of the local
microbiota. One striking feature of intestinal adaptive immunity is
its ability to generate massive amounts of noninflammatory
immunoglobulin A (IgA) antibodies through multiple follicular and
extrafollicular pathways that operate in the presence or absence of
cognate T-B cell interactions. Here we discuss the role of intestinal
IgA in host-commensal mutualism, immune protection, and tolerance and
summarize recent advances on the role of innate immune cells in
intestinal IgA production.
PMID: 18549797
Food can be a drug for the brain. Eat it uP.
http://www.ncbi.nlm.nih.gov/pubmed/18620024?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Docosahexaenoic acid dietary supplementation enhances the effects of
exercise on synaptic plasticity and cognition.
Wu A, Ying Z, Gomez-Pinilla F.
Department of Physiological Science, University of California at Los
Angeles, 621 Charles E. Young Drive, Los Angeles, CA 90095, USA.
Omega-3 fatty acids (i.e. docosahexaenoic acid; DHA), similar to
exercise, improve cognitive function, promote neuroplasticity, and
protect against neurological lesion. In this study, we investigated a
possible synergistic action between DHA dietary supplementation and
voluntary exercise on modulating synaptic plasticity and cognition.
Rats received DHA dietary supplementation (1.25% DHA) with or without
voluntary exercise for 12 days. We found that the DHA-enriched diet
significantly increased spatial learning ability, and these effects
were enhanced by exercise. The DHA-enriched diet increased levels of
pro-brain-derived neurotrophic factor (BDNF) and mature BDNF, whereas
the additional application of exercise boosted the levels of both.
Furthermore, the levels of the activated forms of CREB and synapsin I
were incremented by the DHA-enriched diet with greater elevation by
the concurrent application of exercise. While the DHA diet reduced
hippocampal oxidized protein levels, a combination of a DHA diet and
exercise resulted in a greater reduction rate. The levels of activated
forms of hippocampal Akt and CaMKII were increased by the DHA-enriched
diet, and with even greater elevation by a combination of diet and
exercise. Akt and CaMKII signaling are crucial step by which BDNF
exerts its action on synaptic plasticity and learning and memory.
These results indicate that the DHA diet enhanced the effects of
exercise on cognition and BDNF-related synaptic plasticity, a capacity
that may be used to promote mental health and reduce risk of
neurological disorders.
PMID: 18620024
Gut Intuition?
http://www.ncbi.nlm.nih.gov/pubmed/18568016?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Brain foods: the effects of nutrients on brain function.
Gómez-Pinilla F.
Department of Neurosurgery, University of California at Los Angeles
School of Medicine, Los Angeles 90095, California, USA.
fgom...@mednet.ucla.edu
It has long been suspected that the relative abundance of specific
nutrients can affect cognitive processes and emotions. Newly described
influences of dietary factors on neuronal function and synaptic
plasticity have revealed some of the vital mechanisms that are
responsible for the action of diet on brain health and mental
function. Several gut hormones that can enter the brain, or that are
produced in the brain itself, influence cognitive ability. In
addition, well-established regulators of synaptic plasticity, such as
brain-derived neurotrophic factor, can function as metabolic
modulators, responding to peripheral signals such as food intake.
Understanding the molecular basis of the effects of food on cognition
will help us to determine how best to manipulate diet in order to
increase the resistance of neurons to insults and promote mental
fitness.
PMID: 18568016
------------------------
randall
ravi
> On Jul 18, 9:30 pm, manfred <manfre...@lycos.com> wrote:
>
>
>
>
>
> > On Jul 18, 8:17 pm, JXStern <JXSternChange...@gte.net> wrote:
>
> > > Manfred,
>
> > > I don't quite know what to say. This would explain how someone with
> > > AIDS could still suffer from psoriasis - excess TNF. Can a simple
> > > blood test measure TNF levels?
>
> > > Would Enbrel possibly help with AIDS - if anything beyond a little
> > > prednisone is even needed? I'm sure Amgen would be happy if it did!
>
> > > J.
>
> > Just so happens, this article just showed up:
>
> >http://www.sciencedaily.com/releases/2008/07/080717193027.htm
>
> > ScienceDaily (July 17, 2008) — Drugs that have helped treat millions
> > medical conditions, including atherosclerosis -- a leading cause of
> > heart disease -- says the researcher who jointly invented and
> > developed them.
>
> > Professor Marc Feldmann <sniP>
>
> We should give Marc a HERO designation for his
>
> read more »- Hide quoted text -
>
> - Show quoted text -
I am Ravi chandren from India.I am not a Docter and I don't know
proper English.In 12 years my research,Psoriasis,arthritis,Psoriatic
arthritis,vericose vein,Migrine and some types of Asthma are linked
with only one separate viruse or bacteria.Because only one herbal
treatment complete cured all these diseases.please visit www.curewithherbs.info