Immune Potpourri
randall
The GREAT Secret to Hormones and STRESS & GENETICs.
http://www.medicalnewstoday.com/articles/115183.php
Identification Of Mechanism Behind Mind-Body Connection Explains How
Chronic Emotional Stress Ages The Immune System
Every cell contains a tiny clock called a telomere, which shortens
each time the cell divides. Short telomeres are linked to a range of
human diseases, including HIV, osteoporosis, heart disease and aging.
Previous studies show that an enzyme within the cell, called
telomerase, keeps immune cells young by preserving their telomere
length and ability to continue dividing.
FINDINGS:
UCLA scientists found that the stress hormone cortisol suppresses
immune cells' ability to activate their telomerase. This may explain
why the cells of persons under chronic stress have shorter telomeres.
IMPACT:
The study reveals how stress makes people more susceptible to illness.
The findings also suggest a potential drug target for preventing
damage to the immune systems of persons who are under long-term
stress, such as caregivers to chronically ill family members, as well
as astronauts, soldiers, air traffic controllers and people who drive
long daily commutes.
=========================
Galderma Announces Approval For Differin Gel 0.1 Percent In Japan
http://www.medicalnewstoday.com/articles/115472.php
Savvy Use Of Sunscreen Reduces The Risk Of Getting Too Much Summer Sun
http://www.medicalnewstoday.com/articles/114950.php
The usage of etanercept to keep your mental wits about you when
you have alzheimers.
http://www.medicalnewstoday.com/articles/115627.php
Life extension site has the tnf blocker trifecta today:
http://www.lef.org/newsletter/2008/0722_Wonder-Drugs-May-Treat-Many-Conditions.htm?source=eNewsLetter2008Wk30-1&key=Article&l=0#article
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http://www.medicalnewstoday.com/articles/115257.php
Oxytocin breast feeding hormones linkages
[...]
Prof. Jianfeng Feng, co-author of the study, said, "For thirty years
we have known that these pulses arise because, during suckling,
oxytocin neurons fire together in dramatic synchronized bursts, but
exactly how these bursts come about has puzzled us so far." However,
this latest research by a group of experimental and theoretical
neuroscientists has led to a breakthrough in understanding oxytocin.
The researchers were able to demonstrate that during suckling,
oxytocin cells being releasing the hormone not only from their nerve
endings, but also from their dendrites - part of the neuron that is
usually associated with receiving information, not transmitting it.
Dendrites usually construct a weak neural network, but the scientists
have determined that oxytocin coming from the dendrites enhances the
communication between neurons and begins a positive-feedback process
on activity. This ultimately leads to and manages the observed "swarm"
of oxytocin - massively intense and recurring bursts of release.
"Many neurons make peptides that act as messengers within the brain,
and many of these are also released from dendrites, so this model may
reflect a common pattern-generating mechanism in the brain," conclude
the authors.
<sniP>
===================================
http://www.sciencedaily.com/releases/2008/07/080714172151.htm
or:
http://www.medicalnewstoday.com/articles/115056.php
Shedding Light On How Intracellular Pathogens Trigger The Immune
System
Disease-causing microbes like the food-borne bacterium Listeria
monocytogenes specialize in invading and replicating inside their
animal hosts' own cells, making them particularly tricky to defeat.
Now, a new study led by biologists at the University of California,
Berkeley, has identified a molecular alarm system in which the
intracellular pathogen sends out signals that kick the immune response
into gear.
The findings, to be reported the week of July 14 in the journal
Proceedings of the National Academy of Sciences, shed light on how the
cells recognize and destroy the pathogenic bugs living within their
walls, and may even provide new targets for the research and
development of new vaccines and drugs.
The pathogens' signals come from multidrug resistance transporters
(MDRs), membrane proteins used by a wide variety of organisms to pump
out a broad range of molecules from their systems. Similar
transporters have been linked in other studies to the development of
resistance to multiple drugs that are toxic to the pathogen. This
study is the first to connect multidrug resistance transporters
directly to stimulation of the immune system, although the nature of
the molecules that the bacteria are spitting out remains unclear.
"For the MDRs to work, the pathogen needs to be alive, so this study
actually shows how the immune system can tell the difference between a
living, harmful microbe and one that is dead," said the study's
principal investigator, Daniel Portnoy, a UC Berkeley professor with
joint appointments in the Department of Molecular and Cell Biology and
the School of Public Health, and associate director of the Berkeley
Center for Emerging and Neglected Diseases. "This is important because
you don't want the immune system to overreact to non-threats, which is
what happens in autoimmune disorders such as inflammatory bowel
disease, asthma and multiple sclerosis."
The Listeria bacterium makes headlines when it contaminates deli
meats, raw cheeses, cole slaw and other foods. According to the
Centers for Disease Control and Prevention, Listeria causes some 2,500
infections and 500 deaths each year, and at greatest risk are people
who have weakened immune systems or are pregnant.
The bacteria first trick immune cells into swallowing them, where they
become encased in bubbles called vacuoles. The bacteria become
dangerous when they break out of these bubbles into the cells'
internal fluid, or cytosol, to multiply and spread the infection. The
role of MDRs is not clearly known, but the results of this study
plainly show that one particular MDR transporter is necessary for the
host to respond to the infection, the authors said. In addition,
overexpression of this or other related MDRs leads to an enhanced host
immune response.
"The only way the bug molecule enters into the cytosol is if the
bacterium is virulent," said Portnoy, who is also a member of UC
Berkeley's Health Sciences Initiative. "We know that there are
different immune system receptors in different compartments of a cell,
but until this paper, it was not understood exactly how the cytosolic
surveillance system was triggered. Our findings suggest that the
molecules pumped out by the pathogen while it's in the cellular fluid
help the immune system gauge whether a bacterium is a threat based
upon its location inside the cell."
The researchers isolated the role of multidrug resistance transporters
by manipulating specific genes in the bacteria that controlled their
expression and then measuring how increased or decreased activity by
the transporter proteins impacted levels of interferon beta, a protein
produced by the immune system that rally more disease-fighting cells
when infections are detected.
They found that greater MDR expression led to greater stimulation of
the immune system, as measured by interferon beta levels.
Strains of Listeria with higher levels of MDR expression increased
interferon beta levels up to 20-fold compared with unmodified, wild-
type Listeria in cell cultures, the study found. Tests in mice
infected with those same mutant strains of Listeria had bacterial
loads that were 20 times lower in their livers, although the
researchers could not attribute the decreased levels solely to the
higher levels of interferon beta.
"This paper raises the classic issue of the tug-of-war in the
evolution of the host and the pathogen; it's a never-ending arms
race," said Gregory Crimmins, UC Berkeley graduate student in
molecular and cell biology who, along with former UC Berkeley post-
doctoral researcher Anat Herskovits, was the study's co-lead author.
The study results could provide clues to the actions of other
intracellular pathogens, such as the bacteria responsible for
tuberculosis and Legionnaires' disease, since they also activate
similar immune mechanisms, the researchers said.
Crimmins noted that better understanding of how the class of
interferons in this study is triggered could have implications for a
variety of diseases. "Type I interferons have wide-ranging effects on
the immune system, and are used to treat multiple sclerosis, hepatitis
C and some types of cancer," he said. "The strains generated in this
study may provide novel insight into the role of Type I interferons in
coordinating the host immune response."
"By understanding the pathways of innate immunity, we can better
understand acquired immunity, and that is important for vaccine
development," added Portnoy. "The concept of making safe but fully
effective vaccines is still a challenge, especially for intracellular
pathogens."
Portnoy pointed out that weakened Listeria is already being used to
develop cancer vaccines by Anza Pharmaceuticals, a Concord-based
biopharmaceutical company with which he consults.
======================
U-boat invades your cells.... or UL18 anyway
http://www.sciencedaily.com/releases/2008/07/080718085117.htm
Viral Cloaking Device: How Viruses Evade The Immune System
ScienceDaily (July 18, 2008) — Viruses achieve their definition of
success when they can thrive without killing their host. Now,
biologists Pamela Bjorkman and Zhiru Yang of the California Institute
of Technology have uncovered how one such virus, prevalent in humans,
evolved over time to hide from the immune system.
The human immune system and the viruses hosted by our bodies are in a
continual dance for survival--viruses ever seek new ways to evade
detection, and our immune system devises new methods to hunt them
down. Human Cytomegalovirus (HCMV), says Bjorkman, Caltech's Delbrück
Professor of Biology and a Howard Hughes Medical Institute (HHMI)
Investigator, "is the definition of a successful virus--it thrives but
it doesn't affect the host."
HCMV is carried by eight in 10 people. Although it generally harms
only those who are immunocompromised, it has also been linked with
brain tumors like the one for which Ted Kennedy recently had surgery.
Understanding how HCMV survives may help in the development of a
vaccine, as well as in the fight against other viruses with similar
evasive tactics.
"We are interested in mechanisms taken by viruses to escape our immune
system," says Caltech biology postdoc and HHMI associate Zhiru Yang.
She and Bjorkman published their findings on HCMV survival mechanisms
in the July 15 edition of Proceedings of the National Academy of
Sciences. They describe the underpinnings of a viral cloaking device,
partly made of stolen goods from healthy cells, that helps HCMV to
move undetected through the body.
For 20 years, Bjorkman's lab has been dedicated to understanding class
1 major histocompatibility complex (MHC) proteins and the immune
response, most recently related to AIDS research. MHC proteins carry
peptides, small pieces that are chopped up from the cell's internal
proteins, to the cell's surface. If a cell has been infected, MHC
presents viral peptides to signal T cells to kill it. So some viruses
evolved to evade T cells by keeping MHC from reaching the cell
surface. In turn, the immune system recruited other hunters to search
for cells that don't show MHC proteins.
Sometime along its treacherous evolutionary path, HCMV stole a class 1
MHC molecule from its host and modified it for supreme stealth. "This
is a decoy," Bjorkman says. She and Yang analyzed the structure of the
mimic, called UL18, to compare how similar it is to the real thing.
They found that despite a mere 23 percent match in genetic sequences,
UL18 looks almost exactly the same as a true class 1 MHC.
The same immune cells that search for missing MHC proteins are
designed to bind to them when they find them, thereby inhibiting an
immune response. Yang and Bjorkman found that UL18 happens to bind
1,000 times tighter to these inhibitory receptors than real MHC
molecules do. "This is exactly what the virus wants--to avoid being
recognized by T cells, but to engage inhibitory receptors to turn off
immune cells," Yang notes. "Only a small number of UL18 molecules are
required to have the same inhibitory effect as a large number of MHC
class I molecules."
"What I find astounding is that the virus stole this gene and kept it
almost identical but improved upon its binding," Bjorkman says.
UL18 didn't stop there. "It also binds peptides--that's unique to this
MHC mimic. We don't know why," Bjorkman adds. The peptide is obscured
from killer cells by yet another shield, Yang says. In a trait it
shares with HIV proteins, HCMV's UL18 covers itself with
carbohydrates, which are unrecognizable to the immune system. A real
class 1 MHC molecule has one site for adding carbohydrates; the fake
has 13, Bjorkman notes. The only place where it's not covered is where
it binds to the inhibitory receptor.
All its efforts have made UL18 virtually undetectable. "It's a good
example of a viral protein that evolved from its host ancestor to
block unwanted interactions," Yang says. "The more we understand that,
the more effectively we can fight viruses that hide out," Bjorkman
adds.
This study was supported by HHMI.
==========================
MDA-5
http://www.medicalnewstoday.com/articles/115278.php
innate immune sensor has been discovered that detects the presence of
stomach viruses in the body. This protein, named MDA-5, triggers an
immune response, and might give scientists information to develop a
treatment to prevent or reduce infections of this kind, according to
an article released on July 18, 2008 in the open access journal PLoS
Pathogens.
Norovirus, commonly called the stomach flu but actually unrelated to
influenza, is a common infection in areas where people live close
together. These might include cruise ships, nursing homes, military
bases and schools. Therapy methods are limited for this kind of
infection, because it is a virus and thus unaffected by antibiotics.
Recently, scientists have developed methods to grow noroviruses in the
laboratory and study them in vitro.
The initial study concluded that the absence of MDA-5 in cells
inhibits the immune response against norovirus. However, this is not
the only protein involved in this process. "Our research strongly
indicates that MDA-5 is the primary sensor for norovirus infection,
but the body's ability to detect the virus is so important that it
doesn't just rely on one sensor," stated Marco Colonna, M.D.,
professor of pathology and immunology. "We found that another protein
sensor [TLR3] serves as a back-up and there may be others that have
not yet been discovered."
To investigate the immune response more completely, scientists at the
Washington University School of Medicine in St. Louis investigated two
groups of mice: one incapable of synthesizing the protein MDA-5, and
one unable to make the protein TLR3. Both groups were exposed to
norovirus and the response was measured. Both groups of deficient mice
had defective immune responses to the norovirus in their bodies, and
the mice missing MDA-5 had higher levels of the virus in their bodies.
Both of these proteins are intracellular signals. MDA-5, and to some
degree TLR3, induce other cells to produce interferon, a chemical that
terminates virus production and begins the immune attack in the body.
The researchers suspected that they might be important in norovirus
recognition because they are already known to recognize similar
infections. While this work was done in mice, there is a relatively
high level of homology between mice and humans, so it is likely that
similar proteins exist in humans. In fact, some people have common
variations of the MDA-5 gene that could make them more sensitive to
norovirus infection -- for these people, a potential norovirus
treatment would be especially useful.
<sniP>
MDA-5 jpg's
http://www.nature.com/cdd/journal/v13/n5/fig_tab/4401850f4.html
http://www.biken.osaka-u.ac.jp/act/images/akiraD.png
What exactly is mda-5? Seems to be the same as IFIH1.
http://en.wikipedia.org/wiki/IFIH1
Interferon induced with helicase C domain 1, also known as IFIH1, is a
human gene.[1]
DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-
Asp (DEAD), are putative RNA helicases. They are implicated in a
number of cellular processes involving alteration of RNA secondary
structure such as translation initiation, nuclear and mitochondrial
splicing, and ribosome and spliceosome assembly. Based on their
distribution patterns, some members of this family are believed to be
involved in embryogenesis, spermatogenesis, and cellular growth and
division. This gene encodes a DEAD box protein that is upregulated in
response to treatment with beta-interferon (IFNB) and a protein kinase
C-activating compound, mezerein (MEZ). Irreversible reprogramming of
melanomas can be achieved by treatment with both these agents;
treatment with either agent alone only achieves reversible
differentiation.[1]
<sniP>
CARD signalling
http://en.wikipedia.org/wiki/CARD_domain#Antiviral_signaling
Antiviral signaling
Recently, a subset of CARD proteins has been shown to participate in
recognition of intracellular double-stranded RNA, a common constituent
of a number of viral genomes, including the para- and orthomyxoviridae
and rhabdoviridae. Unlike NLRs, these proteins, termed RIG-I and MDA5,
contain twin N-terminal CARD domains and C-terminal RNA helicase
domains that directly interact with and process the double-stranded
viral RNA. This processing makes the CARD domains available for
interaction with the CARD motif of IPS-1/MAVS/VISA/Cardif, a
downstream adapter anchored in the mitochondria. Although the
interactions between IPS-1 and RIG-I/MDA-5 have been shown in vitro,
the nature of the complex formed upon viral detection has not been
characterized.
Autoimmunity
Because of their role as regulators of inflammation, constitutive
activation of certain CARD proteins, either conferred by mutation or
by constant presence of stress signals, has been suggested to play a
causative role in a number of inflammatory syndromes. Gain-of-function
mutations in the intracellular NOD2 protein has been linked to
increased risk for Crohn's disease. Activating mutations in at least
two related PYD-containing proteins, cryopyrin/CIAS-1 and pyrin/MEFV,
have been linked to Muckle-Wells Syndrome and familial Mediterranean
fever, respectively.
<sniP>
randall
Filaggrin gene variations (atopic dermatitis culprit)
http://www.medicalnewstoday.com/articles/117032.php
[...]
8% of the German population carry variations of the filaggrin gene,
which raise the risk to develop atopic dermatitis more than threefold.
In addition, these genetic variations predispose to hay fever and
asthma in those with atopic dermatitis.
<sniP>
------------
Duel of coal tar versus Dovenex cream.... who wins?
http://www.medicalnewstoday.com/articles/116866.php
NeoStrata announced findings from an ongoing 12-week study that
demonstrates benefits of a novel topically applied LCD (coal tar)
solution (Psorent(TM)) versus calcipotriol cream (Dovonex(R)) in
treatment of moderate plaque psoriasis. Specifically, results of an
interim analysis reveal the LCD solution is outperforming calcipotriol
cream in achieving improvement of psoriasis symptoms (PASI 75) and is
significantly better in reducing redness/irritation at both the 2- and
12-week point.
<sniP>
--------------------
The enzyme indoleamine 2,3-dioxygenase and tryptophan metabolites
contribute to immune homeostasis by inducing Tregs and taming
overzealous or heightened inflammatory responses.
PMID: 18608915
11 hits for INDOLEAMinE
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=indoleamine+&qt_g=Search+this+group
-------
http://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase
Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 1.13.11.42) is an
immunomodulatory enzyme secreted by some alternatively activated
macrophages and other immunoregulatory cells (also used as an immune
subversion strategy by many tumors).
Gamma-interferon (IFNG; MIM 147570) has an antiproliferative effect on
many tumor cells and inhibits intracellular pathogens such as
Toxoplasma and Chlamydia, at least partly because of the induction of
indoleamine 2,3-dioxygenase (INDO; EC 1.13.11.42). This enzyme
catalyzes the degradation of the essential amino acid L-tryptophan to
N-formylkynurenine.[supplied by OMIM][1]
IDO is the first and rate limiting enzyme of Tryptophan catabolism
through Kynurenine pathway, thus causing depletion of tryptophan which
can cause halted growth of microbes as well as T cells.
It catalyzes conversion of L-tryptophan to N-formylkynurenine.
------------
Please recall we called tryptophan on the carpet many times..
-----------------------------
Seems easier to do the wit kit implant and stay on some sort of
probiotic?
probiotics
http://www.vrp.com/articles.aspx?ProdID=art2399&zTYPE=2
-------------------
Fix your gray cells so you can figure it ALL out. LOL
Brain regeneration. ALA
http://www.vrp.com/articles.aspx?ProdID=art2256&zTYPE=2
====================================================
P genes caused (expressed) by TNF-alpha
http://www.ncbi.nlm.nih.gov/pubmed/18669614?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Development and Validation of Human Psoriatic Skin Equivalents.
Tjabringa G, Bergers M, van Rens D, de Boer R, Lamme E, Schalkwijk J.
From the Department of Dermatology, Radboud University Nijmegen
Medical Centre, and the Nijmegen Centre for Molecular Life Sciences,
Nijmegen, The Netherlands.
Psoriasis is an inflammatory skin disease driven by aberrant
interactions between the epithelium and the immune system. Anti-
psoriatic drugs can therefore target either the keratinocytes or the
immunocytes. Here we sought to develop an in vitro reconstructed skin
model that would display the molecular characteristics of psoriatic
epidermis in a controlled manner, allowing the screening of anti-
psoriatic drugs and providing a model in which to study the biology of
this disease. Human skin equivalents generated from normal human adult
keratinocytes after air exposure and stimulation by keratinocyte
growth factor and epidermal growth factor displayed the correct
morphological and molecular characteristics of normal human epidermis
whereas the psoriasis-associated proteins, hBD-2, SKALP/elafin, and
CK16, were absent. Skin equivalents generated from foreskin
keratinocytes were clearly abnormal both morphologically and with
respect to gene expression. When normal skin equivalents derived from
adult keratinocytes were stimulated with psoriasis-associated
cytokines [tumor necro sis factor-alpha, interleukin (IL)-1alpha,
IL-6, and IL-22] or combinations thereof, strong expression of hBD-2,
SKALP/elafin, CK16, IL-8, and tumor necrosis factor-alpha was induced
as shown by quantitative polymerase chain reaction and
immunohistochemistry. Retinoic acid but not cyclosporin A was found to
inhibit cytokine-induced gene expression at both the mRNA and protein
levels. These results illustrate the potential of this disease model
to study the molecular pathology and pharmacological intervention in
vitro.
PMID: 18669614
------------------
http://en.wikipedia.org/wiki/Spondyloarthropathy
http://www.ncbi.nlm.nih.gov/pubmed/18668556?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Increased numbers of circulating polyfunctional Th17 memory cells in
patients with seronegative spondylarthritides.
Jandus C, Bioley G, Rivals JP, Dudler J, Speiser D, Romero P.
Ludwig Institute for Cancer Research, University Hospital (CHUV),
Lausanne, Switzerland, and the National Center for Competence in
Research, Epalinges, Switzerland.
OBJECTIVE: A distinct subset of proinflammatory CD4+ T cells that
produce interleukin-17 was recently identified. These cells are
implicated in different autoimmune disease models, such as
experimental autoimmune encephalomyelitis and collagen-induced
arthritis, but their involvement in human autoimmune disease has not
yet been clearly established. The purpose of this study was to assess
the frequency and functional properties of Th17 cells in healthy
donors and in patients with different autoimmune diseases. METHODS:
Peripheral blood was obtained from 10 psoriatic arthritis (PsA), 10
ankylosing spondylitis (AS), 10 rheumatoid arthritis (RA), and 5
vitiligo patients, as well as from 25 healthy donors. Synovial t issue
samples from a separate group of patients were also evaluated
(obtained as paraffin-embedded sections). Peripheral blood cells were
analyzed by multiparameter flow cytometry and immunohistochemistry.
Cytokine production was examined by enzyme-linked immunosorbent assay
and intracellular cytokine staining using specific monoclonal
antibodies. Synovial tissue was examined for infiltrating T cells by
immunohistochemical analysis. RESULTS: We found increased numbers of
circulating Th17 cells in the peripheral blood of patients with
seronegative spondylarthritides (PsA and AS), but not in patients with
RA or vitiligo. In addition, Th17 cells from the spondylarthritis
patients showed advanced differentiation and were polyfunctional in
terms of T cell receptor-driven cytokine production. CONCLUSION: These
observations suggest a role of Th17 cells in the pathogenesis of
certain human autoimmune disorders, in particular the seronegative
spondylarthritides.
PMID: 18668556
--------------------
Here's a new way to GET P...or is it?
http://www.ncbi.nlm.nih.gov/pubmed/18664162?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
New-onset psoriasis and psoriatic arthritis in a patient treated with
Bacillus Calmette-Guérin (BCG) immunotherapy.
Dudelzak J, Curtis AR, Sheehan DJ, Lesher JL Jr.
Division of Dermatology, Department of Medicine, Medical College of
Georgia, Augusta, GA, USA.
PMID: 18664162
http://en.wikipedia.org/wiki/Bacillus_Calmette-Gu%C3%A9rin
Bacillus Calmette-Guérin (or Bacille Calmette-Guérin, BCG) is a
vaccine against tuberculosis that is prepared from a strain of the
attenuated (weakened) live bovine tuberculosis bacillus, Mycobacterium
bovis, that has lost it s virulence in humans by being specially
cultured in an artificial medium for years. The bacilli have retained
enough strong antigenicity to become a somewhat effective vaccine for
the prevention of human tuberculosis. At best, the BCG vaccine is 80%
effective in preventing tuberculosis for a duration of 15 years,
however, its protective effect appears to vary according to geography.
<sniP>
===========================
BCG used for bladder cancer
http://en.wikipedia.org/wiki/Cancer_Immunotherapy
=================
keywords:: BCG+psoria* (13 hits on pubmed)
=======================
LacZ gene: (poster: elsie reed, Kevin brought this gene up back in
2002)
http://www.medicalnewstoday.com/articles/117215.php
Preventing Friendly Fire: A Role For The Thymic Cortex In Stopping
Your Body From Attacking Itself
In order to effectively prevent disease, the immune system must be
able to distinguish between self and non-self, and to selectively
target the latter. The process that removes immune cells that would
otherwise react to the body - engage in friendly fire - is called
negative selection. A new paper published in this week's PLoS Biology,
the online open access journal, investigates the inner mechanics of
the thymus, the organ that creates the foot soldiers of the immune
system. The paper, by Sejin Ahn and colleagues, helps shed light on
the timing and regulation of negative selection, a crucial
developmental process.
The thymus creates T cells, white blood cells that destroy harmful
material as part of the immune response to pathogens. Many more
immature T cells are created than are allowed to develop, and the
filtering processes - which select only those immature cells that can
be useful - occurs within the thymus. The thymus is roughly divided
into two main regions, the medulla and the cortex. It has previously
been unclear whether the cortex is involved in negative selection, or
whether this process is restricted to the medulla.
The new paper, a collaboration between researchers from the US, Korea
and the UK, has changed this. The authors have genetically engineered
mice to contain an antigen, ___LacZ,___ in only a small fraction of
the cells of the cortex and nowhere else in the body. They found that
any T cells that were programmed to attack LacZ were absent from the
mature mice. As the T cells could only have been exposed to ___LacZ___
in the cortex, this is strong evidence the cortex has removed them
before they reach the rest of the body. Therefore the cortex also has
a role in negative selection and significantly tolerizes the
developing T cells with impressive efficiency.
This research allows a much clearer understanding of the internal
mechanics of the thymus, and how negative selection might work.
=======================
MyD88 is missing in action
http://www.medicalnewstoday.com/articles/116983.php
=====================
Look at the features of this rare autoimmune condition and you tell
me it doesn't have quite a few near posriasis genes at work.
http://www.mercurynews.com/alamedacounty/ci_9987674
Rare autoimmune disease strikes two Alameda children
By Johyne Taylor Hill
Like many mothers, Suzy Clement is proud of her daughter, Mielle
Gonzalez. Mielle is bright, aware and articulate. But unlike other
mothers, Clement is grateful when Mielle has the strength to briefly
ride her bike or walk up stairs on her own. She never knows if her
daughter, who suffers from Juvenile Myositis, will be able to do these
things in the future.
Juvenile Myositis (JM) is a rare autoimmune disease whose main
symptoms are muscle weakness and skin rashes. JM occurs when the
immune system mobilizes against a "trigger" (which could be a virus,
vaccine or environmental hazard) but is then unable to stop the
infection-fighting process, creating damage to the body.
Other symptoms include inflammation in the digestive system; fever;
calcinosis, which are small lumps of calcium that form under the skin
or in the muscle; and vasculitic ulcers, which are holes in the tissue
that surrounds an inflamed blood vessel.
JM affects only about 5,000 children in the United States. Yet there
are two known cases in Alameda.
Michelle San Nicolas clearly remembers the first time she noticed
symptoms in her daughter, Kendyl. At almost 4 years old, Kendyl woke
up one morning with rosy cheeks, resembling a rash. San Nicolas
thought it might be a reaction to a new laundry detergent. But
switching back didn't help Kendyl.
When she took her son to see a dermatologist for eczema, she asked the
doctor also to look at Kendyl. The doctor speculated
Advertisement
it might be a reaction to too much sun exposure. He put her on
cortisone and advised staying out of the sun. Although San Nicolas
followed this advice, there was no improvement. Kendyl's cheeks turned
a bright red, and she developed foot pain. She also became more tired,
and all her cuticles became painful and seemed to be infected.
San Nicolas learned later that the cuticles weren't infected. Instead,
the disease was causing the blood vessels to atrophy. When Kendyl's
cuticles grew, they turned brown from lack of blood flow.
After another false diagnosis, San Nicolas was referred to a San
Francisco specialist who confirmed JM through a blood test. It is not
uncommon for doctors to misdiagnose JM sufferers since the disease is
so rare that most doctors won't encounter it during their careers.
Although Kendyl had a difficult time taking her pills and dealing with
medication side effects, she responded well to treatment. Now
approaching her eighth birthday and another year at Franklin
Elementary, Kendyl is symptom-free. Her disease is in remission,
meaning she has been off medication for at least a year. San Nicolas
is still cautious, however, because relapses could happen at any time.
One-third of JM sufferers will go into permanent remission, one-third
will enter remission and suffer relapses and one-third will always be
on medication. JM affects each patient differently. Some have mild
symptoms while others might die as a result of the disease.
"I will always worry about it," says San Nicolas. "As a person who
never got sick, I thought it was just a rash. But it was something
terrible. Now I question everything. If she gets sick, I wonder if it
will trigger (the disease). What happens when she grows up and gets
pregnant; will it trigger something?"
San Nicolas was able to provide much-needed support when Suzy
Clement's daughter was diagnosed with JM. Mielle, also a Franklin
student, started having red blotches on her cheeks in early 2007. By
fall of that year, the six-and-a-half-year-old had developed muscle
weakness and soon couldn't walk far without getting tired. To walk up
stairs, she had to pull on the railing or push on her legs. Her
parents, Clement and Lenny Gonzalez, thought her kindergarten schedule
might be wearing her out. But soon, Mielle couldn't go up stairs at
all. She wasn't able to get up off the floor without crawling to a
piece of furniture and using it to push herself up. Initially
suspecting lupus, her doctor referred her to a pediatric
rheumatologist. The diagnosis was JM.
Mielle initially responded well to treatment. But the drugs commonly
used to treat JM are strong with powerful side effects. Mielle began a
high dose of the corticosteroid Prednisone, which can cause mood
swings, increased appetite and weight gain, altered weight
distribution, bone density loss, stunted growth, high blood pressure
and cataracts. She also began Methotrexate (a chemotherapy drug when
used in higher doses), which can partially take the place of
corticosteroids after it has had time to build up in the body.
Mielle has experienced various plateaus during the course of her
treatments. She switched doctors and now goes to Stanford every week
for intravenous injections of Methotrexate. She is also on Prednisone
and Cyclosporine, an immuno-suppressant drug typically used in organ
transplant recipients to prevent rejection of a new organ.
Although her strength has improved and she is occasionally able to
ride her bike for brief periods, she still has a facial rash and signs
of active disease, such as inflammation. Her weekly treatments often
leave her so exhausted that she needs to sleep most of the weekend.
She also deals with mood swings and anger, a side effect of the
Prednisone.
"Mielle recently told me, 'My brain feels like it wants to jump out of
my head and beat someone up,'" said Clement.
One problem of dealing with an uncommon disease is that treatment
methods vary, and effectiveness is not guaranteed.
"There's no standard protocol of treatment," said Clement. "Every case
and every kid is different. Kids don't respond to treatments the same
way. So your kids start to feel like an experiment. Your 6-year-old is
taking a combination of toxic, lethal chemicals, but that's what we
have to do. It's bad enough knowing your kid has this disease and she
has to undergo this treatment with horrible side effects. But we don't
know if it's going to work or if what we're giving her is right."
Next month, the Gonzalez family, which includes 16-month-old brother
Lucien, will travel to Chicago to seek more aggressive treatment from
one of the few facilities specializing in JM. Even in a best-case
scenario, Mielle will be under treatment for at least two to three
more years. Her medical bills are costly for self-employed
photographers Clement and Gonzalez, who pay completely out-of-pocket
for their20medical insurance.
This Saturday, the Gonzalez family and friends will host a multi-
family yard sale that includes a wide variety of items donated by
community members. Proceeds will help pay for the Gonzalez family's
medical bills and a portion will go toward JM research.
Items for sale include toys and other items for babies and children,
furniture, clothes and bikes, and more. Friends of the family, who are
musicians, will be playing for tips, and Mielle will be hosting a
lemonade stand.
=========================
Imiquimod has been mentioned here as skewing the system towards Th1,
and generates TNF to eat that tumor right outa your life many times.
It proves having to much TNF without anything to chomP
on leads to polarization (Th1 skew) that perpetuates the autoimmune
conditions in
general.
Yet how exactly that works is still unfolding.
http://www.medicalnewstoday.com/articles/116128.php
Imiquimod, An Immune Response Modifier, Is Dependent On The OGF-OGFr
Signaling Pathway
Researchers at The Pennsylvania State University College of Medicine,
Hershey, Pennsylvania have discovered that the efficacy of imiquimod,
a clinically important immune response modifier with potent antiviral
and antitumor activity, is dependent on the Opioid Growth Factor (OGF)-
OGF receptor (OGFr) axis for its action. This discovery, reported in
the August 08 issue of Experimental Biology and Medicine, provides new
insights into a widely used drug that may lead to development of new
agents that will enhance effectiveness and attenuate side-effects.
Imiquimod and resiquimod are imidazoquinoline compounds. Imiquimod
(Aldara, R-837, S26308), the best characterized and most widely used,
is highly efficacious in the treatment of external genital and anal
warts, basal cell carcinoma, actinic keratoses, Kaposi's sarcoma,
chronic hepatitis C infection, and intraepithelial carcinoma.
Therefore, the underlying mechanism of imiquimod action is of clinical
importance. Imiquimod has been rep orted to be a toll-like receptor-7
agonist, and its anti-tumor effect exerted by modification of the
immune response and stimulation of apoptosis. The mechanism of
imiquimod on cell proliferation is unclear.
The research team, led by Dr. Ian S. Zagon, Distinguished University
Professor, and Dr. Patricia J. McLaughlin, Professor, along with a pre-
doctoral student Renee N. Donahue, in the Department of Neural &
Behavioral Sciences and collaborator Moshe Rogosnitzky of MedInsight
explored mechanisms responsible for the remarkable clinical action of
this class of drugs.
Specifically, using tissue culture models, the investigators found
that imidazoquinolines upregulate OGFr which in turn stimulates the
interaction of the OGF-OGFr axis. This native, tonically active
inhibitory pathway is known to regulate cell proliferation by
modulating cyclin dependent kinase inhibitors, resulting in a
retardation of cells at the G1-S interface of the cell cycle.
Neutralization of OGF or knockdown of OGFr by siRNA technology
eliminated the inhibitory effects of imidazoquinolines on cell
replication. "Thus our data," Dr. Zagon said, "brings a paradigm shift
to our thinking about a drug widely used in the clinics. Rather than
imiquimod activity being mediated by induction of various cytokines,
including interferon (IFN)-α, IFN-γ, tumor necrosis factor-α (TNFα)
interleukin (IL)-1α, and IL-12 as currently thought, an entirely new
pathway - native to body chemistry - has been discovered to regulate
cell proliferation by imidazoquinolines."
0ACo-author, Moshe Rogosnitzky adds: "The elucidation of imiquimod's
immune-independent mechanism of action in cancer also creates exciting
new therapeutic possibilities for a number of non-cancer conditions,
and these are now being further explored. Such studies could lead to
new off-label applications for imiquimod as well as development of
imiquimod analogues and unique combination therapies." Dr. Steven R.
Goodman, Editor-in-Chief of Experimental Biology and Medicine stated
"Through decades of elegant and ground-breaking work, Zagon and
colleagues have identified the role of met-enkephalin (the opioid
growth factor - OGF) and the OGF receptor in regulating cell
proliferation. The current study demonstrates that the mechanism of
imidazoquinoline activity is via OGF and OGFr which will have a
profound impact on its use as a therapeutic for cancer and many other
non-cancerous disorders."
=====================
56% of psor heads get nail fungus? How can that be right?
http://www.newswise.com/articles/view/543021/
[...]
Nail Fungus
Fungal infections, known as onychomycosis, comprise approximately half
of all visits to the dermatologist for nail-related problems. Since
the infection occurs under the nail plate or in the nail bed, it can
be difficult to treat. Fungal infections – which can be white, green,
yellow or black in color – often cause the end of the nail to separate
from the nail bed, and they may build up under the nail
plate and discolor the nail bed . Because the feet are usually
confined in a warm, moist environment, toenails are more susceptible
to fungal infections.
<sniP>
===================================
randall...
randall
Hi,
In the news today from an eurekalert.
http://www.eurekalert.org/pub_releases/2008-08/joci-joe080408.php
JCI online early table of contents: August 7, 2008
DERMATOLOGY: Possible new treatment for psoriasis
New data, generated by Thomas Jung and colleagues, at Novartis
Exploratory Development, Switzerland, have indicated that a drug known
currently as AEB071 can reduce the clinical symptoms of psoriasis, a
chronic, currently incurable autoimmune skin disease.
In the study, healthy volunteers and patients with psoriasis were
administered AEB071 by mouth. Different groups of individuals received
different doses of the drug, but all doses were well tolerated with no
obvious side effects. The decrease in the clinical symptoms of
psoriasis was associated with a decreased ability of immune cells
known as lymphocytes to divide and express a soluble factor known as
IL-2. The authors therefore suggest that AEB071 might be an effective
new treatment for psoriasis, although they caution that further
clinical trials are needed to more clearly establish that the drug is
safe and effective.
TITLE: The PKC inhibitor AEB071 may be a therapeutic option for
psoriasis
<sniP>
---------------------
http://www.jci.org/articles/view/35636 (whole study from this link)
The PKC inhibitor AEB071 may be a therapeutic option for psoriasis
Hans Skvara1, Markus Dawid1, Elise Kleyn2, Barbara Wolff3, Josef G.
Meingassner3, Hilary Knight4, Thomas Dumortier4, Tamara Kopp1, Nasanin
Fallahi1, Georg Stary1, Christoph Burkhart4, Olivier Grenet4, Juergen
Wagner4, Youssef Hijazi4, Randall E. Morris4, Claire McGeown4,
Christiane Rordorf4, Christopher E.M. Griffiths2, Georg Stingl1 and
Thomas Jung4
PKC isoforms t, α, and β play fundamental roles in the activation of T
cells and other immune cell functions. Here we show that the PKC
inhibitor AEB071 both abolishes the production of several cytokines by
activated human T cells, keratinocytes, and macrophages in vitro and
inhibits an acute allergic contact dermatitis response in rats. To
translate these findings into humans, single and multiple ascending
oral doses of AEB071 were administered to healthy volunteers and
patients with psoriasis, respectively. AEB071 was well tolerated with
no clinically relevant laboratory abnormalities. Ex vivo stimulation
of lymphocytes from subjects exposed to single doses of AEB071
resulted in a dose-dependent inhibition of both lymphocyte
proliferation and IL2 mRNA expression. Clinical severity of psoriasis
was reduced up to 69% compared with baseline after 2 weeks of
treatment, as measured by the Psoriasis Area Severity Index (PASI)
score. The improvement in psoriasis patients was accompanied by
histological improvement of skin lesions and may be partially
explained by a substantial reduction of p40+ dermal cells, which are
known to mediate psoriasis. These data suggest that AEB071 could be an
effective novel treatment regimen for psoriasis and other autoimmune
diseases, and that AEB071 warrants long-term studies to establish
safety and efficacy.
<sniP>
=======================
Back to coPPer chelators?
What's wrong with why the ratio to zinc is amP'ed out?
http://www.ncbi.nlm.nih.gov/pubmed/18677937?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Serum zinc and copper levels in some dermatological diseases.
Butnaru C, Pascu M, Mircea C, Agoroaei L, Solovăstru L, Vâţă D,
Butnaru E, Petrescu Z.
Gr.T. Popa University of Medicine and Pharmacy Iaşi, School of
Pharmacy, Department of Toxicology.
Zinc (Zn) and copper (Cu) are essential metals for biochemical
processes in the body. Many researchers have main interest in these
two metals because it was establish that they are involved in
immunological and inflammatory reactions. MATERIAL AND METHODS: The
study comprised 49 patients of Dermatology Clinic from Iaşi with
different skin diseases (21 with psoriasis and 28 with varicose
ulcer), during January - May 2006. The patients, both sexes, had ages
between 19 and 81 years old. We determinated serum Zn and Cu levels by
atomic absorption spectrophotometry. The results were expressed in mg/
L and we calculated Cu/Zn ratio, too; the values were compared with 50
healthy controls. RESULTS: In psoriasis, serum Zn and Cu mean levels
(5.61 mg/L, respectively 1.27 mg/L) were higher as compared to
controls (significance level p=0.04); the mean Cu/Zn ratio was 0.81 in
psoriasis and 0.96 in control group. In varicose ulcer, mean levels
were significantly increased (Zn-7.62 mg/L, Cu- 1.38 mg/L) compared to
control group (Zn-0.81 mg/L, Cu-0.75 mg/L) and serum normal values;
the mean Cu/Zn ratio was 1.00. 18 of all patients with psoriasis and
varicose ulcer had higher serum Zn and Cu levels than normal values.
PMID: 18677937
http://www.ncbi.nlm.nih.gov/pubmed/18683094?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Tetrathiomolybdate, a copper chelator for the treatment of Wilson
disease, pulmonary fibrosis and other indications.
Medici V, Sturniolo GC.
University of California, Davis, Division of Gastroenterology and
Hepatology, Department of Internal Med, 4150 V Street, Suite 3500,
Sacramento, CA 95817, USA. valentin...@ucdmc.ucdavis.edu.
Tetrathiomolybdate (TTM) is a copper chelator that has also
demonstrated antiangiogenic, antifibrogenic and anti-inflammatory
actions in preclinical studies. The drug, from the University of
Michigan was licensed to Pipex Pharmaceuticals Inc for development for
several indications; development of the drug for cancer was later
licensed to Attenuon LLC. In a phase III clinical trial, TTM
stabilized neurological function in patients with Wilson disease,
causing significant recovery in 81% of patients at 3 years post
initiation of therapy; a second phase III trial was ongoing at the
time of publication. A phase I/II clinical trial demonstrated the
efficacy of TTM in patients with idiopathic pulmonary fibrosis, and
led the FDA to grant TTM Orphan Drug status for this disease. Several
phase II clinical trials had also been completed in patients with
various cancers, and revealed mixed efficacy. TTM was also assessed in
a phase I clinical trial for age-related macular degeneration, but the
results reported from the trial were negative; no further development
has occurred for this indication. TTM was assessed for the treatment
of psoriasis in a phase II clinical trial, but no data have been
reported. At the time of publication, phase II and phase III clinical
trials were ongoing in patients with Alzheimer's disease and primary
biliary cirrhosis, respectively. The most common clinical side effects
observed for TTM over the range of indications have been anemia,
neutropenia, leukopenia and transanimase elevations. These side
effects were generally resolved with either a dose adjustment or
temporary suspension of the dosing regimen. TTM is predicted to most
likely find a niche in the therapy of Wilson disease, for which
current treatment options are limited.
PMID: 18683094
===========================
http://www.ncbi.nlm.nih.gov/pubmed/18681957?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
NullHap - a versatile application to estimate haplotype frequencies
from unphased genotypes in the presence of null alleles.
Nowak RM, Ploski R.
ABSTRACT: BACKGROUND: Laboratory techniques used to determine
haplotypes are often too expensive for large-scale studies and lack of
phase information is commonly overcome using likelihood-based
calculations. Whereas a number of programs are available for that
purpose, none of them can handle loci with both multiple and null
alleles. RESULTS: Here we present a description of a modified
Expectation - Maximization algorithm as well as its implementation
(NullHap) which allow to effectively overcome these limitations. As an
example of application we used Nullhap to reanalyze published data on
distribution of KIR genotypes in Polish psoriasis patients and
controls showing that the KIR2DS4/1D locus may be a marker of KIR2DS1
haplotypes with different effects on disease susceptibility.
CONCLUSIONS: The developed application can estimate haplotype
frequencies for every type of polymorphism and can effectively be used
in genetic research as illustrated by a novel finding regarding the
genetic susceptibility to psoriasis.
PMID: 18681957
----------------------
randall...
randall
Possible new P drug and it's pathway.
http://www.cecu.de/1404+M584ae6c7cd4.html
[...]
In addition, Micromet has established a collaboration with Nycomed for
the development and commercialization of MT203, a human antibody
neutralizing the activity of granulocyte/macrophage colony stimulating
factor (GM-CSF), which has potential applications in the treatment of
various inflammatory and autoimmune diseases, such as rheumatoid
arthritis, ____psoriasis___, or multiple sclerosis.
<sniP>
http://pmid.us/psoria*+gm-csf (62 hits on pubmed)
----------------
Gliadin receptor found in gut
http://www.oea.umaryland.edu/communications/news/?ViewStatus=FullArticle&articleDetail=4355
UM Scientists Pinpoint Key Receptor in Celiac Disease
A study from researchers at the Center for Celiac Research at the
University of Maryland School of Medicine answers a fundamental
question relating to the cause of celiac disease and, possibly, other
autoimmune disorders such as Type I diabetes and multiple sclerosis.
People with celiac disease must not eat foods containing gluten, a
protein found in wheat.
For them, gluten triggers an autoimmune response in which the immune
system attacks the body, leading to a wide spectrum of serious health
problems.
The new study, published in the July 2008 issue of the journal
Gastroenterology, identifies the key gluten receptor in the intestine
that opens the gateway through which gluten enters the body and
triggers a faulty immune response in celiac patients.
The receptor, called CXCR3, is critical to the early stages of the
faulty immune response. Pinpointing it could help doctors treat celiac
disease more effectively, according to Alessio Fasano, MD, professor
of Pediatrics, Medicine and Physiology of the University of Maryland
School of Medicine and medical director of the Center for Celiac
Research.
"This is a scientific question that had never been answered before,"
Fasano says. "It is not only significant in the basic science of
autoimmune disorders such as celiac disease, but in therapeutic
approaches for the future. This opens a new scientific paradigm for
the study of immunity.
There are three key components of celiac disease, according to Fasano.
One is genes, and researchers have already identified a number of
genes that seem common among celiac patients, but none that are
consistently found in all patients.
The second component is the environmental trigger that leads to the
autoimmune attack. Triggers have remained elusive for all autoimmune
diseases except celiac disease, in which gluten is the undisputable
trigger.
The third component is a leaky gut, wherein the barrier of the
intestine becomes permeable enough to allow in the offending antigen -
in this case, gluten, to come through.
Researchers at the Center for Celiac Research found that gliadin, the
component of gluten that proves problematic for celiac patients, binds
to the receptor called CXCR3.
This interaction between gliadin and CXCR3 triggers the release of a
human protein called zonulin, which opens up the intestinal barrier to
make it more permeable. In healthy patients, this effect is temporary.
In celiac patients, the effect is long-term, and the results can be
devastating.
The findings may be significant for other autoimmune disorders as
well, Fasano says. The same process may occur in patients with Type I
diabetes and multiple sclerosis, in which the intestines are the port
of entry or the pathway through which the offending antigens in these
and other autoimmune disorders get into the body, he explains.
"For the first time, we have evidence of how the foreign antigen gains
access to the body, causing the autoimmune response," according to
Fasano, who is also a pediatric gastroenterologist at the University
of Maryland Medical Center. "Further study is needed, but this could
allow us to intervene before the zonulin is either released or
activated, preventing the immune response altogether."
--------------------
http://pmid.us/psoria*+cxcr3 (25 hits on pubmed)
http://pmid.us/psoria*+gliadin (21 hits on pubmed)
Try a zonulin search of the psoriasis newsgroup. :)
Sure sounds better to say you may have a zonulin snp then a leaky gut
uPstream of your butt. LOL
=====================================
At least we know that a leaky gut leads to a Th1 skew due to LPS
gaining systemic
entry.
How come Th1 skewed autoimmune folks don't get more cancers?
We (psoriatics etc) have TNF and IFN to KICK tumor butts...
Understanding Th2 propelled cancers will make autoimmune Th1 pathways
CLEARER.
http://news.biocompare.com/newsstory.asp?id=238006
How Molecules Out of Balance Lead to Human Multiple Myeloma and Other
Cancers
An international team of scientists has identified processes that are
heavily implicated in human multiple myeloma and other B cell cancers,
moving us closer to developing quick tests and readouts that could
help in the tailored treatment of patients.
B cells, the white blood cells that produce antibodies, form a key
part of our 'immune response'. To remain healthy, we need to maintain
the right number of B cells, not too many and not too few. This in
turn relies on an intricate interplay of molecules within our bodies,
and inside our B cells.
Professor Fabienne Mackay, Professor Klaus Rajewsky and Dr Marc
Schmidt-Supprian, from Sydney's Garvan Institute of Medical Research,
Harvard Medical School and Germany's Max Planck Institute of
Biochemistry respectively, have identified two processes that appear
to influence B cell driven cancers. Their findings are published
online this week in the international journal Proceedings of the
National Academy of Sciences (US).
"We already know that the over-expression or mutation of molecules
known as NIK and TRAF3 in B cells is associated with human multiple
myeloma," said Professor Mackay. "Our collaborative research uncovered
two distinct processes involving these molecules that help explain
why."
The first process involves NIK, an enzyme that acts closely with BAFF,
the substance that regulates the number of B cells in our bodies. Work
done previously by Professor Mackay on BAFF showed that levels
correlate with B cell hyperplasia (expansion) and cancer. The current
study shows that if we have too much NIK in our systems, then our B
cells will also expand, and we will be prone to cancer.
The second process, associated with the first, involves TRAF3, the
molecule that negatively regulates NIK.
Professor Mackay explained that in a healthy person, NIK and TRAF3
work together, helping to maintain the right number of B cells for
survival. "But when there are mutations in either molecule, they
become uncoupled. In other words, TRAF 3 no longer represses the
action of NIK when necessary."
"The important thing to note is that when you uncouple NIK from TRAF3
action, its levels are not necessarily going to go up, but its
function is going to be changed. This can lead to B cell hyperplasia
and cancer."
"Our paper is saying 'be careful'! Sometimes you can find a patient
without high expression of NIK, so you think NIK is not implicated,
where it might be."
"In the very near future, we will have the capacity to do blood tests
and test for specific gene mutations in patients. Once you identify a
mutation, you can bypass the action of that gene, with targeted
medications."
"Both NIK and TRAF3 are molecules, so can potentially be targeted by
pharmaceuticals. We anticipate that new treatments for cancers may
emerge from our findings."
==========================
[alt stuff to cure cancer in case your psoriasis treatment leaves you
vulnerable]
Don't these guys right above know, all you need to CURE cancer is some
sodium bicarbonate according to
Oncologist Dr. Tullio Simoncini?
YeP...
Sodium bicarbonate will cure all cancer. Maybe that's what UWE was on
about? <w>
Go to the cure zone:
http://curezone.com/forums/fm.asp?i=1231827
Or same thing basically on mercola:
http://articles.mercola.com/sites/articles/archive/2008/08/05/fungus-causing-cancer-a-novel-approach-to-the-most-common-form-of-death.aspx
---------------------
Gosh will sodium bicarbonate work as a toPical for P?
WE must have some sodium Bicarb in the P ng.
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=sodium+bicarbonate&qt_g=Search+this+group
But is it topical fungus or funky topical microbiome or coming
systemic wide?
++++++++++++++++++
Here's another cancer cure. Injections of Gcmaf do the trick.
http://groups.google.com/group/yeshallknowthetruth/msg/f8e9a3bc5aca96b1
This blog has the same text with pictures included:
http://waccobb.net/forums/showthread.php?t=37661
Gcmaf (vitamin D3) to stop or slow psoriasis?
http://www.google.com/search?sa=N&tab=nw&q=gcmaf
http://jnci.oxfordjournals.org/cgi/content/abstract/94/17/1311
To
http://www.ncbi.nlm.nih.gov/pubmed/18058096?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Immunotherapy of metastatic colorectal cancer with vitamin D-binding
protein-derived macrophage-activating factor, GcMAF.
Yamamoto N, Suyama H, Nakazato H, Yamamoto N, Koga Y.
Division of Cancer Immunology and Molecular Immunology, Socrates
Institute for Therapeutic Immunology, 1040, 66th Ave, Philadelphia, PA
19126-3305, USA. nobut...@verizon.net
Serum vitamin D binding protein (Gc protein) is the precursor for the
principal macrophage-activating factor (MAF). The MAF precursor
activity of serum Gc protein of colorectal cancer patients was lost or
reduced because Gc protein is deglycosylated by serum alpha-N-
acetylgalactosaminidase (Nagalase) secreted from cancerous cells.
Deglycosylated Gc protein cannot be converted to MAF, leading to
immunosuppression. Stepwise treatment of purified Gc protein with
immobilized beta-galactosidase and sialidase generated the most potent
macrophage-activating factor (GcMAF) ever discovered, but it produces
no side effect in humans. Macrophages treated with GcMAF (100 microg/
ml) develop an enormous variation of receptors and are highly
tumoricidal to a variety of cancers indiscriminately. Administration
of 100 nanogram (ng)/ human maximally activates systemic macrophages
that can kill cancerous cells. Since the half-life of the activated
macrophages is approximately 6 days, 100 ng GcMAF was administered
weekly to eight nonanemic colorectal cancer patients who had
previously received tumor-resection but still carried significant
amounts of metastatic tumor cells. As GcMAF therapy progressed, the
MAF precursor activities of all patients increased and conversely
their serum Nagalase activities decreased. Since serum Nagalase is
proportional to tumor burden, serum Nagalase activity was used as a
prognostic index for time course analysis of GcMAF therapy. After
32-50 weekly administrations of 100 ng GcMAF, all colorectal cancer
patients exhibited healthy control levels of the serum Nagalase
activity, indicating eradication of metastatic tumor cells. During 7
years after the completion of GcMAF therapy, their serum Nagalase
activity did not increase, indicating no recurrence of cancer, which
was also supported by the annual CT scans of these patients.
PMID: 18058096
So we hook up psor heads (you and me) to cancer patients and filter
out the GcMaF and tnf and ifn
and CURE the folks with cancer. Simple.
Why isn't anyone doing this? LOL
++++++++++++++++
Not only is the gut biota suspect, the skin is as WELL.
Then why haven't they nailed the exact mechanism?
http://www.ncbi.nlm.nih.gov/pubmed/18648509?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Substantial alterations of the cutaneous bacterial biota in psoriatic
lesions.
Gao Z, Tseng CH, Strober BE, Pei Z, Blaser MJ.
Department of Medicine, New York University School of Medicine, New
York, New York, United States of America.
For psoriasis, an idiopathic inflammatory disorder of the skin, the
microbial biota has not been defined using cultivation-independent
methods. We used broad-range 16S rDNA PCR for archaea and bacteria to
examine the microbiota of normal and psoriatic skin. From 6 patients,
19 cutaneous samples (13 from diseased skin and 6 from normal skin)
were obtained. Extracted DNA was subjected to the broad range PCR, and
1,925 cloned products were compared with 2,038 products previously
reported from healthy persons. Using 98% sequence identity as a
species boundary, 1,841 (95.6%) clones were similar to known bacterial
16S rDNA, representing 6 phyla, 86 genera, or 189 species-level
operational taxonomic unit (SLOTU); 84 (4.4%) clones with <98%
identity probably represented novel species. The most abundant and
diverse phylum populating the psoriatic lesions was Firmicutes
(46.2%), significantly (P<0.001) overrepresented, compared to the
samples from uninvolved skin of the patients (39.0%) and healthy
persons (24.4%). In contrast, Actinobacteria, the most prevalent and
diverse phylum in normal skin samples from both healthy persons
(47.6%) and the patients (47.8%), was significantly (P<0.01)
underrepresented in the psoriatic lesion samples (37.3%).
Representation of Propionibacterium species were lower in the
psoriatic lesions (2.9+/-5.5%) than from normal persons (21.1+/-18.2%;
P<0.001), whereas normal skin from the psoriatic patients showed
intermediate levels (12.3+/-21.6%). We conclude that psoriasis is
associated with substantial alteration in the composition and
representation of the cutaneous bacterial biota.
PMID: 18648509
-----------------
MyD88 in the pathway? LPS from a leaky gut then ramPs uP Th1 skew?
http://www.ncbi.nlm.nih.gov/pubmed/18641322?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced
dendritic cell maturation.
Shen H, Tesar BM, Walker WE, Goldstein DR.
Department of Internal Medicine, Yale University School of Medicine,
New Haven, CT 06510, USA.
TLR4 is a unique TLR because downstream signaling occurs via two
separate pathways, as follows: MyD88 and Toll IL-1 receptor (TIR)
domain-containing adaptor-inducing IFN-beta (TRIF). In this study, we
compared and contrasted the interplay of these pathways between murine
dendritic cells (DCs) and macrophages during LPS stimulation. During
TLR4 activation, neither pathway on its own was critical for up-
regulation of costimulatory molecules in DCs, whereas the up-
regulation of costimulatory molecules was largely TRIF dependent in
macrophages. LPS-induced secreted factors, of which type I IFNs were
one of the active components, played a larger role in promoting the up-
regulation of costimulatory molecules in macrophages than DCs. In both
cell types, MyD88 and TRIF pathways together accounted for the
inflammatory response to LPS activation. Furthermore, signaling of
both adaptors allowed maximal T cell priming by LPS-matured DCs, with
MyD88 playing a larger role than TRIF. In sum, in our experimental
systems, TRIF signaling plays a more important role in LPS-induced
macrophage activation than in DC activation.
PMID: 18641322
----------------------------
From Life extension: Why stress is BAD? This snippet goes with the
first post in this thread.
Certainly Susan can attest to increased cortisol effects for psoriasis
iatrogenesis.
Readers of Life Extension Update may recall the November 29, 2004
issue which described an association between emotional stress and
shortened telomeres, a marker of cellular aging. Now, in research
published in the May, 2008 issue of Brain, Behavior and Immunity, a
team at the University of California, Los Angeles report that they may
have discovered why.
Telomeres are caps at the ends of chromosomes (the genetic material of
the cell) that contribute to their stability. Each time a cell
divides, telomeres lose length. Telomeres also lose length in response
to chronic stress. Shortened telomeres in white blood cells known as
lymphocytes have been associated with HIV, osteoporosis, heart disease
and aging. An enzyme within the cell known as telomerase helps prevent
telomere shortening and maintains the cells' ability to continue
dividing.
For the current investigation, UCLA David Geffen School of Medicine
professor of pathology and laboratory medicine Rita Effros and
colleagues studied lymphocytes from healthy male and female donors
between the ages of 25 and 55. The cells were treated with varying
concentrations of cortisol, the hormone released by the body when
under stress, or with DMSO (as a control).
After three days, cultures treated with cortisol had fewer cells than
the control cultures. While treatment with a concentration of cortisol
equivalent to that normally found in humans had no effect on
telomerase activity, concentrations of the hormone comparable to
levels found in the body under stress were demonstrated to reduce
telomerase activity by up to 50 percent compared with telomerase
activity measured in the control cultures.
The discovery explains how stress reduces telomerase, thereby
accelerating cellular aging, via increased cortisol production. "When
the body is under stress, it boosts production of cortisol to support
a "fight or flight" response," Dr Effros explained. "If the hormone
remains elevated in the bloodstream for long periods of time, though,
it wears down the immune system. We are testing therapeutic ways of
enhancing telomerase levels to help the immune system ward off
cortisol's effect. If we're successful, one day a pill may exist to
strengthen the immune system's ability to weather chronic emotional
stress."
==================================
randall.... No Gold in this bunch?
randall
New mAB from down under.
http://newsstore.smh.com.au/apps/previewDocument.ac?docID=GCA00870278AAH
This is odd. But if you take the time you'll find ART621
-------
That took me to this as it's easier to follow.
http://www.arana.com/inflammation_franchise_art621.htm
ART621 - PHASE II TRIAL UNDERWAY
ART621 is a new type of therapeutic antibody called a domain antibody.
A number of anti-TNF products (Humira®, Remicade® and Enbrel®) are
currently on the market for the treatment of rheumatoid arthritis.
Unlike previous treatments, such as aspirin, that deal with the signs
and symptoms, the anti-TNF products prevent further progression of the
disease.
Global sales for these products totalled over US$13 billion in 2007
and are projected to rise to about $20 billionby 2012.
However, new antibody-based treatments are still needed because some
patients have developed resistance and many stop responding to a
particular anti-TNF antibody after pro-longed use, yet respond when
switched to a different one.
ART621 is the first human framework domain antibody (dAb) to be used
in human trials. Domain antibodies exhibit the binding properties to a
target characteristic of a full-sized antibody, but are considerably
smaller. This has the potential to make them effective in the
treatment of inflammation, as they may have advantages in entry into
diseased joints and tissues.
In addition, its smaller size means ART621 can be readily manufactured
at high levels and purified at high yield, which is favorable to cost
effective manufacture.
In animal models of rheumatoid arthritis, ART621 matched the
performance of one blockbuster anti-TNF antibody product currently on
the market and displayed favourable properties in terms of stability,
duration of action and tissue localisation within the body.
In October 2007, ART621 completed a Phase I clinical trial of
escalating doses in 30 healthy volunteers. In the trial, at St
Vincent’s Hospital in Sydney, single doses of ART621 administered
intravenously and under the skin, were well tolerated and free of side
effects.
<sniP>
======================================
As GM-CSF is in the P pathway, it's alway on the radar.
http://en.wikipedia.org/wiki/Granulocyte_macrophage_colony-stimulating_factor
Granulocyte-macrophage colony-stimulating factor, often abbreviated to
GM-CSF, is a protein secreted by macrophages, T cells, mast cells,
endothelial cells and fibroblasts.
Functions
GM-CSF is a cytokine that functions as a white blood cell growth
factor. GM-CSF stimulates stem cells to produce granulocytes
(neutrophils, eosinophils, and basophils) and monocytes. Monocytes
exit the circulation and migrate into tissue, whereupon they mature
into macrophages. It is thus part of the immune/inflammatory cascade,
by which activation of a small number of macrophages can rapidly lead
to an increase in their numbers, a process crucial for fighting
infection. The active form of the protein is found extracellularly as
a homodimer.
<sniP>
------------
http://en.wikipedia.org/wiki/Granulocyte_macrophage_colony-stimulating_factor_receptor
-----------------------
GM-CSF in the P NG:
That first one is a hit, makes this one look like an instant replay...
But i'll find a new abstract to dress this one uP.
-----------------
http://www.kalobios.com/kb_pipeline_002.php
[...]
Role of GM-CSF in Autoimmune Disease
GM-CSF plays a role in activating and maintaining the viability of
macrophages, white blood cells that play a key role in both
nonspecific defense (innate immunity) and cell-mediated immunity.
These cells help rid the body of cellular debris and pathogens, and
stimulate lymphocytes and other immune cells to respond to pathogens
as part of the inflammatory immune response. In autoimmune diseases,
where the body mounts an immune response against its own tissue,
macrophages play an important role. In the autoimmune state,
macrophages produce excess cytokines that prolong inflammation.
Secondly, activated macrophages produce enzymes that directly cause
tissue damage. Finally, macrophages
amplify the undesirable response by producing GM-CSF that activates
additional macrophages. The role of GM-CSF in activating and
maintaining the viability of macrophages thus provides a strong
rationale for neutralizing this molecule as a treatment for
inflammatory autoimmune diseases such as rheumatoid arthritis.
The therapeutic potential of inhibiting GM-CSF in autoimmune disease
is supported by a significant body of research data generated by
researchers at the Ludwig Institute and elsewhere:
1. 1.GM-CSF gene knock-out mice are resistant to the induction of
autoimmune diseases e.g. collagen-induced arthritis (CIA),
experimental encephalomyelitis (EAE) but show no major changes in
hematopoiesis (Campbell et al J.Immunology 161:3639-3644, 1998,
McQualter et al J. Exp. Med. 194:873-881,2001)
2. 1.Transgenic mice over-expressing GM-CSF in different tissues
develop tissue-specific autoimmune reactions (Biondo et al J.
Immunology 166:2090-2099, 2001)
3. 1.An antibody that neutralizes murine GM-CSF prevents and treats
CIA and EAE in mice (Cook et al, Arthritis Research: 3(5); 293- 298,
2001)
4. GM-CSF dosed to patients can reactivate their autoimmune disease
5. 1.Rheumatoid arthritis patients have elevated levels of GM-CSF
in their diseased joints (Xu et al J. Clin. Invest.83: 876-882,1989)
<sniP>
=================
I wonder if this miracle cream (thymulen 4) causes increased psoriasis
due to it's properties of increasing
GM-CSF?
http://www.isxperia.com/_personal/images/mechofaction.jpg
==================================
http://www.ncbi.nlm.nih.gov/pubmed/18701168?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
GM-CSF enhances a CpG-independent pathway of neutrophil activation
triggered by bacterial DNA.
Bass JI, Alvarez ME, Gabelloni ML, Vermeulen ME, Amaral MM, Geffner
JR, Trevani AS.
Departamento de Inmunología, Instituto de Investigaciones
Hematológicas e Instituto de Estudios Oncológicos "Fundación Maissa";
Academia Nacional de Medicina, Buenos Aires, Argentina; Departamento
de Fisiología, Biología Molecular y Celular, Facultad de Ciencias
Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires,
Argentina.
We have previously demonstrated that bacterial DNA induces neutrophil
activation through a CpG- and TLR9-independent but MyD88-dependent-
pathway. In this study we determined that GM-CSF enhances the
activation of neutrophils by bacterial DNA. Granulocyte-macrophage
colony-stimulating factor increased IL-8 and IL-1beta secretion, and
CD11b-upregulatio n induced by single-stranded bacterial DNA. It also
enhanced neutrophil IL-8 production induced by double-stranded
bacterial DNA, methylated single-stranded DNA, plasmid DNA, and
phosphorothioated-CpG and non-CpG-oligodeoxynucleotides. Together
these observations indicated that GM-CSF enhances neutrophil responses
triggered by bacterial DNA in a CpG-independent fashion. We also found
that GM-CSF enhanced the activation of the MAPKs p38 and ERK1/2
induced by bacterial DNA. Moreover, the pharmacological inhibition of
these pathways significantly diminished GM-CSF ability to increase
neutrophil activation by bacterial DNA. Finally, we observed that GM-
CSF was unable to increase the activation of MyD88(-/-) neutrophils by
bacterial DNA. Our findings suggest that GM-CSF modulates the CpG-
independent, MyD88-dependent neutrophil response to bacterial DNA, by
increasing the activation of the MAPKs p38 and ERK1/2.
PMID: 18701168
And as stated in this group many times, IL-10 will slow psoriasis and
also GM-CSF
http://www.ncbi.nlm.nih.gov/pubmed/18691071?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Role of IL-10 in the resolution of airway inflammation.
Ogawa Y, Duru EA, Ameredes BT.
Division of Allergy, Pulmonary, Immunology, Critical Care, and Sleep
(APICS), Department of Internal Medicine, Medical Research Building
8.104, University of Texas Medical Branch, 301 University Blvd.,
Galveston, TX 77555-1083, USA. Bill.A...@utmb.edu.
IL-10 can be considered an important agent in the resolution of
inflammation. Original ly named "cytokine synthesis inhibitory factor"
for its ability to inhibit IFN-gamma and IL-2 production in Th2 cells,
it is secreted by monocytes, macrophages, mast cells, T and B
lymphocytes, and dendritic cells (DCs). IL-10 production and release
by monocytic cells in response to allergic challenge is upregulated by
TNF-alpha, and by negative feedback regulation of itself. However, it
is also secreted by T regulatory cells (Tregs), under the control of
IL-2. Importantly in the context of asthma, IL-10 inhibits
eosinophilia, by suppression of IL-5 and GM-CSF, by direct effects on
eosinophil apoptosis, and effects on cell proliferation through down-
regulation of IL-1. A number of its cytokine suppressive
characteristics are now thought to occur through its upregulation of
suppressor of cytokine signaling (SOCS)-3. IL-10 is also a suppressor
of nitric oxide (NO) production, which may have ramifications for its
role in airway inflammatory diseases. Initial clinical trials have
demonstrated relative safety and few clinically adverse events at
doses of recombinant human IL-10 below 50 microg/kg, with mixed
success in treatment of patients with inflammatory bowel disease and
psoriasis. However, both steroid therapy and allergen specific
immunotherapy are known to elevate endogenous IL-10 levels, which may
account for their efficacy, suggesting that further study of IL-10 as
a target for treatment of airway inflammatory diseases such as asthma
and COPD is warranted.
PMID: 18691071
==========================================
Will the stats turn up the key to why inflammation begins?
http://www.ncbi.nlm.nih.gov/pubmed/18708155?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
New insights into the roles of Stat5a/b and Stat3 in T cell
development and differentiation.
Wei L, Laurence A, O'Shea JJ.
Molecular Immunology and Inflammation Branch, National Institute of
Arthritis and Musculoskeletal and Skin Diseases, National Institutes
of Health, Bethesda, MD, USA.
T cell development and differentiation is carefully orchestrated by a
series of cytokines. The importance of STAT family proteins in
mediating signals by these cytokines is well-known, but new
information on the role of STATs in novel aspects of T cell function
and T cell subsets continues to accumulate. Recent studies have placed
Stat5a/b and Stat3 center stage in T cell development and
differentiation. Stat5a/b are indispensable in T regulatory (Treg)
cell development and maintenance, and negatively regulate T helper 17
(Th17) cell differentiation. Conversely, Stat3 is essential for Th17
differentiation and inhibits Treg cells. The balance of Treg and Th17
cells is thought to be critical in maintaining immune tolerance, while
preserving effective host defense. Therefore, Stat5a/b and Stat3 are
emerging to be key players in T cell differentiation and homeostasis.
PMID: 18708155
Or do go back to hedgehog signaling?
randall...