5th August 16:46
TLR7, the flu, asthma, opioids and natural-killer cell tolerance of antigens (asthma diabetes stress influenza cytomegalovirus)
TLR7 is an antiviral receptor for single-stranded RNA and sometimes part
of the PKR/ER stress pathway. It seems the flu - along with H. Pylori -
triggers TLR7, which induces a certain subset of natural-killer cells
that then induce antigen tolerance via FoxP3+ Tregs. This effect,
though, only happens in a narrow window for infants.
In skin cells, Imiquimod, the TLR7 agonist, acts like low-dose
naltrexone to upregulate the OGF-OGFr axis (aka the
met-enkephalin/opioid growth factor receptor axis) [PMID 20975079].
Given the astonishing benefits low-dose naltrexone provides for several
autoimmune diseases, I have to wonder if LDN doesn't, in some way,
affect this NKT population. Could we be looking at an opioid/TLR7/NKT
pathway of some sort?
Before you wax too poetic about the flu, it's also associated with the
development of schizophrenia.
A Benefit of Flu: Protection from Asthma?
ScienceDaily (Dec. 14, 2010) ‹ In a paper that suggests a new strategy
to prevent asthma, scientists at Children's Hospital Boston and their
colleagues report that the influenza virus infection in young mice
protected the mice as adults against the development of allergic asthma.
The same protective effect was achieved by treating young mice with
compound isolated from the bacterium Helicobacter pylori (H. pylori), a
bacterium that colonizes the stomach and is best known for causing
ulcers and increasing the risk of gastric cancers.
The findings, published online December 13 in the Journal of Clinical
Investigation, provide a potential immunological mechanism in support of
the "hygiene hypothesis," an idea that attributes the increasing rate of
asthma and allergies to the successful reduction of childhood infections
with vaccines and antibiotics. The hygiene hypothesis is also supported
by epidemiological studies associating certain childhood infections,
such as respiratory viral infections or gastrointestinal infection with
H. pylori, with a lower risk of developing asthma.
"Some infections appear to result in important protective effects
against asthma," says Dale Umetsu, MD, PhD, of Children's Division of
Immunology, a senior author of the paper, and Professor of Pediatrics at
Harvard Medical School. "But we certainly don't want to give people
dangerous infections to prevent asthma. So if we can understand how
infections prevent asthma, we may be able to replicate the good parts
and avoid the bad parts of infection and develop new treatments for
children to prevent asthma."
In mice, influenza A infection appeared to confer its benefits by
expanding an immature cell type in the lung known as natural killer T
(NKT) cells, part of the innate immune system. The same beneficial NKT
cells in the lung could be expanded by several NKT-stimulating molecules
known as glycolipids, including one isolated from H. pylori.
The active infectious agents protected against asthma only if the mice
were exposed when very young (2 weeks). "Flu infection in adult mice
makes the allergic reaction worse," says Ya-Jen Chang, PhD, first author
and a postdoctoral fellow in Umetsu's lab.
Previous studies examining the hygiene hypothesis have focused on the
adaptive immune system, which features immune cells that are slow to
respond but are able to develop long-term memory, such as those
stimulated by each year's flu vaccine or those involved in seasonal
In contrast, the new paper examines the innate immune system, which
responds rapidly to infections and shapes adaptive immune responses.
This study specifically focuses on NKT cells, one of the first
responders to many infections. Previous work by Umetsu's team implicated
NKT cells as a cause of asthma. In contrast, the latest study reports on
a new subset of inhibitory NKT cells that seem to prevent allergic
reactions in the airways -- if stimulated at the right time by the right
infectious agents or the right glycolipid.
"In the absence of influenza A or the H. pylori compound, we see an
expansion of NKT cells that cause asthma and allergies," says Umetsu.
"We're now trying to understand how to specifically activate the
inhibitory subset of NKT cells. Treatments focused on specifically
expanding this inhibitory subset of cells in children might prevent the
development of asthma."
The researchers want to explore the the****utic applications of the H.
pylori glycolipid compound, synthesized by British lipid biochemist Petr
Illarionov, PhD. "It might be a good candidate for an asthma vaccine,"
says Chang. Umetsu wants to test the next generation of glycolipid
compounds, and to illuminate their specific mechanism of action, with a
more detailed characterization of the inhibitory NKT cells.
Funding: US National Institutes of Health, including stimulus funding
from the 2009 Recovery Act; Bunning Food Allergy Project; and Ministry
of Education, Culture, Sports, Science, and Technology of Japan.
The above story is reprinted (with editorial adaptations by ScienceDaily
staff) from materials provided by Children's Hospital Boston.
1. Ya-Jen Chang, Hye Young Kim, Lee A. Albacker, Hyun Hee Lee, Nicole
Baumgarth, Shizuo Akira, Paul B. Savage, Shin Endo, Takashi Yamamura,
Janneke Maaskant, Naoki Kitano, Abel Singh, Apoorva Bhatt, Gurdyal S.
Besra, Peter Van Den Elzen, Ben Appelmelk, Richard W. Franck, Guangwu
Chen, Rosemarie H. Dekruyff, Michio Shimamura, Petr Illarionov and Dale
T. Umetsu. Influenza infection in ****ling mice expands an NKT cell
subset that protects against airway hyperreactivity. Journal of Clinical
Investigation, 2010 DOI: 10.1172/JCI44845
J Clin Invest. 2010 Dec 13; [Epub ahead of print]Related Citations,
Influenza infection in ****ling mice expands an NKT cell subset that
protects against airway hyperreactivity.
* Chang YJ,
* Kim HY,
* Albacker LA,
* Lee HH,
* Baumgarth N,
* Akira S,
* Savage PB,
* Endo S,
* Yamamura T,
* Maaskant J,
* Kitano N,
* Singh A,
* Bhatt A,
* Besra GS,
* Elzen PV,
* Appelmelk B,
* Franck RW,
* Chen G,
* Dekruyff RH,
* Shimamura M,
* Illarionov P,
* Umetsu DT.
Infection with influenza A virus represents a major public health threat
worldwide, particularly in patients with asthma. However, immunity
induced by influenza A virus may have beneficial effects, particularly
in young children, that might protect against the later development of
asthma, as suggested by the hygiene hypothesis. Herein, we show that
infection of ****ling mice with influenza A virus protected the mice as
adults against allergen-induced airway hyperreactivity (AHR), a cardinal
feature of asthma. The protective effect was associated with the
preferential expansion of CD4-CD8-, but not CD4+, NKT cells and required
T-bet and TLR7. Adoptive transfer of this cell population into
allergen-sensitized adult mice suppressed the development of
allergen-induced AHR, an effect associated with expansion of the
allergen-specific forkhead box p3+ (Foxp3+) Treg cell population.
Influenza-induced protection was mimicked by treating ****ling mice with
a glycolipid derived from Helicobacter pylori (a bacterium associated
with protection against asthma) that activated NKT cells in a
CD1d-restricted fashion. These findings suggest what we believe to be a
novel pathway that can regulate AHR, and a new the****utic strategy
(treatment with glycolipid activators of this NKT cell population) for
the human body can create its own vaccine, which boosts the immune
system and helps prevent chronic inflammatory diseases; a protein
normally found in the body that can act to prevent chronic tissue
inflammation. When administered in the form of a the****utic vaccine it
is able to effectively prevent and treat a number of different
inflammatory disease models for multiple sclerosis (MS), rheumatoid
arthritis (RA), skin hypersensitivity and allergic asthma (AA); this
newly discovered protein could be a treatment for multiple autoimmune
conditions, such as Alzheimer¹s, Parkinson¹s, RA, AA, MS, type II
diabetes and cancers. The vaccine discovered by the researchers boosts
special cells of the immune system, called NKT cells. NKT cells are a
type of T cell that exert profound and diverse regulatory effects in
disease, from autoimmunity to responses to pathogens and cancer. For
over two decades since their discovery NKT cells have traditionally been
considered to be activated by lipid antigens presented by CD1 molecules;
for the first time this shows the ability of a self peptide to activate
NKT cells to suppress many tissue-specific inflammatory conditions
including experimental autoimmune diseases <http://news.ku.dk/all
news/2010/2010.12/vaccineboostsyourimmunesystem/>, abstract: NKT cells
in the mouse recognize antigen in the context of the MHC class I-like
molecule CD1d and play an important role in peripheral tolerance and
protection against autoimmune and other diseases. NKT cells are usually
activated by CD1d-presented lipid antigens. However, peptide recognition
in the context of CD1 has also been do***ented, although no self-peptide
ligands have been reported to date. Here, we have identified an
endogenous peptide that is presented by CD1d to activate mouse NKT
cells. This peptide, the immunodominant epitope from mouse collagen type
II (mCII707-721), was not associated with either MHC class I or II.
Activation of CD1d-restricted mCII707-721-specific NKT cells was induced
via TCR signaling and classical costimulation. In addition,
mCII707-721-specific NKT cells induced T cell death through Fas/FasL, in
an IL-17A-independent fashion. Moreover, mCII707-721-specific NKT cells
suppressed a range of in vivo inflammatory conditions, including
delayed-type hypersensitivity, antigen-induced airway inflammation,
collagen-induced arthritis, and EAE, which were all ameliorated by
mCII707-721 vaccination. The findings presented here offer new insight
into the intrinsic roles of NKT cells in health and disease. Given the
results, endogenous collagen peptide activators of NKT cells may offer
promise as novel the****utics in tissue-specific autoimmune and
inflammatory diseases [PMID 21157037], ³Endogenous collagen peptide
activation of CD1d-restricted NKT cells ameliorates tissue-specific
inflammation in mice²
The imidazoquinolines are immune response modifiers that have potent
antiviral and antitumor properties. The mechanism by which they exert
their effects on cell replication has been investigated in vitro and is
related to the upregulation of the opioid growth factor receptor (OGFr)
and modulation of opioid growth factor (OGF; [Met(5)]-enkephalin). The
OGF-OGFr axis regulates cell proliferative events through a
cyclin-dependent kinase inhibitory pathway. The present study examined
the mechanism whereby imiquimod repressed cell proliferation in vivo.
Using a **** mouse model that has a compromised T-cell immune system, as
well as C57BL/6 mice with an intact immune system, the effects of
topical imiquimod (Aldara((R)); the first marketed, topically active
TLR7 agonist) on DNA synthesis of basal epithelial cells in skin were
examined. Imiquimod's effects on DNA synthesis were detected 24 h after
application, and could be observed for one week after a single
treatment. The magnitude of change in DNA synthesis following imiquimod
was similar for one, three or six applications. Naloxone, an opioid
antagonist, blocked the inhibitory effect of imiquimod. Imiquimod in
combination with OGF or a low dose of naltrexone (LDN; known to
upregulate the OGF-OGFr axis) had no greater inhibitory response on DNA
synthesis than either OGF or LDN alone. Both OGF and OGFr were
upregulated in basal epithelium after imiquimod treatment. Both **** and
C57BL/6 mice exhibited the same repressive action of imiquimod on
epithelial DNA synthesis. Imiquimod was neither an opioid agonist nor
antagonist using nociceptive testing, and did not induce apoptosis or
necrosis. Exposure to imiquimod was found to depress DNA synthesis in
cells located in distant epithelium from day 3 and lasted until day 5.
These results suggest that the target of imiquimod on DNA synthesis is
dependent on an opioid receptor-mediated pathway, and infers that
imiquimod is reliant on the OGF-OGFr axis for modulating cell
proliferation [PMID 20975079]
PDCs mediate type I interferon (IFN-I - mainly IFN-alpha and IFN-beta)
responses to viruses that are recognized through TLR7 and TLR9; pDC-
depleted mice were challenged with viruses known to activate pDCs. In
murine cytomegalovirus (MCMV) infection, pDC depletion reduced early
IFN-I production and augmented viral burden facilitating the expansion
of natural killer (NK) cells expressing the MCMV-specific receptor
Ly49H. During vesicular stomatitis virus (VSV) infection, pDC depletion
enhanced early viral replication and impaired the survival and
ac***ulation of virus-specific cytotoxic T lymphocytes. We conclude that
pDCs mediate early antiviral IFN-I responses and influence the accrual
of virus-specific NK or CD8(+) T cells in a virus-dependent manner [PMID