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Body's Own DNA Coupled With A
Peptide Ignites Immune Response Usually Aimed At Fighting Infection
edited by Joint-Pain-Forum.com
A human peptide that acts as a natural antibiotic against invading microbes can
also bind to the body's own DNA and trigger an immune response in the absence of
an infection, a research team led by scientists at The University of Texas M. D.
Anderson Cancer Center reports in an early online publication in Nature.
"This combination of the peptide and self-DNA activates the same immune
response pathway as a virus does," says senior author Michel Gilliet, M.D.,
assistant professor in M. D. Anderson's Departments of Immunology and Melanoma
Researchers believe this response is both a likely key
driver of autoimmune disease and an integral part of an early warning system
that flags tissue damage to launch a protective inflammatory response to injury.
"We show that this pathway may drive autoimmunity in psoriasis, a
chronic inflammatory skin disease," Gilliet says. But the key peptide, called
both LL37 and CAMP, is also heavily expressed in other autoimmune diseases such
as inflammatory bowel disease and rheumatoid arthritis.
LL37 provides a
new potential target to block in the treatment of chronic inflammatory diseases
and a possible component for vaccines against infectious diseases and cancers,
the authors note.
The team tracked down this new pathway by studying the
activation of important immune defense cells in psoriasis. Plasmacytoid
dendritic cells (pDCs) are highly specialized to recognize viral and other
microbial infections. They engulf a virus and set off an immune system cascade
to fight the infection by producing interferons. Gilliet and colleagues
previously showed that pDC activation in psoriatic skin drives the development
of human psoriasis
"These dendritic cells normally do not respond to
self-DNA," Gilliet explains. This unresponsiveness prevents the cells from
launching an attack on the body's own tissue. However, researchers had
accumulated evidence of a connection between skin damage with release of
self-DNA and pDC activation in psoriatic skin leading to disease formation. They
lacked a molecular mechanism connecting these factors.
In a series of
lab experiments, they identified LL37 as the key ingredient in psoriatic tissue
that activates the dendritic cells. The peptide is a member of a family of
antimicrobial peptides long known to defend against infection through their
ability to directly destroy bacteria and viruses.
The team then
demonstrated that LL37 activates the dendritic cells by binding to the self-DNA
to form a structure that allows it into the dendritic cells, as if it were an
The complex is taken up inside a walled-off chamber in
the pDCs called an endosome, where it connects to a sensitive internal receptor
that launches production of interferon-alpha, setting off the immune response.
"We think LL37's normal job is to alert the immune system to tissue
damage and stimulate a temporary inflammatory response that enhances resistance
to infection and initiates wound healing," Gilliet says.
"When tissue is
injured, cells are destroyed and they spill DNA into the areas surrounding the
cells. LL37, released by epithelial cells, binds this extracellular DNA, which
is then taken up by the pDCs to launch the protective inflammatory immune
response," Gilliet says.
But in the case of autoimmune disease, LL-37
remains persistently produced, well beyond the temporary jolt needed to dampen
infection and promote healing.
Gilliet says follow-up research to better
understand the pathway and to exploit it to treat autoimmune disease and cancer
is under way.
www.Joint-Pain-Forum.com from original press release.
A grant from the M. D. Anderson Cancer Foundation funded the project, while part
of the work was supported by grants from the Deutsche Forschungsmemeinschaft.
Co-authors with Gilliet and first author Roberto Lande are Josh
Gregorio, Valeria Facchinetti, Yi-Hong Wang, Wei Cao, Yui-Hsi Wang, Bing Su,
Tomasz Zal and Yong-Jun Liu, all of the M. D. Anderson Department of Immunology;
Bithi Chatterjee and Ira Mellman, both of Yale University and Genentech; Frank
O. Nestle, of King's College London School of Medicine; Bernhard Homey of
Heinrich-Heine University of Dusseldorf, Germany; and Jens-Michael Schröder of
University Hospital Schlewsig-Holstein, University of Kiel, Germany.
Source: Scott Merville
University of Texas M. D. Anderson Cancer Center
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