August 23, 2005
Penn Study Finds a New Role
for RNA in
Human Immune Response
Findings Could Lead To New Types of Therapeutic
for Cancer, Genetic Diseases
(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have published
the first study to test the role of RNA chemical modifications
on immunity. They have demonstrated that RNA from bacteria
stimulates immune cells to orchestrate destruction of
invading pathogens. Most RNA from human cells is recognized
as being self and does not stimulate an immune response
to the same extent as invading bacteria or viruses.
The researchers hypothesize that if this self-recognition
fails, then autoimmune diseases such as systemic lupus
erythematosus could result.
The research was a collaborative work led by Drew
Weissman, MD, PhD, of the Division of Infectious
Diseases and Katalin Karikó, PhD,
of the Department of Neurosurgery. The investigators
published their findings in the August issue of Immunity.
“We think this study will open a new area of research
in understanding how our immune systems protect us,”
“One application of our findings is that scientists
will be able to design better therapeutic RNAs, including
anti-sense or small-interfering RNAs, for treating diseases
such as cancer and single-gene genetic diseases,”
RNA is the genetic material that programs cells to make
proteins from DNA’s blueprint and specifies which
proteins should be made. There are many types of RNA
in the cells of mammals, such as transfer RNA, ribosomal
RNA, messenger RNA, and all of them have specific types
of chemical tags, or modifications. In contrast, RNAs
from bacteria have fewer or no modifications.
Another type of RNA in mammalian cells is found in mitochondria,
the powerhouses of cells. Mitochondrial RNA is thought
to have originated from bacteria millions of years ago.
Similar to RNA from bacteria, mitochondrial RNA has
fewer chemical tags. It is the absence of modifications
that causes RNA from bacteria and mitochondria to activate
the immune response. The researchers suggest that these
modifications have evolved in animals as one of the
ways for the innate immune system to discriminate self
When a tissue is damaged by injury, infection, or inflammation,
cells release their mitochondrial RNA. This RNA acts
as a signal to the immune system to recognize the damage
and help defend and repair the tissue.
Conversely, the presence of the modifications on the
other types of RNA does not activate an immune response
and thus allows the innate immune system to discriminate
self from non-self. “We showed that special proteins
on the surface of immune cells, called Toll-like receptors,
are instrumental in recognizing bacterial and mitochondrial
RNA,” explains Weissman. The amount of modification
on the RNA is important because as little as one or
two tags per RNA molecule could prevent or suppress
the immune reaction.
The authors concluded that the potential of RNA to activate
immunity seems to be inversely correlated with the extent
of its chemical modification and may explain why some
viral RNA that is overly modified evades immune surveillance.
The authors plan to investigate whether longer RNAs
with specific tags will be useful for delivering therapeutic
molecules to diseased cells.
This study was funded by the National Institutes of
Health. Co-authors are Michael Buckstein and Houping
Ni, both from Penn.
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