article
New insights could lead to better vaccines, treatments for rheumatoid
arthritis, study suggests
Contact: Anne Rueter
arueter@umich.edu
734-764-2220
University of Michigan Health System
Immune cells that are the body's front-line defense don't necessarily
rest quietly until invading bacteria lock onto receptors on their
outside skins and rouse them to action, as previously thought. In a
new paper, University of Michigan scientists describe their findings
that bacteria can barge inside these guard cells and independently
initiate a powerful immune response.
The study, published online ahead of print in the April issue of the
journal Immunity and accompanied by a special commentary, adds
important new details to an emerging picture of how the body
recognizes invading bacteria and responds. The work of the U-M team
and researchers elsewhere - now taking place in laboratory animal
studies - offers a different way of thinking about how best to design
future human vaccines, as well as drugs that could more precisely
target the body's inflammatory response in rheumatoid arthritis and
some other autoimmune diseases.
"In our study, the presence of bacterial microbes inside the cell is
what triggers the immune response. That creates a new perspective for
developing new drugs," says senior author Gabriel Nunez, M.D., the
Paul H. de Kruif professor of pathology at the U-M Medical School and
a member of the U-M Comprehensive Cancer Center.
For years, scientists have believed that when bacteria invade the
body, they set off alarms in the immune system by interacting with
receptors on a cell's surface. But, now new studies are revealing that
bacteria can also plunge inside immune system cells and trigger the
immune response there. In the new study, Nunez' team sheds light on
one major pathway in which this process occurs.
When invading bacteria enter immune system cells, a protein called
cryopyrin, present in the fluid inside the cells, responds and
activates a key pathogen-fighting molecule, Nunez' team reported last
year in Nature. Cryopyrin is implicated in the development of several
inflammatory syndromes characterized by recurrent fever, skin rash and
arthritis.
Cryopyrin triggers a key enzyme involved in the body's inflammatory
response, capsase-1, which in turn causes production of IL-1beta, a
powerful molecule which signals the immune system to attack pathogens
and induces fever to help the body fend off infection. IL-1beta plays
an important role, too, in excessive immune system activity in
inflammatory diseases.
The researchers report in the new paper how cryopyrin is activated to
start the process. In experiments that exposed mouse immune cells
called macrophages to bacteria, Thirumala-Devi Kanneganti, Ph.D., a U-
M research investigator in pathology, and Mohamed Lamkanfi, Ph. D, a U-
M research fellow, the study's co-first authors, find that cryopyrin's
call to action inside the cells occurs without requiring a well-known
set of cell-surface receptors called Toll-like receptors or TLRs. "We
prove that these TLRs are not required to activate cryopyrin. That is
a major step," says Nunez.
Instead, bacteria were able to enter the cells through a pore in the
cell membrane, and stimulate the cryopyrin-initiated immune response
without activating TLRs. The researchers discovered that a protein
called pannexin-1 creates the pore, like a devious undersea diver
drilling a hole in a ship hull.
The team's work joins a growing body of research revealing the
importance of recently discovered receptors such as cryopyrin inside
cells, known collectively as NOD-like receptors. Knowledge about NOD-
like receptors is moving forward rapidly and will contribute to a
fuller understanding of the human immune system, say the U-M
researchers.
arthritis, study suggests
Contact: Anne Rueter
arueter@umich.edu
734-764-2220
University of Michigan Health System
Immune cells that are the body's front-line defense don't necessarily
rest quietly until invading bacteria lock onto receptors on their
outside skins and rouse them to action, as previously thought. In a
new paper, University of Michigan scientists describe their findings
that bacteria can barge inside these guard cells and independently
initiate a powerful immune response.
The study, published online ahead of print in the April issue of the
journal Immunity and accompanied by a special commentary, adds
important new details to an emerging picture of how the body
recognizes invading bacteria and responds. The work of the U-M team
and researchers elsewhere - now taking place in laboratory animal
studies - offers a different way of thinking about how best to design
future human vaccines, as well as drugs that could more precisely
target the body's inflammatory response in rheumatoid arthritis and
some other autoimmune diseases.
"In our study, the presence of bacterial microbes inside the cell is
what triggers the immune response. That creates a new perspective for
developing new drugs," says senior author Gabriel Nunez, M.D., the
Paul H. de Kruif professor of pathology at the U-M Medical School and
a member of the U-M Comprehensive Cancer Center.
For years, scientists have believed that when bacteria invade the
body, they set off alarms in the immune system by interacting with
receptors on a cell's surface. But, now new studies are revealing that
bacteria can also plunge inside immune system cells and trigger the
immune response there. In the new study, Nunez' team sheds light on
one major pathway in which this process occurs.
When invading bacteria enter immune system cells, a protein called
cryopyrin, present in the fluid inside the cells, responds and
activates a key pathogen-fighting molecule, Nunez' team reported last
year in Nature. Cryopyrin is implicated in the development of several
inflammatory syndromes characterized by recurrent fever, skin rash and
arthritis.
Cryopyrin triggers a key enzyme involved in the body's inflammatory
response, capsase-1, which in turn causes production of IL-1beta, a
powerful molecule which signals the immune system to attack pathogens
and induces fever to help the body fend off infection. IL-1beta plays
an important role, too, in excessive immune system activity in
inflammatory diseases.
The researchers report in the new paper how cryopyrin is activated to
start the process. In experiments that exposed mouse immune cells
called macrophages to bacteria, Thirumala-Devi Kanneganti, Ph.D., a U-
M research investigator in pathology, and Mohamed Lamkanfi, Ph. D, a U-
M research fellow, the study's co-first authors, find that cryopyrin's
call to action inside the cells occurs without requiring a well-known
set of cell-surface receptors called Toll-like receptors or TLRs. "We
prove that these TLRs are not required to activate cryopyrin. That is
a major step," says Nunez.
Instead, bacteria were able to enter the cells through a pore in the
cell membrane, and stimulate the cryopyrin-initiated immune response
without activating TLRs. The researchers discovered that a protein
called pannexin-1 creates the pore, like a devious undersea diver
drilling a hole in a ship hull.
The team's work joins a growing body of research revealing the
importance of recently discovered receptors such as cryopyrin inside
cells, known collectively as NOD-like receptors. Knowledge about NOD-
like receptors is moving forward rapidly and will contribute to a
fuller understanding of the human immune system, say the U-M
researchers.