Chemical Attraction Needed To Launch An Immune Attack

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[ ] Chemical Attraction Needed To Launch An Immune

Attack

Posted 3/8/2002

Chemical Attraction Needed To Launch An Immune Attack

A team led by UCSF scientists has determined how the weapons producers

of the immune system - the B cells that make antibodies - find the T

cells they must team up with to attack invading pathogens. The discovery

may provide a strategy to block autoimmune diseases, the study's leaders

suggests.

Chemical attraction is the key, the researchers found. Before they

encounter foreign microbes, B cells concentrate in regions where few T

cells reside, moored by their attraction to a certain kind of molecule

called a chemokine. But contact with antigen from an invading microbe

triggers changes in the B cell surface that draw them, irresistibly, to

another type of chemokine, concentrated in T cell-rich sites.

This shifting balance of opposing chemical attractants may underlie a

broad range of cellular movement in embryological development, the

scientists conclude.

The research, based on studies of mice, is published in the March 7

issue of the journal Nature.

In their " naïve " state, before they encounter antigen from potential

pathogens, B cells cruise through the lymphatic system - principally the

spleen and lymph nodes - seeking signs of foreign invaders. In this

state, they are receptive to a type of chemical attractant, or chemokine

called CXCL13, largely restricted to a neighborhood populated by other B

cells and known simply as the " B zone " .

But when stimulated by an antigen signal from a foreign microbe, the B

cell doubles the number of receptors on its surface cued to a different

group of chemical attractants known as CCL19 and CCL21, the researchers

found. This makes all the difference, since these attractants are found

in far greater concentration where T cells reside -- the " T zone. " The

increased receptiveness to these signals prompts the B cell to migrate

within the lymphatic tissue from the B zone to the boundary between the

B and T zones where cells of the two types can pair up. The pairing is

known to be essential for the immune system to mount an antibody attack.

" We have known for some time that the antigen triggers a change that

prompts B cell migration, but we didn't know how the process worked, "

said Cyster, PhD, a Medical Investigator and UCSF

associate professor of microbiology and immunology. " This process is not

only critical in the action of most vaccines, but it likely plays a

central role in autoimmune diseases. Blocking these attractants may

prove an effective strategy to block auto-antibody mediated disease. "

Cyster is senior author on the Nature paper.

In experiments with mice and mice cells, the researchers used a gene

therapy approach to show that artificially increasing the numbers of

receptors for T zone chemokines, CCL19 and CCL21, on B cells was

sufficient to cause B cell migration to the T zone. Reciprocally, B

cells with artificially increased receptors for the B zone chemokine,

CXCL13, " overcame " the attractive signals from the T zone and headed

back home to the B cell neighborhood.

Using B cells from mice with mutations in the receptor for the T zone

chemokines, the researchers showed that this receptor was essential for

the re-routing behavior. B cells with increased receptors for T zone

chemokines (CCL19 and CCL21) but no receptors for the B zone chemokine

CXCL13 no longer took the route that ran along the boundary of the two

neighborhoods, but instead headed directly toward " T zone central. "

The findings led to the conclusion that B cell movement in response to

the antigen is determined by the balance of responsiveness to the two

kinds of chemical attractants made in adjacent zones - a kind of

push-pull in which the B cells are much more responsive to being pulled

toward the T zone after they are exposed to the antigen. While the

mechanism is clear and convincing, other factors, such as adhesion

molecules, may also play a role the researchers suggest.

Cell migration is critical not only in the adult immune defense, but in

all phases of embryonic development when, for example, neurons must find

their way to their targets and muscle cells must interact and fuse. The

role of chemokines or other chemical attractants uncovered in this

study, creating zones that draw cells in depending on subtle changes in

the amount of receptors arrayed on the cell's surface, may be a general

pattern found widely in development, Cyster suggests.

The researchers now hope to determine whether similar changes in

chemokine receptor levels are involved in redirecting the movement of

autoreactive B cells. If this proves to be true, they think they may be

on the path to resolving what goes wrong in some people to cause

auto-antibody-mediated disease. Understanding this malady at the

molecular level has been a long standing problem in immune system

research.

### Co-first authors on the Nature paper are Karin Reif, PhD,

postdoctoral scientist, and H. Ekland, BS, an HHMI predoctoral

fellow, both in microbiology and immunology at UCSF.

Collaborators on the research and co-authors are Lars Ohl, PhD, a

postdoctoral scientist at Nikolaus-Fiebiger Center, Erlangen, Germany;

Hideki Nakano, PhD, a postdoctoral researcher at Duke University;

Lipp, PhD, a professor in immunology at the Max Delbruck Center for

Molecular Medicine, Berlin, Germany; and Reinhold Forster, PhD, a

professor of immunology at the Nikolaus-Fiebiger Center.

The research was supported in part by the National Institutes of Health.

###

Editors Note: A diagram and caption describing the newly discovered

immune system process can be accessed at this UCSF site:

http://pub.ucsf.edu/ imagedb/imsearch.php?iname=030420024

http://www.sciencedaily.com/releases/2002/03/020307074842.htmhttp://www.

sciencedaily.com/releases/2002/03/020307074842.htm

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Posted 3/8/2002

Chemical Attraction Needed To Launch An Immune Attack

A team led by UCSF scientists has determined how the weapons producers of the

immune system - the B cells that make antibodies - find the T cells they must

team up with to attack invading pathogens. The discovery may provide a strategy

to block autoimmune diseases, the study's leaders suggests.

Chemical attraction is the key, the researchers found. Before they encounter

foreign microbes, B cells concentrate in regions where few T cells reside,

moored by their attraction to a certain kind of molecule called a chemokine. But

contact with antigen from an invading microbe triggers changes in the B cell

surface that draw them, irresistibly, to another type of chemokine, concentrated

in T cell-rich sites.

This shifting balance of opposing chemical attractants may underlie a broad

range of cellular movement in embryological development, the scientists

conclude.

The research, based on studies of mice, is published in the March 7 issue of the

journal Nature.

In their " naïve " state, before they encounter antigen from potential pathogens,

B cells cruise through the lymphatic system - principally the spleen and lymph

nodes - seeking signs of foreign invaders. In this state, they are receptive to

a type of chemical attractant, or chemokine called CXCL13, largely restricted to

a neighborhood populated by other B cells and known simply as the " B zone " .

But when stimulated by an antigen signal from a foreign microbe, the B cell

doubles the number of receptors on its surface cued to a different group of

chemical attractants known as CCL19 and CCL21, the researchers found. This makes

all the difference, since these attractants are found in far greater

concentration where T cells reside -- the " T zone. " The increased receptiveness

to these signals prompts the B cell to migrate within the lymphatic tissue from

the B zone to the boundary between the B and T zones where cells of the two

types can pair up. The pairing is known to be essential for the immune system to

mount an antibody attack.

" We have known for some time that the antigen triggers a change that prompts B

cell migration, but we didn't know how the process worked, " said Cyster,

PhD, a Medical Investigator and UCSF associate professor of

microbiology and immunology. " This process is not only critical in the action of

most vaccines, but it likely plays a central role in autoimmune diseases.

Blocking these attractants may prove an effective strategy to block

auto-antibody mediated disease. " Cyster is senior author on the Nature paper.

In experiments with mice and mice cells, the researchers used a gene therapy

approach to show that artificially increasing the numbers of receptors for T

zone chemokines, CCL19 and CCL21, on B cells was sufficient to cause B cell

migration to the T zone. Reciprocally, B cells with artificially increased

receptors for the B zone chemokine, CXCL13, " overcame " the attractive signals

from the T zone and headed back home to the B cell neighborhood.

Using B cells from mice with mutations in the receptor for the T zone

chemokines, the researchers showed that this receptor was essential for the

re-routing behavior. B cells with increased receptors for T zone chemokines

(CCL19 and CCL21) but no receptors for the B zone chemokine CXCL13 no longer

took the route that ran along the boundary of the two neighborhoods, but instead

headed directly toward " T zone central. "

The findings led to the conclusion that B cell movement in response to the

antigen is determined by the balance of responsiveness to the two kinds of

chemical attractants made in adjacent zones - a kind of push-pull in which the B

cells are much more responsive to being pulled toward the T zone after they are

exposed to the antigen. While the mechanism is clear and convincing, other

factors, such as adhesion molecules, may also play a role the researchers

suggest.

Cell migration is critical not only in the adult immune defense, but in all

phases of embryonic development when, for example, neurons must find their way

to their targets and muscle cells must interact and fuse. The role of chemokines

or other chemical attractants uncovered in this study, creating zones that draw

cells in depending on subtle changes in the amount of receptors arrayed on the

cell's surface, may be a general pattern found widely in development, Cyster

suggests.

The researchers now hope to determine whether similar changes in chemokine

receptor levels are involved in redirecting the movement of autoreactive B

cells. If this proves to be true, they think they may be on the path to

resolving what goes wrong in some people to cause auto-antibody-mediated

disease. Understanding this malady at the molecular level has been a long

standing problem in immune system research.

### Co-first authors on the Nature paper are Karin Reif, PhD, postdoctoral

scientist, and H. Ekland, BS, an HHMI predoctoral fellow, both in

microbiology and immunology at UCSF.

Collaborators on the research and co-authors are Lars Ohl, PhD, a postdoctoral

scientist at Nikolaus-Fiebiger Center, Erlangen, Germany; Hideki Nakano, PhD, a

postdoctoral researcher at Duke University; Lipp, PhD, a professor in

immunology at the Max Delbruck Center for Molecular Medicine, Berlin, Germany;

and Reinhold Forster, PhD, a professor of immunology at the Nikolaus-Fiebiger

Center.

The research was supported in part by the National Institutes of Health.

###

Editors Note: A diagram and caption describing the newly discovered immune

system process can be accessed at this UCSF site: http://pub.ucsf.edu/

imagedb/imsearch.php?iname=030420024

http://www.sciencedaily.com/releases/2002/03/020307074842.htmhttp://www.scienced\

aily.com/releases/2002/03/020307074842.htm