Biologists Track Down Central Cause Of Lupus

[Guest guest]

Source:

Princeton University (http://www.princeton.edu/)

Date:

Posted 4/23/2002

Biologists Track Down Central Cause Of Lupus

In a finding that could lead to better treatments for lupus, a Princeton

biologist has pinpointed what appears to be a central cause of the

disease.

Weigert and colleagues have discovered a point at which the immune

system's procedure for making disease-fighting antibodies breaks down and

allows antibodies to attack the body's own DNA, which is the hallmark of

lupus.

Although the processes involved are complex and remain partly

unexplained, the failure comes down to a relatively simple mechanism that

may be an attractive target for drug developers, said Weigert. He already

is developing molecules that would block the disease in mice and could be

the starting-point for a drug for humans.

Lupus is part of a diverse group of disorders called autoimmune diseases,

in which the immune system mistakenly attacks the body's own tissue. In

lupus, the mistaken target is DNA, which is present throughout the body.

The disease has various forms that range in severity from mild rashes to

fatal complications. It affects about 1.4 million Americans, 90 percent

of whom are women, according to the Lupus Foundation of America.

Doctors currently use essentially the same treatment for all autoimmune

conditions: steroids or other drugs that suppress the immune system in a

very broad way. Often this approach cannot control the disease without

causing a dangerous immune deficiency.

" We are now in a position to be able to tailor our approach to very

specific autoimmune diseases, " said Weigert, a professor in the

Department of Molecular Biology.

Weigert and collaborators at Princeton, the University of Pennsylvania

and the University of Tennessee published their discoveries regarding

lupus in a series of recent papers, including one in the December issue

of Cell and another in the Jan. 21 issue of the Journal of Experimental

Medicine.

The researchers started with mice that have lupus and isolated the gene

responsible for making one section of their DNA-attacking antibodies.

They introduced the gene into healthy mice and were surprised to find

that it did not cause these mice to have lupus. The mice turned out to

have a natural mechanism for " editing " the antibodies so they no longer

reacted with DNA.

The most recent studies showed, again unexpectedly, that mice with lupus

also successfully edit their antibodies. However, they then mistakenly

" re- edit " them, restoring their attraction for DNA.

These editing processes occur in an immune system component called B

cells, which produce antibodies. The researchers found that normal,

healthy editing has the effect of covering or neutralizing certain DNA-

attracting chemical units on the surface of the B cells. The re-editing

in lupus mice re- exposes these chemical units, which have a strong

chemical attraction for the phosphates that make up the backbone of all

DNA.

Weigert believes the phosphate-attracting chemicals could be a prime

target for a drug to treat lupus. He has begun to design small protein

fragments, called peptides, that could bind to these chemicals and

neutralize them, which may have the same effect as editing.

" I think it's quite important work, " said Nemazee, an immunologist

at the Scripps Research Institute in California, who independently

discovered the healthy editing process at the same time as Weigert

several years ago. Nemazee said Weigert pioneered the use of genetically

altered mice to explore how B cells are regulated and how that regulation

relates to autoimmune disease.

Nemazee added, however, it is too early to say whether the processes

Weigert discovered in mice will explain lupus in people, even though

mouse and human immune systems are very similar. " As with all these

diseases, we are using fairly artificial animal models, " said Nemazee.

Weigert started his research with a longstanding quandary in immunology:

How does the immune system distinguish viruses, bacteria and other

disease-causing agents from its own tissue? " To me, it's one of the most

fascinating questions in all of science, " he said.

Weigert's discovery of B-cell editing showed one important way in which

the body eliminates self-directed antibodies. He realized, however, that

such a general mechanism could not completely answer the question. It

required finding the precise mechanism of a particular disease in which

self-tolerance failed, he said.

" The fundamental scientific questions that we set out to answer just came

closer and closer to -- and, in fact, depended on -- the disease, " said

Weigert.

Weigert noted that the lupus finding probably is not directly applicable

to other autoimmune diseases. In fact, it helps to show that each form of

autoimmunity is likely to be caused by a specific and unique kind of

failure. " The tendency has been to look for some general breakdown in

self- tolerance that explains all autoimmune diseases, " he said. Even

though there may be no such universal mechanism, he said, " tracking down

the unique aspects of each one is within our ability. "

[Guest guest]

Very cool, a!

[ ] Biologists Track Down Central Cause Of Lupus

> Source:

>

> Princeton University (http://www.princeton.edu/)

>

>

>

> Date:

>

> Posted 4/23/2002

>

> Biologists Track Down Central Cause Of Lupus

>

> In a finding that could lead to better treatments for lupus, a

Princeton

> biologist has pinpointed what appears to be a central cause of the

> disease.

>

> Weigert and colleagues have discovered a point at which the

immune

> system's procedure for making disease-fighting antibodies breaks down

and

> allows antibodies to attack the body's own DNA, which is the hallmark

of

> lupus.

>

> Although the processes involved are complex and remain partly

> unexplained, the failure comes down to a relatively simple mechanism

that

> may be an attractive target for drug developers, said Weigert. He

already

> is developing molecules that would block the disease in mice and could

be

> the starting-point for a drug for humans.

>

> Lupus is part of a diverse group of disorders called autoimmune

diseases,

> in which the immune system mistakenly attacks the body's own tissue.

In

> lupus, the mistaken target is DNA, which is present throughout the

body.

> The disease has various forms that range in severity from mild rashes

to

> fatal complications. It affects about 1.4 million Americans, 90

percent

> of whom are women, according to the Lupus Foundation of America.

>

> Doctors currently use essentially the same treatment for all

autoimmune

> conditions: steroids or other drugs that suppress the immune system in

a

> very broad way. Often this approach cannot control the disease without

> causing a dangerous immune deficiency.

>

> " We are now in a position to be able to tailor our approach to very

> specific autoimmune diseases, " said Weigert, a professor in the

> Department of Molecular Biology.

>

> Weigert and collaborators at Princeton, the University of Pennsylvania

> and the University of Tennessee published their discoveries regarding

> lupus in a series of recent papers, including one in the December

issue

> of Cell and another in the Jan. 21 issue of the Journal of

Experimental

> Medicine.

>

> The researchers started with mice that have lupus and isolated the

gene

> responsible for making one section of their DNA-attacking antibodies.

> They introduced the gene into healthy mice and were surprised to find

> that it did not cause these mice to have lupus. The mice turned out to

> have a natural mechanism for " editing " the antibodies so they no

longer

> reacted with DNA.

>

> The most recent studies showed, again unexpectedly, that mice with

lupus

> also successfully edit their antibodies. However, they then mistakenly

> " re- edit " them, restoring their attraction for DNA.

>

> These editing processes occur in an immune system component called B

> cells, which produce antibodies. The researchers found that normal,

> healthy editing has the effect of covering or neutralizing certain

DNA-

> attracting chemical units on the surface of the B cells. The

re-editing

> in lupus mice re- exposes these chemical units, which have a strong

> chemical attraction for the phosphates that make up the backbone of

all

> DNA.

>

> Weigert believes the phosphate-attracting chemicals could be a prime

> target for a drug to treat lupus. He has begun to design small protein

> fragments, called peptides, that could bind to these chemicals and

> neutralize them, which may have the same effect as editing.

>

> " I think it's quite important work, " said Nemazee, an

immunologist

> at the Scripps Research Institute in California, who independently

> discovered the healthy editing process at the same time as Weigert

> several years ago. Nemazee said Weigert pioneered the use of

genetically

> altered mice to explore how B cells are regulated and how that regulat

ion

> relates to autoimmune disease.

>

> Nemazee added, however, it is too early to say whether the processes

> Weigert discovered in mice will explain lupus in people, even though

> mouse and human immune systems are very similar. " As with all these

> diseases, we are using fairly artificial animal models, " said Nemazee.

>

> Weigert started his research with a longstanding quandary in

immunology:

> How does the immune system distinguish viruses, bacteria and other

> disease-causing agents from its own tissue? " To me, it's one of the

most

> fascinating questions in all of science, " he said.

>

> Weigert's discovery of B-cell editing showed one important way in

which

> the body eliminates self-directed antibodies. He realized, however,

that

> such a general mechanism could not completely answer the question. It

> required finding the precise mechanism of a particular disease in

which

> self-tolerance failed, he said.

>

> " The fundamental scientific questions that we set out to answer just

came

> closer and closer to -- and, in fact, depended on -- the disease, "

said

> Weigert.

>

> Weigert noted that the lupus finding probably is not directly

applicable

> to other autoimmune diseases. In fact, it helps to show that each form

of

> autoimmunity is likely to be caused by a specific and unique kind of

> failure. " The tendency has been to look for some general breakdown in

> self- tolerance that explains all autoimmune diseases, " he said. Even

> though there may be no such universal mechanism, he said, " tracking

down

> the unique aspects of each one is within our ability. "

[Guest guest]

Source:

Princeton University (http://www.princeton.edu/)

Date:

Posted 4/23/2002

Biologists Track Down Central Cause Of Lupus

In a finding that could lead to better treatments for lupus, a

Princeton

biologist has pinpointed what appears to be a central cause of the

disease.

Weigert and colleagues have discovered a point at which the

immune

system's procedure for making disease-fighting antibodies breaks down

and

allows antibodies to attack the body's own DNA, which is the hallmark

of

lupus.

Although the processes involved are complex and remain partly

unexplained, the failure comes down to a relatively simple mechanism

that

may be an attractive target for drug developers, said Weigert. He

already

is developing molecules that would block the disease in mice and

could be

the starting-point for a drug for humans.

Lupus is part of a diverse group of disorders called autoimmune

diseases,

in which the immune system mistakenly attacks the body's own tissue.

In

lupus, the mistaken target is DNA, which is present throughout the

body.

The disease has various forms that range in severity from mild rashes

to

fatal complications. It affects about 1.4 million Americans, 90

percent

of whom are women, according to the Lupus Foundation of America.

Doctors currently use essentially the same treatment for all

autoimmune

conditions: steroids or other drugs that suppress the immune system

in a

very broad way. Often this approach cannot control the disease

without

causing a dangerous immune deficiency.

" We are now in a position to be able to tailor our approach to very

specific autoimmune diseases, " said Weigert, a professor in the

Department of Molecular Biology.

Weigert and collaborators at Princeton, the University of

Pennsylvania

and the University of Tennessee published their discoveries regarding

lupus in a series of recent papers, including one in the December

issue

of Cell and another in the Jan. 21 issue of the Journal of

Experimental

Medicine.

The researchers started with mice that have lupus and isolated the

gene

responsible for making one section of their DNA-attacking antibodies.

They introduced the gene into healthy mice and were surprised to find

that it did not cause these mice to have lupus. The mice turned out

to

have a natural mechanism for " editing " the antibodies so they no

longer

reacted with DNA.

The most recent studies showed, again unexpectedly, that mice with

lupus

also successfully edit their antibodies. However, they then

mistakenly

" re- edit " them, restoring their attraction for DNA.

These editing processes occur in an immune system component called B

cells, which produce antibodies. The researchers found that normal,

healthy editing has the effect of covering or neutralizing certain

DNA-

attracting chemical units on the surface of the B cells. The re-

editing

in lupus mice re- exposes these chemical units, which have a strong

chemical attraction for the phosphates that make up the backbone of

all

DNA.

Weigert believes the phosphate-attracting chemicals could be a prime

target for a drug to treat lupus. He has begun to design small

protein

fragments, called peptides, that could bind to these chemicals and

neutralize them, which may have the same effect as editing.

" I think it's quite important work, " said Nemazee, an

immunologist

at the Scripps Research Institute in California, who independently

discovered the healthy editing process at the same time as Weigert

several years ago. Nemazee said Weigert pioneered the use of

genetically

altered mice to explore how B cells are regulated and how that

regulation

relates to autoimmune disease.

Nemazee added, however, it is too early to say whether the processes

Weigert discovered in mice will explain lupus in people, even though

mouse and human immune systems are very similar. " As with all these

diseases, we are using fairly artificial animal models, " said

Nemazee.

Weigert started his research with a longstanding quandary in

immunology:

How does the immune system distinguish viruses, bacteria and other

disease-causing agents from its own tissue? " To me, it's one of the

most

fascinating questions in all of science, " he said.

Weigert's discovery of B-cell editing showed one important way in

which

the body eliminates self-directed antibodies. He realized, however,

that

such a general mechanism could not completely answer the question. It

required finding the precise mechanism of a particular disease in

which

self-tolerance failed, he said.

" The fundamental scientific questions that we set out to answer just

came

closer and closer to -- and, in fact, depended on -- the disease, "

said

Weigert.

Weigert noted that the lupus finding probably is not directly

applicable

to other autoimmune diseases. In fact, it helps to show that each

form of

autoimmunity is likely to be caused by a specific and unique kind of

failure. " The tendency has been to look for some general breakdown in

self- tolerance that explains all autoimmune diseases, " he said. Even

though there may be no such universal mechanism, he said, " tracking

down

the unique aspects of each one is within our ability. "

--- End forwarded message ---