Deficiency of immune system 'peacekeeper' pinpointed in mice as cause of ulcerative colitis

[Guest guest]

Public release date: 4-Oct-2007

Harvard School of

Public Health

Deficiency

of immune system 'peacekeeper' pinpointed in mice as cause of ulcerative

colitis

Boston,

MA -- In a

series of mouse experiments, researchers at the Harvard School of Public Health

(HSPH) have pinpointed a specific immune deficiency as the likely fundamental

cause of ulcerative colitis, a chronic, sometimes severe inflammatory

disease of the colon or large intestine that afflicts half a million Americans. Remarkably, the researchers also found that once the

disease was established in mice, it could be passed from mother to offspring

and even between adult animals, with potential implications for public health

and prevention.

The researchers have linked ulcerative colitis

in mice to a deficiency of a molecular " peacekeeper " in the immune

system, allowing harmful bacteria in the large intestine to breach the bowel's

protective lining and trigger damaging inflammation.

In a

paper being posted online on Thursday, October 4, 2007, by the journal Cell, a team

led by Laurie Glimcher, Irene Heinz Given Professor

of Immunology at HSPH, details a series of immunological events by which a

shortage of a regulatory protein called T-bet opens the way to a bacterial

attack on the intestinal wall. The resulting

inflammation, in turn, causes the characteristic colitis marked by open sores,

or ulcerations, throughout the colon. The first

co-authors of the paper are Garrett, a research fellow in the laboratory

of Glimcher and a clinical fellow at Dana-Farber

Cancer Institute, and Graham Lord, formerly at HSPH and now a Professor of

Medicine at King's College, London.

The key

abnormality is a deficiency of the T-bet protein in " dendritic "

cells - white blood cells that capture identifying antigens of foreign microbes

and activate the immune defenses. T-bet, discovered in

2000 in Glimcher's laboratory, is a " master

regulator gene, " a transcription factor that orchestrates a

pro-inflammatory response of the immune system. T-bet

had been found to play a role in the body's handling of infectious microbes and

cancer cells and has been implicated in rheumatoid arthritis and asthma, but

the discovery of its pivotal part in the innate immune system in inflammatory

bowel disease came as a total surprise.

" We

have identified a new molecular player, T-bet, and when it's missing, there is

spontaneous onset of the disease in the mice, " said Glimcher. " The importance of this study is that we now have a

novel model for ulcerative colitis: The disease appears in 100 percent of the

animals and looks just like the human disease. "

If some

people develop ulcerative colitis because of T-bet DNA variation or

polymorphisms, it may be because of an inherited variation in the DNA affecting

the T-bet gene. The researchers are following up this

lead.

With its close mimicry of human ulcerative

colitis, the animal model will have unprecedented value for testing new

therapies and preventive measures, said Glimcher, who

is also a professor of medicine at Harvard Medical School.

Ulcerative

colitis and a related disorder, Crohn's disease, are known collectively as

inflammatory bowel disease: they affect an estimated one million people in the United

States. Crohn's

disease tends to involve the small intestine as well as the colon. Ulcerative colitis usually appears between ages 15 and 30

but also can begin in the 50s and 60s, especially in men. The

disease is somewhat more common among men than women, whites than non-whites,

and Ashkenazi Jewish individuals than non-Jewish individuals.

Since about

20 percent of patients with ulcerative colitis have a close relative with the

disease or with Crohn's disease, scientists have hunted specific genes that may

be involved. Studies of the pathology of the inflamed

intestine have suggested that an abnormal immune reaction and injury by

bacterial residents of the colon are to blame. The

T-bet shortage described in the Glimcher paper links

these two mechanisms.

Beneficial

bacteria in the colon aid in digestion and extraction of nutrients from food. However, harmful microbes also reside in the intestine, so

animals that harbor bacteria have evolved a boundary, or barrier, in the form

of the intestinal lining to keep the dangerous bacteria from injuring the colon

wall.

The key

to maintaining this mucosal barrier, the scientists discovered, is the

" peacekeeper " activity of T-bet in the dendritic

cells of the intestine's immune system. When T-bet is

at normal levels, the boundary - a kind of demilitarized zone - remains intact

and prevents trouble from pathogenic bacteria. But if

T-bet is insufficient, the dendritic cells

overproduce a powerful chemical called TNF-alpha (tumor necrosis factor-alpha)

that triggers inflammation and causes normal cells to die. In

ulcerative colitis, the T-bet-related excess of TNF-alpha leads to the death of

cells making up the epithelial barrier of the colon, enabling harmful bacteria

to chronically inflame the intestinal wall.

The

scientists bred strains of mice that lacked T-bet and showed that the resulting

disease was virtually identical to human ulcerative colitis.

Moreover,

the investigators demonstrated that female mice with the disease could transmit

it to baby mice that had adequate levels of T-bet. (The

scientists placed genetically normal infant mice with the sick foster mother on

their day of birth.) Presumably, the flourishing

colonies of colitis-causing bacteria were passed down from the sick mother to

the fostered mice. The disease was even

" horizontally " transmissible from T-bet-deficient adult mice with

ulcerative colitis to other adults with normal T-bet, through fecal-oral and

skin-to-skin contact.

Inflammatory bowel disease can be treated

with antibody drugs that block TNF-alpha activity, though their toxicity limits

their use. The researchers showed that such antibody

drugs cured and also prevented ulcerative colitis in T-bet-deficient mice. However, they are pursuing other potential therapies, such

as increasing T-bet levels in the immune cells, administering natural

immunity-dampening cells called T-regulatory cells, or giving " probiotics " - healthful bacteria that can keep the

harmful microbes under control.

The

research was supported by grants from the National Institutes of Health and by

an Ellison Scholar Award to Glimcher.

Communicable

Ulcerative Colitis Induced by T-bet Deficiency in the Innate Immune System. S. Garrett, Graham M. Lord, Shivesh

Punit, Geanncarlo Lugo-Villarino, Sarkis K. Mazmanian, Susumu Ito, N. Glickman,

and Laurie H. Glimcher. Cell

131, 1-13, October 5,

2007.

With love, Barb in Texas - Together in the Fight, Whatever it Takes!

Son Ken (33) UC 91 - PSC 99 - Tx 6/21 & 6/30/07 @ Baylor in Dallas

[Guest guest]

Barb, thanks for sending this.

Please help me understand something. The article says...

researchers have linked ulcerative colitis in mice to a deficiency of a molecular "peacekeeper" in the immune system, allowing harmful bacteria in the large intestine to breach the bowel's protective lining and trigger damaging inflammation.

To me a "deficiency of molecular" in the immune system means that if the immune system was stronger, the body would not allow ("allowing harmful bacteria in the large intestine") to enter our body.

My question is this... why do the doctor's prescribe immune suppressing drugs?? Doesn't it just feed into the deficiency?? Am I missing something?

Thanks.

Arman

arman_shirin@...

Deficiency of immune system 'peacekeeper' pinpointed in mice as cause of ulcerative colitis

Public release date: 4-Oct-2007Harvard School of Public Health

Deficiency of immune system 'peacekeeper' pinpointed in mice as cause of ulcerative colitis

Boston, MA -- In a series of mouse experiments, researchers at the Harvard School of Public Health (HSPH) have pinpointed a specific immune deficiency as the likely fundamental cause of ulcerative colitis, a chronic, sometimes severe inflammatory disease of the colon or large intestine that afflicts half a million Americans. Remarkably, the researchers also found that once the disease was established in mice, it could be passed from mother to offspring and even between adult animals, with potential implications for public health and prevention.

The researchers have linked ulcerative colitis in mice to a deficiency of a molecular "peacekeeper" in the immune system, allowing harmful bacteria in the large intestine to breach the bowel's protective lining and trigger damaging inflammation.

In a paper being posted online on Thursday, October 4, 2007 , by the journal Cell, a team led by Laurie Glimcher, Irene Heinz Given Professor of Immunology at HSPH, details a series of immunological events by which a shortage of a regulatory protein called T-bet opens the way to a bacterial attack on the intestinal wall. The resulting inflammation, in turn, causes the characteristic colitis marked by open sores, or ulcerations, throughout the colon. The first co-authors of the paper are Garrett, a research fellow in the laboratory of Glimcher and a clinical fellow at Dana-Farber Cancer Institute, and Graham Lord, formerly at HSPH and now a Professor of Medicine at King's College, London .

The key abnormality is a deficiency of the T-bet protein in "dendritic" cells - white blood cells that capture identifying antigens of foreign microbes and activate the immune defenses. T-bet, discovered in 2000 in Glimcher's laboratory, is a "master regulator gene," a transcription factor that orchestrates a pro-inflammatory response of the immune system. T-bet had been found to play a role in the body's handling of infectious microbes and cancer cells and has been implicated in rheumatoid arthritis and asthma, but the discovery of its pivotal part in the innate immune system in inflammatory bowel disease came as a total surprise.

"We have identified a new molecular player, T-bet, and when it's missing, there is spontaneous onset of the disease in the mice," said Glimcher. "The importance of this study is that we now have a novel model for ulcerative colitis: The disease appears in 100 percent of the animals and looks just like the human disease."

If some people develop ulcerative colitis because of T-bet DNA variation or polymorphisms, it may be because of an inherited variation in the DNA affecting the T-bet gene. The researchers are following up this lead.

With its close mimicry of human ulcerative colitis, the animal model will have unprecedented value for testing new therapies and preventive measures, said Glimcher, who is also a professor of medicine at Harvard Medical School.

Ulcerative colitis and a related disorder, Crohn's disease, are known collectively as inflammatory bowel disease: they affect an estimated one million people in the United States. Crohn's disease tends to involve the small intestine as well as the colon. Ulcerative colitis usually appears between ages 15 and 30 but also can begin in the 50s and 60s, especially in men. The disease is somewhat more common among men than women, whites than non-whites, and Ashkenazi Jewish individuals than non-Jewish individuals.

Since about 20 percent of patients with ulcerative colitis have a close relative with the disease or with Crohn's disease, scientists have hunted specific genes that may be involved. Studies of the pathology of the inflamed intestine have suggested that an abnormal immune reaction and injury by bacterial residents of the colon are to blame. The T-bet shortage described in the Glimcher paper links these two mechanisms.

Beneficial bacteria in the colon aid in digestion and extraction of nutrients from food. However, harmful microbes also reside in the intestine, so animals that harbor bacteria have evolved a boundary, or barrier, in the form of the intestinal lining to keep the dangerous bacteria from injuring the colon wall.

The key to maintaining this mucosal barrier, the scientists discovered, is the "peacekeeper" activity of T-bet in the dendritic cells of the intestine's immune system. When T-bet is at normal levels, the boundary - a kind of demilitarized zone - remains intact and prevents trouble from pathogenic bacteria. But if T-bet is insufficient, the dendritic cells overproduce a powerful chemical called TNF-alpha (tumor necrosis factor-alpha) that triggers inflammation and causes normal cells to die. In ulcerative colitis, the T-bet-related excess of TNF-alpha leads to the death of cells making up the epithelial barrier of the colon, enabling harmful bacteria to chronically inflame the intestinal wall.

The scientists bred strains of mice that lacked T-bet and showed that the resulting disease was virtually identical to human ulcerative colitis.

Moreover, the investigators demonstrated that female mice with the disease could transmit it to baby mice that had adequate levels of T-bet. (The scientists placed genetically normal infant mice with the sick foster mother on their day of birth.) Presumably, the flourishing colonies of colitis-causing bacteria were passed down from the sick mother to the fostered mice. The disease was even "horizontally" transmissible from T-bet-deficient adult mice with ulcerative colitis to other adults with normal T-bet, through fecal-oral and skin-to-skin contact.

Inflammatory bowel disease can be treated with antibody drugs that block TNF-alpha activity, though their toxicity limits their use. The researchers showed that such antibody drugs cured and also prevented ulcerative colitis in T-bet-deficient mice. However, they are pursuing other potential therapies, such as increasing T-bet levels in the immune cells, administering natural immunity-dampening cells called T-regulatory cells, or giving "probiotics" - healthful bacteria that can keep the harmful microbes under control.

The research was supported by grants from the National Institutes of Health and by an Ellison Scholar Award to Glimcher.

Communicable Ulcerative Colitis Induced by T-bet Deficiency in the Innate Immune System. S. Garrett, Graham M. Lord, Shivesh Punit, Geanncarlo Lugo-Villarino, Sarkis K. Mazmanian, Susumu Ito, N. Glickman, and Laurie H. Glimcher. Cell 131, 1-13, October 5, 2007 .

With love, Barb in Texas - Together in the Fight, Whatever it Takes!

Son Ken (33) UC 91 - PSC 99 - Tx 6/21 & 6/30/07 @ Baylor in Dallas

Boardwalk for $500? In 2007? Ha! Play Monopoly Here and Now (it's updated for today's economy) at Yahoo! Games.

[Guest guest]

-----Original

Message-----

To me a " deficiency of molecular " in the immune

system means that if the immune system was stronger, the body would not allow

( " allowing harmful bacteria in the large intestine " ) to enter our

body.

“I think” (just a housewife here) the

deficiency they speak of is genetic.

For example; I have colitis and might have passed on this trait (lack of

molecular peacekeeper) to Ken – who then got colitis & PSC. Does that sound right?

With love, Barb in Texas - Together in the Fight,

Whatever it Takes!

Son Ken (33) UC 91 - PSC 99 - Tx 6/21 & 6/30/07 @ Baylor in Dallas

[Guest guest]

Yeah Arman, I think you're question makes a lot of sense. It doesn't

seem to help when the GI's suppress our immune system.

Thanks,

Jarad

>

> Barb, thanks for sending this.

>

> Please help me understand something. The article says...

>

> researchers have linked ulcerative colitis in mice to a deficiency

of a molecular " peacekeeper " in the immune system, allowing harmful

bacteria in the large intestine to breach the bowel's protective

lining and trigger damaging inflammation.

>

> To me a " deficiency of molecular " in the immune system means that

if the immune system was stronger, the body would not allow

( " allowing harmful bacteria in the large intestine " ) to enter our

body.

>

> My question is this... why do the doctor's prescribe immune

suppressing drugs?? Doesn't it just feed into the deficiency?? Am I

missing something?

>

> Thanks.

>

>

> Arman

> arman_shirin@...

>

>

>

> Deficiency of immune system 'peacekeeper'

pinpointed in mice as cause of ulcerative colitis

>

> Public release date: 4-Oct-2007

>

> Harvard School of Public Health

> Deficiency of immune system 'peacekeeper' pinpointed in mice as

cause of ulcerative colitis

> Boston, MA -- In a series of mouse experiments, researchers at the

Harvard School of Public Health (HSPH) have pinpointed a specific

immune deficiency as the likely fundamental cause of ulcerative

colitis, a chronic, sometimes severe inflammatory disease of the

colon or large intestine that afflicts half a million Americans.

Remarkably, the researchers also found that once the disease was

established in mice, it could be passed from mother to offspring and

even between adult animals, with potential implications for public

health and prevention.

> The researchers have linked ulcerative colitis in mice to a

deficiency of a molecular " peacekeeper " in the immune system,

allowing harmful bacteria in the large intestine to breach the

bowel's protective lining and trigger damaging inflammation.

> In a paper being posted online on Thursday, October 4, 2007 , by

the journal Cell, a team led by Laurie Glimcher, Irene Heinz Given

Professor of Immunology at HSPH, details a series of immunological

events by which a shortage of a regulatory protein called T-bet opens

the way to a bacterial attack on the intestinal wall. The resulting

inflammation, in turn, causes the characteristic colitis marked by

open sores, or ulcerations, throughout the colon. The first co-

authors of the paper are Garrett, a research fellow in the

laboratory of Glimcher and a clinical fellow at Dana-Farber Cancer

Institute, and Graham Lord, formerly at HSPH and now a Professor of

Medicine at King's College, London .

> The key abnormality is a deficiency of the T-bet protein

in " dendritic " cells - white blood cells that capture identifying

antigens of foreign microbes and activate the immune defenses. T-bet,

discovered in 2000 in Glimcher's laboratory, is a " master regulator

gene, " a transcription factor that orchestrates a pro-inflammatory

response of the immune system. T-bet had been found to play a role in

the body's handling of infectious microbes and cancer cells and has

been implicated in rheumatoid arthritis and asthma, but the discovery

of its pivotal part in the innate immune system in inflammatory bowel

disease came as a total surprise.

> " We have identified a new molecular player, T-bet, and when it's

missing, there is spontaneous onset of the disease in the mice, " said

Glimcher. " The importance of this study is that we now have a novel

model for ulcerative colitis: The disease appears in 100 percent of

the animals and looks just like the human disease. "

> If some people develop ulcerative colitis because of T-bet DNA

variation or polymorphisms, it may be because of an inherited

variation in the DNA affecting the T-bet gene. The researchers are

following up this lead.

> With its close mimicry of human ulcerative colitis, the animal

model will have unprecedented value for testing new therapies and

preventive measures, said Glimcher, who is also a professor of

medicine at Harvard Medical School.

> Ulcerative colitis and a related disorder, Crohn's disease, are

known collectively as inflammatory bowel disease: they affect an

estimated one million people in the United States. Crohn's disease

tends to involve the small intestine as well as the colon. Ulcerative

colitis usually appears between ages 15 and 30 but also can begin in

the 50s and 60s, especially in men. The disease is somewhat more

common among men than women, whites than non-whites, and Ashkenazi

Jewish individuals than non-Jewish individuals.

> Since about 20 percent of patients with ulcerative colitis have a

close relative with the disease or with Crohn's disease, scientists

have hunted specific genes that may be involved. Studies of the

pathology of the inflamed intestine have suggested that an abnormal

immune reaction and injury by bacterial residents of the colon are to

blame. The T-bet shortage described in the Glimcher paper links these

two mechanisms.

> Beneficial bacteria in the colon aid in digestion and extraction of

nutrients from food. However, harmful microbes also reside in the

intestine, so animals that harbor bacteria have evolved a boundary,

or barrier, in the form of the intestinal lining to keep the

dangerous bacteria from injuring the colon wall.

> The key to maintaining this mucosal barrier, the scientists

discovered, is the " peacekeeper " activity of T-bet in the dendritic

cells of the intestine's immune system. When T-bet is at normal

levels, the boundary - a kind of demilitarized zone - remains intact

and prevents trouble from pathogenic bacteria. But if T-bet is

insufficient, the dendritic cells overproduce a powerful chemical

called TNF-alpha (tumor necrosis factor-alpha) that triggers

inflammation and causes normal cells to die. In ulcerative colitis,

the T-bet-related excess of TNF-alpha leads to the death of cells

making up the epithelial barrier of the colon, enabling harmful

bacteria to chronically inflame the intestinal wall.

> The scientists bred strains of mice that lacked T-bet and showed

that the resulting disease was virtually identical to human

ulcerative colitis.

> Moreover, the investigators demonstrated that female mice with the

disease could transmit it to baby mice that had adequate levels of T-

bet. (The scientists placed genetically normal infant mice with the

sick foster mother on their day of birth.) Presumably, the

flourishing colonies of colitis-causing bacteria were passed down

from the sick mother to the fostered mice. The disease was

even " horizontally " transmissible from T-bet-deficient adult mice

with ulcerative colitis to other adults with normal T-bet, through

fecal-oral and skin-to-skin contact.

> Inflammatory bowel disease can be treated with antibody drugs that

block TNF-alpha activity, though their toxicity limits their use. The

researchers showed that such antibody drugs cured and also prevented

ulcerative colitis in T-bet-deficient mice. However, they are

pursuing other potential therapies, such as increasing T-bet levels

in the immune cells, administering natural immunity-dampening cells

called T-regulatory cells, or giving " probiotics " - healthful

bacteria that can keep the harmful microbes under control.

> The research was supported by grants from the National Institutes

of Health and by an Ellison Scholar Award to Glimcher.

> Communicable Ulcerative Colitis Induced by T-bet Deficiency in the

Innate Immune System. S. Garrett, Graham M. Lord, Shivesh

Punit, Geanncarlo Lugo-Villarino, Sarkis K. Mazmanian, Susumu Ito,

N. Glickman, and Laurie H. Glimcher. Cell 131, 1-13, October

5, 2007 .

> With love, Barb in Texas - Together in the Fight, Whatever it Takes!

> Son Ken (33) UC 91 - PSC 99 - Tx 6/21 & 6/30/07 @ Baylor in Dallas

>

>

>

>

>

>

>

______________________________________________________________________

______________

> Pinpoint customers who are looking for what you sell.

> http://searchmarketing.yahoo.com/

>

[Guest guest]

I think a better way to look at it is that the " molecular peacekeeper " is not

doing it's job of preventing the immune system from attacking the body (the

inflammatory response runs amok). This results in inflammation that never goes

away when the trigger is gone. The immune system is TOO strong and doesn't

recognize self adequately, thus immune suppression drugs are administered.

I don't think of myself as immune deficient, rather my immune system is not

moderated - doesn't know when to stop. An extremely complex dance to be sure.

Arne

=============

....To me a " deficiency of molecular " in the immune system means that if the

immune system was stronger, the body would not allow ( " allowing harmful bacteria

in the large intestine " ) to enter our body...