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Tumor Necrosis Factor-alpha Response To Escherichia Coli Is Mediated By CD48



Ravi Malaviya*,dagger , Zhimin Gao*, Krishnan Thankavel*, P. Anton van der MerweDagger , and Soman N. Abraham*,§
PSNAS, Vol. 96, Issue 14, 8110-8115, July 6, 1999
Duke Univ, Medical Center, *Dept of Pathology and Microbiology, Durham, NC 27710; and
Univ of Oxford, Dagger Sir William Dunn School of Pathology, Oxford OX1 3RE, United Kingdom

Abstract

Mast Cells are well known for their harmful role in IgE-mediated HyperSensitivity reactions, but their physiological role remains a mystery.

Several recent studies have reported that Mast Cells play a critical role in Innate Immunity in mice by releasing Tumor Necrosis Factor-alpha (TNF-alpha ) to recruit Neutrophils to sites of EnteroBacterial infection.

In some cases, the Mast Cell TNF-alpha response was triggered when these cells directly bound FimH on the surface of Escherichia coli.

We have identified CD48, a GlycosylPhosphatidyLinositol-anchored molecule, to be the Complementary FimH-binding moiety in rodent Mast Cell membrane fractions.

We showed that (i) pretreatment of Mast Cell membranes with AntiBodies to CD48 or phospholipase C inhibited binding of FimH+ E. coli, (ii) FimH+ E. coli but not a FimH- derivative bound isolated CD48 in a mannose-inhibitable manner, (iii) binding of FimH+ bacteria to Chinese Hamster Ovary (CHO) cells was markedly increased.

When these cells were transfected with CD48 cDNA, and (iv) AntiBodies to CD48 specifically blocked the Mast Cell TNF-alpha response to FimH+ E. coli.

Thus, CD48 is a functionally relevant microbial receptor on Mast Cells that plays a role in triggering inflammation.


Mast Cells Stimulate Immune Response Against Bacteria


Proceedings of the National Academy of Science 1999;96:1-6
July 6, 1999

The body's Mast Cells apparently do more than just cause misery to people with Allergies, Asthma and certain Bowel Diseases, according to results in animal studies that may have implications for treating human disorders.

A research team at Duke Univin Durham, N.C. has discovered that Mast Cells, which are responsible for the sneezing, watery eyes and similar symptoms that characterize Hay Fever, for example, act as lookouts for the Immune System against bacteria that are attacking.

"We see the Mast Cell as a sentry with a rifle at the body's borders that's equipped to kill some of the invading bacteria," said team leader Soman Abraham, associate professor of pathology at Duke Univ, Medical Center.

"Its main role is to signal the heavy artillery of the Immune System that the body is under attack."

Although the research at Duke was carried out using mouse Bone Marrow Cells, the Duke team in earlier research found substantial similarities between mouse Mast Cells and human cells developed from blood cells from umbilical cords.

Mast Cells are large cells, which are found just under the Skin, in the Gut, Nasal Passages, Lungs and Urinary Tract - those places where the body comes in contact with the outside world.

They look quite distinct from other cells because they are loaded with Granules, which according to Abraham act essentially "like grenades."

These are activated when, for example, an Allergy or Asthma sufferer encounters a pollen grain. The Granules release a barrage of chemical signals that unleash Histamines and other chemical signals that cause Hay Fever or Asthma attacks.

Mast Cells are also found in disproportionate numbers in the bowls of those suffering for Crohn's Disease and Inflammatory Bowel Disease.

Abraham and his colleagues wondered if Mast Cells had any redeeming qualities in addition to causing misery for the allergy sufferer. "We asked a simple question: "Do Mast Cells recognize bacteria?' And sure enough," said Abraham, "we found they did."

In a study published in the July 6 issue of the Proceedings of the National Academy of Science(http://www.pnas.org/) the Duke team (http://pathology.mc.duke.edu/research/postabraham.html) found a molecule called CD48 on the Mast Cell surface.

The CD48 recognizes a protein, called FimH, formed on the hair-like tips of many infectious bacteria.

This CD48-FimH connection triggers Mast Cells to alert the immune system by releasing a third substance called Tumor Necrosis Factor-alpha (TNF-alpha) which then signals the Immune System to move in.

"If we can learn how to stimulate CD48 activity only when it's needed during an infection," said Abraham "we could amplify the Immune Response in people with sluggish Immune Systems."

Abraham also indicated that use of AntiAllergy and Asthma drugs that target Mast Cell activity may need to be re-assessed.

"When we give medication to suppress Mast Cells we may be opening up patients - especially young ones - to a number of respiratory illnesses," said Abraham.

But since association between these drugs and increased vulnerability to infectious disease has yet to be found, Abraham noted that such a connection may be a subtle one.

Dr. Stephen J. Galli, chair of Pathology at Stanford University, said the Duke findings were important. He added that Mast Cells could be activated by additional mechanisms that are independent of CD48.

His research group recently published evidence that in mice, increasing the number of Mast Cells or enhancing their function can increase a resistance to a type of bacterial infection.

"These findings certainly support the idea that the Mast Cell can promote resistance to some infections," said Galli.



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