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Archive for May 30th, 2006

New Pathways For Autoimmune Treatment Identified

Posted by tumicrobiology on May 30, 2006

A rare genetic defect that can trigger a host of diseases from type 1 diabetes to alopecia has helped explain the imbalance of immune regulator and killer cells in autoimmune disease.

Mutation in the Aire gene causes APS1, a disease causing two out of three problems – an underactive parathyroid, yeast infection of the skin and/or mucous membrane and adrenal gland insufficiency – by age 5 and up to 16 autoimmune diseases over a lifetime.

The same mutation causes a defect in iNKT cells, a type of regulatory cell that helps the immune system fight infections while suppressing errant T cells bent on attacking the body, Medical College of Georgia researchers say.

This finding opens new pathways for treating or preventing APS1, or autoimmune polyglandular syndrome type 1, and potentially other autoimmune diseases as well, researchers report in the June issue of Nature Medicine.

“The body should maintain a balance between killing and suppression,” says Dr. Qing-Sheng Mi, immunologist and lead and co-senior author. “If you are killing too hard, it can induce autoimmune disease. If you regulate suppression too hard, you can get cancer. iNKT cells help maintain a healthy balance. But patients with autoimmune disease may not have enough functional iNKT cells.”

“Aire controls the development and function of iNKT cells,” says Drs. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and co-senior author. “This relationship means that iNKT cells are critical to most autoimmune diseases and manipulating the iNKT cell population is one possible way to cure autoimmune disease.”

A lipid purified from sea plants, called alpha-GalCer, is already under study as a way to boost iNKT cell numbers and fight autoimmune disease as well as cancer. iNKT cells’ reactivity to alpha-GalCer, prompted the scientists to use it as a marker to examine the status of these cells in a mouse missing the Aire gene. That Aire knockout is a good model for humans with APS1.

They found significantly fewer iNKT cells in the thymus, spleen, liver and bone marrow and severely impaired maturation of those cells in mice missing the Aire gene. And the mice given alpha-GalCer had significantly reduced autoantibody production.

In 2001, Dr. Terry L. Delovitch and his colleagues at Canada’s Robarts Research Institute, including Dr. Mi, reported in Nature Medicine that using alpha-GalCer to boost iNKT cells and re-establish a healthy balance of good and bad immune cells prevented development of type 1 diabetes in an animal model for the disease.

But Drs. Mi and She say new iNKT boosters likely are needed because the action of alpha-GalCer somehow depends on individual genetic architecture as well as other factors. Under certain conditions, the drug can help or worsen an autoimmune disease by producing good or bad cytokines. That’s why it also has worked for some cancers and why a modified version of the glycolipid or totally different drugs may work better, Dr. She says. “By understanding more, we are better able to come up with better targets,” he says.

“iNKT development is still the big question,” says Dr. Mi. “Not only how they develop, but how they develop properly.”

The researchers watched the key regulatory cells come out of the bone marrow and go to the thymus where all T cells go for a process of positive and negative selection and maturation. Positive selection eliminates cells that are dysfunctional. Negative selection is eliminating T-cells that recognize the body’s own proteins, Dr. She says.

Other researchers recently confirmed that the Aire gene is involved in negative selection by controlling some protein expression in the thymus, Dr. Mi says. The thymus is supposed to express most body proteins so any T cells that would react to them can be eliminated through negative selection, he says. “But Aire’s role in protein expression is not sufficient to explain all the clinical symptoms of patients with APS1,” Dr. Mi says. “The Aire gene must have other immune functions.”

iNKT cells also go through a development process but via a somewhat different path than that of other T cells. MCG researchers have learned medullary epithelial cells in the thymus are critical to proper iNKT cell development. A defective Aire gene disrupts this natural nurturing relationship by disrupting medullary epithelial cell function, leading to insufficient numbers of iNKT cells.

“Whether or not you develop autoimmune disease to a large degree depends on the balance of these bad T cells that recognize the body’s own protein and regulatory T cells,” Dr. She says. “It’s all about balance.”
Source: Medical College of Georgia

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New Potential Drug Target In Tuberculosis

Posted by tumicrobiology on May 30, 2006

Tuberculosis remains one of the deadliest threats to public health. Every year two million people die of the disease, which is caused by the microorganism Mycobacterium tuberculosis. Roughly one third of the world’s population is infected and more and more bacterial strains have developed resistance to drugs. Researchers from the Hamburg Outstation of the European Molecular Biology Laboratory (EMBL) and the Max Planck Institute for Infection Biology (MPIIB) in Berlin have now obtained a structural image of a protein that the bacterium needs for survival in human cells. This image reveals features of the molecule that could be targeted by new antibiotic drugs. The results appear in this week’s online issue of the Proceedings of the National Academy of Sciences (PNAS).
Tuberculosis is dangerous because it hides and persists in the immune cells of our bodies. “It can only persist there because of the activity of key molecules,” says Matthias Wilmanns, Head of EMBL Hamburg. “We are investigating the functions of tuberculosis proteins and determining their atomic structures, in hopes of finding weak points and new inhibitors.”

A protein called LipB is essential for the organism because it activates cellular machines that drive the bacterium’s metabolism. Stefan Kaufmann’s department at the MPIIB has specialised in the biology of M. tuberculosis infection and its ability to survive in immune cells. They discovered that LipB is highly active in acutely infected cells, particularly in patients infected by multidrug-resistant forms of M. tuberculosis.

“In these cells we see a 70-fold increase in the production of LipB when compared to other cells,” says Stefan Kaufmann, Director at the MPIIB. “This strongly indicates an involvement in pathogenesis and makes it a particularly interesting target where traditional drugs have lost their efficacy.”

A structural picture of the protein – a kind of technical diagram of its building plan – has yielded important clues about its activity. Qingjun Ma from Wilmanns’ group purified LipB and obtained crystals of the molecule. Using the high-energy synchrotron radiation beamlines at EMBL Hamburg, on the campus of the German Electron Synchrotron Radiation Facility (DESY), he created an atom-by-atom map of the protein’s structure. A high-resolution picture of the active site of LipB bound to a lipid inhibitor helped to determine the function of the enzyme. In collaboration with EMBL’s Proteomics Core Facility in Heidelberg and researchers from the University of Illinois (USA), the Hamburg group discovered how LipB attaches specific fatty acids onto other proteins.

“LipB is a very promising drug target,” Wilmanns says, “because it belongs to a vital pathway. Unlike other organisms M. tuberculosis has no backup mechanism that could take over LipB’s role. This means that an inhibitor blocking its active site would shut down key processes the bacterium needs to survive and replicate. This would be a very effective strategy for a drug.”

The scientists will now search for compounds that can do so. At the same time, they are continuing to look for other proteins as drug targets. Wilmanns and his colleagues from various other institutes are now focusing on structures of molecules that help M. tuberculosis to persist in its dormant state and could become drug targets.

Over the past three years, EMBL has coordinated an “M. tuberculosis structural proteomics” consortium, supported by the German Ministry of Education and Research (BMBF), and produced high resolution images of more than 30 proteins. “Structure-based drug discovery has been a big success in the battle against many other diseases. We are now applying these tools to tuberculosis, one of the most devastating infectious diseases of mankind,” Wilmanns concludes.

Source: European Molecular Biology Laboratory

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