New Research Shows How Chronic Stress Worsens Neurodegenerative Disease Course

Newswise — The evidence is accumulating on how bad stress is for health. Chronic stress can intensify inflammation and increase a person’s risk for developing central nervous system infections, neurodegenerative diseases, like multiple sclerosis (MS), and other inflammatory diseases, say researchers presenting at the 115th Annual Convention of the American Psychological Association (APA). These researchers have demonstrated for the first time that stress-related increases in central nervous system inflammation are behind the adverse effects of stress in an animal model of MS.
Researchers from Texas A & M University used mice to show what role social stress plays in the immune process to influence the course of an MS-like disease. They proposed that stress-induced increases of pro-inflammatory cytokines, which are proteins that regulate immune and inflammatory functions, inhibit the clearing of a virus and allow the inflammatory process to run amok. Stress, say the authors, may interact with viral infections to increase vulnerabilityto diseases such as MS. Meta-analysis of studies investigating the impact of stressful events in patients with MS show an increased risk of worsening symptoms of the disease.
In a series of experiments on mice, the authors showed that increases in a particular cytokine – interleukin-6 (IL-6), which is released during stress and regulates the part of the immune system that fights infection – can make socially stressed mice vulnerable to MS-like illnesses.
The researchers used a social disruption model (SDR) to simulate social stress for mice and then infected the mice with Theiler’s murine encephalomyelitis (TMEV). Infection with TMEV results in an acute infection of the central nervous system followed by a chronic autoimmune disease similar to that seen in humans with MS. Their laboratory has previously shown that exposure to social stress prior to infection exacerbates both the early viral infection and the later autoimmune demyelinating MS-like phase of the disease.
To create a stressful environment, researchers housed three young male mice together for several weeks. After the mice established a stable social hierarchy, researchers introduced an older aggressive male into the residence for a couple of hours. The intruder exhibits aggressive behavior – posturing, fighting, wounding, pursuit – that results in submissive behaviors and social defeat in the younger resident mice. This procedure was repeated for three consecutive nightly two-hour sessions with one night off, followed by an additional three nightly sessions. To keep the mice from getting used to the intruder, a new intruder was introduced for each session.
What they found was this stress appears to elevate levels of IL-6, which subsequently increases the severity of the MS-like illness. Furthermore, using specific IL-6 neutralizing antibody treatments during the stress exposure can prevent the stress-related worsening of the disease, said the authors.
In one experiment, they showed that mice exposed to social disruption had elevated central and peripheral levels of IL-6. However, infusing the neutralizing antibody into the brain prevented this stress-induced increase in IL-6. This demonstrated that the antibody could effectively reverse the stress-related increases in IL-6 in brain and in circulating blood.
Results from a second experiment showed that administering the IL-6 neutralizing antibody during the stress exposure prevented worsening of the TMEV infection. By blocking the stress-induced elevation of IL-6, TMEV infection was weakened, which lessened some of the disease symptoms, such as motor impairment, inflammation in the brain and spinal cord, and the viral level in the central nervous system. Based on these findings, Dr. Mary Meagher, the lead researcher, proposes that the adverse effects of stress-induced IL-6 on TMEV infection are enough to create a pro-inflammatory environment that interferes with the immune response to infection. Because the early immune response shapes the later specific immune response to infection, impairment of the early response could account for the increased viral level, prolonged viral infection, increased CNS inflammation, and the subsequent exacerbation of the chronic autoimmune disease.
There is a growing body of evidence in both animal and human studies that suggests that exposure to stress can increase and sustain the release of pro-inflammatory cytokines following an assault on the immune system. Thus, the present findings might help scientists unravel which biobehavioral mechanisms offset the adverse health effects of chronic social stress in humans. “Similar to mice exposed to repeated social defeat by an aggressive intruder, people exposed to chronic social conflict experience high levels of stress and consequent dysregulation of the immune system, thereby increasing vulnerability to infectious and autoimmune disease,” said Meagher. “The cytokine response during chronic stress appears to play a key role in exacerbating the acute CNS infection and the development of subsequent autoimmune responses.”
Furthermore, interventions that prevented or reversed the stress-induced increases in IL-6 in the mouse model may have implications for humans, said Meagher. It is possible that the adverse effects of social conflict on people who are vulnerable to certain inflammatory diseases may be prevented or reversed by treatments aimed at blocking increases in this cytokine. Recent evidence suggests that some potential interventions include certain anti-inflammatory drugs, exercise, antidepressant medication, omega-3 fatty acids, and mindfulness relaxation training. However, human clinical trials are needed to fully evaluate this issue.
Presentation: “Severe or Traumatic Stress and Inflammation in Multiple Sclerosis,” Mary W. Meagher, PhD, Texas A&M University
Session 1157 – Symposium: Traumatic Stress, Cardiovascular Disease, Metabolic Syndrome, and Neurodegenerative Disease, 11:00 – 11:50 AM, Friday, August 17, Moscone Center, Second Floor-West Building, Room 2020
Full text of the article is available from the APA Public Affairs Office
The American Psychological Association (APA), in Washington, DC, is the largest scientific and professional organization representing psychology in the United States and is the world’s largest association of psychologists. APA’s membership includes more than 148,000 researchers, educators, clinicians, consultants and students. Through its divisions in 54 subfields of psychology and affiliations with 60 state, territorial and Canadian provincial associations, APA works to advance psychology as a science, as a profession and as a means of promoting health, education and human welfare.

First human trial of DNA-based vaccine cheers MS researchers

First human trial of DNA-based vaccine cheers MS researchers
· Number and size of lesions drop sharply during tests · Scientists urge caution and call for further work
Ian Sample, science correspondent
The Guardian
Tuesday August 14 2007
The first human trial of a DNA-based vaccine to combat multiple sclerosis has been declared a success by doctors in America after tests on patients revealed signs that their condition had improved. However, the trial is only the first small step in developing an effective treatment against the debilitating degenerative disease, which affects about 85,000 people in the UK.
The vaccine works by dampening down the immune system, which is believed to become overactive in people who develop multiple sclerosis.
The disease is caused by a small group of immune cells that start to attack the body by targeting the fatty sheaths of myelin that coat nerves in the central nervous system. After waves of attacks, the nerves are eventually destroyed. The myelin coating helps to ensure that signals passed along the nerves travel quickly.
Doctors led by Amit Bar-Or at the Montreal Neurological Institute in Canada developed a vaccine which contains the strands of DNA that produce myelin.
In the trial, 30 patients had the vaccine injected into their muscles over one, three, five and nine weeks, with half also receiving a statin drug to boost the effect of the vaccine. The vaccine was administered at three different doses.
All of the patients in the study had the most common form of the disease, known as relapsing and remitting multiple sclerosis, in which symptoms come and go over long periods, or steadily worsen with spells of remission between.
The main purpose of the trial was to test the safety of the vaccine, the first to be tested in humans to treat an autoimmune disease such as MS.
Any side effects were brief and were considered to be mild or moderate, according to a report in the US journal Archives of Neurology.
The doctors went on to test blood from the patients to see how their immune systems had responded to the vaccine. They found that levels of immune cells that specifically attack myelin sheaths had fallen, along with levels of antibodies which are also implicated in the disease.
The doctors recorded eight relapses, though only one occurred in a patient who was receiving the experimental vaccine. After treatment, the patient continued on the trial and experienced no further relapses. All of the other relapses happened five to 29 weeks after the patients received their final dose of vaccine.
The patients were later given magnetic resonance imaging brain scans to examine the damage caused by the disease. As the disease progresses, it produces lesions which can be counted and measured. In the trial, the researchers saw the number of lesions fall by 18% to 64% in patients who were given the DNA vaccine alone. The size of the lesions also dropped, by between 38% and 83%. The statin drug did not seem to improve the vaccine's effectiveness.
The researchers were excited by the results, but cautioned against reading too much into the trial's findings. "We have demonstrated in this first, to our knowledge, in-human trial of a DNA vaccine for autoimmune disease that the approach is safe and well-tolerated. We describe evidence for induction of favourable trends on brain MRI, indicating a reduction in the inflammatory response in the central nervous system," they wrote.
The team has now begun a 12-month trial of 290 patients. If that is a success, it could pave the way for DNA vaccines for a range of other diseases caused by an over-active immune system, such as type I diabetes and rheumatoid arthritis.

DNA Vaccine Against Multiple Sclerosis Appears Safe, Potentially Beneficial

Newswise — A newly developed DNA vaccine appears safe and may produce beneficial changes in the brains and immune systems of individuals with multiple sclerosis, according to an article posted online today that will appear in the October 2007 print issue of Archives of Neurology, one of the JAMA/Archives journals.
In patients with multiple sclerosis (MS), the immune system attacks the myelin sheaths that protect nerve cells in the brain and spinal cord, according to background information in the article. The nerve cell’s axon, which transmits messages to other neurons, is eventually destroyed. The cause of MS is unknown, but evidence points to the involvement of immune cells and antibodies that recognize and attack specific substances in the myelin, such as myelin basic protein. Certain cytokines, small proteins produced by cells that trigger inflammation, also may play a role.
Amit Bar-Or, M.D., of the Montreal Neurological Institute and colleagues tested a DNA vaccine, BHT-3009, that encodes a full-length human myelin basic protein. Between 2004 and 2006, the researchers administered the vaccine to 30 patients with relapsing-remitting MS [characterized by symptomatic periods and periods of remission] or secondary progressive MS [when symptoms progressively worsen, but there still may be periods of remission]. After one, three, five and nine weeks, participants received intramuscular injections of placebo or BHT-3009 (in doses of .5 milligrams, 1.5 milligrams or 3 milligrams), with or without 80-milligram pills of atorvastatin calcium, a lipid-lowering drug previously shown to be effective in autoimmune conditions. After 13 weeks, participants who initially received placebo received four injections of BHT-3009.
Magnetic resonance imaging (MRI) and other safety evaluations were performed at the beginning of the study, and again after five, nine, 13, 26, 38 and 50 weeks. “BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI and produced beneficial antigen-specific immune changes,” the authors write. These changes included a reduction in the number of cytokine-producing CD4+ T cells (a type of white blood cell) specifically targeting myelin proteins. This reduction was found in the blood as well as in the cerebrospinal fluid of three patients who voluntarily underwent lumbar puncture after completing the course of BHT-3009. Atorvastatin did not appear to provide additional benefit.
“There were no increases in clinical relapses, disability, drug-associated laboratory abnormalities, adverse events or the number and volume of contrast-enhancing [visible on MRI] lesions on brain MRI with BHT-3009 treatment compared with placebo,” the authors write. “In fact, there was a trend toward a decrease in the number and volume of contrast-enhancing lesions in the brain in patients treated with BHT-3009 compared with placebo.”
Based on these results, a phase 2b trial—a randomized clinical trial in approximately 290 patients—of BHT-3009 is already under way. “If successful in MS, antigen-specific DNA vaccines can be developed for prevention or treatment of related diseases, such as type 1 diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis and myasthenia gravis,” the authors conclude.(ArchNeurol. 2007;64(10):(doi:10.1001/archneur.64.10.nct70002). Available pre-embargo to the media at www.jamamedia.org.)
Editor’s Note: The work described in this article was funded by Bayhill Therapeutics, Inc. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
© 2007 Newswise. All Rights Reserved.

New Treatment Boosts Muscle Function in Myasthenia GravisNewswise — A new type of treatment significantly reduces the severity of muscle weakness in m

Newswise — A new type of treatment significantly reduces the severity of muscle weakness in myasthenia gravis (MG), giving hope for a new class of drugs to treat neurological disorders, according to a study published in the August 14, 2007, issue of Neurology®, the medical journal of the American Academy of Neurology.
The drug, oral EN101antisense, inhibits the production of acetylcholine esterase, which is an important enzyme in the function of the neuromuscular junction, where nerves connect with muscles. Antisense is a synthetic, short segment of DNA that locks onto a strand of mRNA and blocks production of specific proteins.
“This is the first time we’ve been able to show that antisense is effective and safe when taken orally for a neurological disease,” said study author Zohar Argov, MD, with Hadassah Hebrew University Medical Center in Jerusalem and member of the American Academy of Neurology. “Oral delivery of antisense has long been sought after since it is expected to improve patient compliance because daily injections won’t be needed.”
People with myasthenia gravis have increased fatigue and reduced strength in their voluntary muscles. Symptoms may also include a drooping eyelid, double vision, difficulty in swallowing, or slurred speech. Myasthenia gravis is believed to affect 20 out of every 100,000 people.
For the study, 16 people with myasthenia gravis were given daily doses of oral EN101 antisense for four days and monitored for one month. Four of the people later took the drug for a month. The study found that oral antisense reduced disease severity by an average of 46 percent, with patients experiencing improved muscle function, improved swallowing time and the disappearance of a drooping eyelid. Side effects reported during the study were dryness of eyes and mouth.
Experts say this discovery may have implications beyond myasthenia gravis. “Oral antisense may become another mode of therapy in neuromuscular disease and further study is needed,” said Argov. “However, these preliminary results should be evaluated with caution since this was an open label study.”
Argov says further research is underway to look at the effects of this drug over a longer period of time.
The study was supported by Ester Neuroscience Ltd., a biotechnology company.
The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, and multiple sclerosis.
For more information about the American Academy of Neurology, visit http://www.aan.com.
© 2007 Newswise. All Rights Reserved.

Studies show that exposure to the airborne toxins generated by the WTC attacks triggered the development of sarcoidosis and sarcoidosis-like respirato

The death toll from 9/11 reached 2,750 when Felicia Dunn-Jones’s name was added to the official death list. An attorney, Dunn-Jones fled her office, located a block away from the towers, and died of sarcoidosis 5 months after the attack. Dust from exposure to Ground Zero has also directly contributed to the death of others not yet on the list such as James Zadroga, a 34-year old police officer. Of the 10,000 clients represented by attorney David Worby involved in a lawsuit accusing the city of negligence, 5 have recently died of sarcoidosis.
The confirmation of Dunn-Jone’s sarcoidosis came in a letter by Dr. Charles S. Hirsch, the city's Chief Medical Examiner on May 18 stating that "Accumulating evidence indicates that in some persons exposure to WTC dust has caused sarcoidosis or an inflammatory reaction indistinguishable from sarcoidosis.”
Chemical Dust Exposure and Sarcoidosis
Sarcoidosis, which is also known as Besnier-Boeck disease, is an autoimmune disorder that usually starts in the lungs or the lymph nodes of the chest cavity. Sarcoidosis of the thyroid gland can also develop. Since its identification in the 1860s, no direct cause of sarcoidosis had been identified.
Although airborne toxins had long been suspected, recent evidence confirms that toxins, such as those that clouded the World Trade Center, can trigger sarcoidosis. A pathologist for Ocean County, New Jersey concluded in April 2006 that the January 2006 death of James Zadroga was directly linked to 9/11 recovery operations.
Post WTC Sarcoidosis
As of May, 2007, twenty-six New York City Ground Zero firefighters and emergency medical service workers have developed evidence of a sarcoid-like granulomatous pulmonary disease. The condition, called World Trade Center sarcoid-like granulomatous pulmonary disease, consists of abnormalities in the pulmonary parenchyma, hilar and/or mediastinal adenopathies, clinical features resembling asthma, and, occasionally, involvement of the bones, joints, skin, or spleen.
Investigators had previously shown that even before 9/11, New York City firefighters and rescue personnel had an elevated incidence of sarcoidosis or sarcoid-like granulomatous disease linked to occupational or environmental exposures to organic dusts, metals, chemical dust, silica, and wood dust or smoke.
However, the incidence of sarcoidosis or sarcoid-like pulmonary disease increased significantly after 9/11 compared to the years before the World Trade Center dust exposure, particularly during the first 12 months following 9/11/2001.
The Proof
To determine whether prolonged, repeated exposure to airborne particulates might increase the risk of sarcoidosis or sarcoid-like granulomatous pulmonary disease in a population already at risk, the investigators followed fire department employees. Those with chest radiograph findings suggestive of sarcoidosis underwent additional evaluation using chest CT imaging, pulmonary function tests, airway challenge tests, and biopsies.
The investigators calculated an annual incidence rate of sarcoidosis and compared it with the 15 years before the World Trade Center attacks. They found that 26 patients, all at the World Trade Center site within 72 hours of the towers’ collapse, when particulate levels were highest, had evidence of new-onset sarcoidosis.
Conclusion
Studies of the 26 firefighters showed that 18 (69%) had findings that were consistent with asthma, and fifteen of these patients had clinical symptoms: cough, dyspnea, and/or wheeze exacerbated by exercise and/or irritant exposure, or improved by the use of bronchodilators. All patients had intrathoracic adenopathy, and six (23%) had extrathoracic disease, involving the spleen, abdominal and pelvic lymph nodes, bones, joints, skin, and, in one case, hematuria.
Half the patients were identified within the first year following exposure, indicating an annual incidence rate of 86 per 100,000. The remaining 13 patients were identified within the second to fifth years after 9/11, showing an annual incidence rate of 22 per 100,000.
The average annual incidence rate of sarcoidosis among firefighters during the 15 years before the World Trade Center attacks was 15/100,000, and among controls (rescue personnel without exposure to fire conditions) the rate was 12.9/100,000.
Resources
Carren Bersch, Zac’s Rocky Mountain High, From the Editor, Medical Laboratory Observer, August 2007, Vol 39 (8): 4.

Body Clock Shift May Cause Sickness-Linked Fatigue

THURSDAY, July 19 (HealthDay News) -- As anyone who has battled the flu knows, "sick and tired" often go hand-in-hand.
Now, research suggests that illness-linked biochemistry may interfere with the body's "clock" to bring on the low-energy blahs.
Especially for patients battling chronic fatigue, the new findings "could pave the way for further exploration of the interaction between the immune system and the circadian system, hopefully leading to a better understanding of how daytime fatigue could be treated," said study co-lead researcher Thomas Birchler, of the University Hospital Zurich, in Switzerland.
His team published its findings in this week's online edition of the Proceedings of the National Academy of Sciences.
A sudden, profound loss of daytime energy is one of those "uh-oh" symptoms that signals the onset of acute illness, such as colds or influenza. Fatigue of a more chronic kind is also one of the most common and debilitating hallmarks of a wide variety of disorders, from cancer to autoimmune disease to Chronic Fatigue Syndrome.
Up until now, however, scientists knew little as to why fatigue so often accompanies illness.
In the new study, Birchler's team sought to determine how TNF-alpha -- an immune system inflammatory protein or "cytokine" -- might induce daytime tiredness.
A jump in TNF-alpha activity "is found in most of the acute and chronic infectious diseases and is also part of the inflammatory response in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and Crohn's disease," Birchler explained.
TNF-alpha helps spur immune-fighting cells that then seek out and destroy the agent causing the illness.
However, the Swiss group's work with both cell cultures and mice found that TNF-alpha has other physiological effects.
"Besides the known functions of TNF-alpha to eliminate infectious agents, we provide evidence that TNF-alpha interferes with clock gene expression," Birchler said.
In other words, the cytokine may affect genes that, in turn, upset the body's normal sleep/wake rhythms -- the "biological clock." This circadian clock guides the daily cycle of alertness and fatigue that people typically feel when healthy, but TNF-alpha appears to help put this cycle into disarray.
According to the study, TNF-alpha activity also "impairs locomotor activity and induces increased rest periods in mice," Birchler noted.
From an evolutionary and survival standpoint, feeling listless and sleepy during short-term illness probably isn't such a bad thing, the Swiss expert said.
"There's evidence that sleep is a helper for the fight against infections, and sleep deprivation leads to worsened immune response," Birchler explained. "From an evolutionary standpoint, fatigue -- by preventing the affected individual from joining social life -- may thereby hinder spread of infectious agents in the population," he added. "Fatigue in animals may be a mechanism which puts pressure on the affected animal to hide and thereby be protected from enemies."
Unfortunately, many patients can suffer from a chronic, unending form of fatigue, usually linked to long-term illness. That kind of tiredness is not useful, Birchler said, and is often the leading complaint of people battling disease.
"So, in the short term, illness-linked fatigue is an advantageous adaptation, but in the long term not necessarily so," said Wilfred Pigeon, an assistant professor of psychiatry at the University of Rochester, N.Y., and the director of the university's Sleep & Neurophysiology Research Laboratory.
Pigeon said the Swiss findings are intriguing and "point the way to some potential therapeutic targets" to help patients ease chronic fatigue. "We probably don't want to tinker with it in flu, for instance, but we may want to tinker with those targets for people who have some chronic illness or autoimmune diseases," he said.
And that "tinkering" might not always come in the form of a pill, Pigeon said.
In numerous studies, exercise "has successfully alleviated fatigue symptoms," Pigeon noted. "Of course, people with Chronic Fatigue Syndrome or cancer-related fatigue really don't want to go to the gym, but, in fact, when they do go, it does alleviate [fatigue] symptoms," he said. The reasons for the effect remain unclear, he added, but "it would be interesting to look at exercise or other behavioral interventions to see if we actually change [clock] gene function."
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Potential Role For Retinoic Acid In Autoimmune And Inflammatory Diseases Identified

Science Daily — An important finding, which could eventually lead to a new therapeutic approach for treating autoimmune and inflammatory diseases such as rheumatoid arthritis, colitis, psoriasis and others, was announced today by researchers at the La Jolla Institute for Allergy & Immunology (LIAI). The studies, conducted in laboratory mice, demonstrated the role of retinoic acid, a substance derived when Vitamin A is broken down in the body, in regulating inflammation.
In these studies, published in the journal Science, the LIAI researchers showed that by manipulating the amount of retinoic acid in mice, they could affect the number of pro-inflammatory T cells, a type of white blood cell responsible for several autoimmune and inflammatory diseases. The finding is an important first step that, if eventually found to be true in humans, points to the potential of a new avenue of therapies using retinoic acid to treat these diseases.
"What's exciting about this finding is they've found that retinoic acid plays a role in modulating the switch between these two distinct (T cell) lineages -- the induced regulatory T cells, which are anti-inflammatory, and the TH-17 lineage, which promotes inflammatory responses, " said Casey Weaver, M.D., a University of Alabama, Birmingham, professor and prominent immunology researcher, who was key in the discovery of TH-17 in 2005.
Further, Dr. Weaver said, the LIAI researchers had developed a "mechanism by which you can prevent the development of the (inflammatory) lineage. This is very exciting because it provides a potential pharmacological application for this finding."
The LIAI team tested three approaches with retinoic acid. In one model, they injected the mice with retinoic acid, essentially giving them more of the substance than they would have through normal body processes. This suppressed the formation of pro-inflammatory T cells in the intestines of the mice, demonstrating that increases in retinoic acid reduced inflammation. In another approach, designed to test how reducing retinoic acid would affect inflammation, the team used an inhibitor to block retinoic acid in the mice.
This led to the decrease of anti-inflammatory T cells, showing that reducing retinoic acid increased inflammation. In a third, particularly exciting approach, the scientists treated T cells with retinoic acid in a test tube. When put back into the mice, these T cells prevented the formation of inflammatory T cells in the mice. This is especially noteworthy because combining the retinoic acid and T cells outside the body may avoid possible side effects that are more likely when scientists attempt to manipulate body processes internally.
"We found that you can control inflammation in a living animal with retinoic acid or you can treat cells with retinoic acid in a test tube and transfer them to the organism to suppress inflammation in vivo," said Dr. Cheroutre. "This may offer an important new avenue for treatment of autoimmune diseases like colitis and rheumatoid arthritis or other inflammatory diseases, as well as potentially providing a mechanism for the control of graft rejections, where you don't want the immune system to attack the grafted tissue."
The finding was published in a paper entitled "Reciprocal Th-17 and regulatory T cell differentiation mediated by retinoic acid." Hilde Cheroutre, Ph.D., led the research team, entirely from LIAI, in which Daniel Mucida, Ph.D., and Yunji Park, Ph.D., were key contributors.
Note: This story has been adapted from a news release issued by La Jolla Institute for Allergy and Immunology

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Breakthrough Developments in Rheumatoid Arthritis Reported at Federation of Clinical Immunology Services Meeting in San Diego

Feinstein Researchers to present latest genetic findings on rheumatoid arthritis at San Diego conference.
Manhasset, NY (Vocus/PRWEB ) June 9, 2007 -- Peter K. Gregersen, MD, stares at x-rays of hands, searching out the telltale signs of inflamed joints and wrists from his research subjects with rheumatoid arthritis. With these clinical features at his side, he turns to the basic building blocks of life - the human genome - to figure out what makes these people susceptible to the disabling inflammatory condition.
Dr. Gregersen has finally closed the circle between key genes identified in his laboratory at the Robert S. Boas Center for Genomics and Human Genetics at The Feinstein Institute for Medical Research in Manhasset, NY and more than a 1,000 patients with rheumatoid arthritis. The genes will help tell the story of how the immune system works to create specific antibodies that in turn increase a person's risk for this crippling disease.
Helvetica, sans-serif; TEXT-DECORATION: none" href="http://www.feinsteininstitute.org/" alt="Link to website">The more patients and controls that we have, the more power we will have to pull out new genes and make associations. On Monday at the Federation of Clinical Immunology Services' (FOCIS) meetings in San Diego, CA, Dr. Gregersen and his colleagues will be presenting the lab's latest genetic findings. The group conducted genome-wide scans to identify polymorphisms, or genetic variants, that are associated with the inflammatory condition and can be used to understand the triggers of the disease. This will provide key insights into the pathways underlying rheumatoid arthritis and other autoimmune diseases. It may ultimately provide tests to predict who will respond to the available new treatments. Franak Batliwalla, PhD, also of The Feinstein Institute, will be presenting related studies on biomarkers and genetic influences on drug response at the same meeting. Identifying Immune System Mediators About one percent of the US population will develop rheumatoid arthritis, an autoimmune disease that leads to painful joint swelling. Scientists are cracking the genetic code that makes the immune system wage an attack on a person's joints. Over the last decade, Dr. Gregersen and his colleagues have been amassing a genetic database complete with siblings with rheumatoid arthritis (and some family members without it) in an attempt to single out those genes that are involved in the autoimmune process. In fact, in 2004, they identified a gene called PTPN2 that confers a two-fold risk for rheumatoid arthritis and a number of other autoimmune diseases. The Feinstein now holds the largest collection from rheumatoid arthritis patients in the world. Following the cellular pathway, it has been shown that PTPN22 influences the "trigger point" for activation of T-cells, immune cells that are normally called on to wage battle against infection. In autoimmune diseases like rheumatoid arthritis, PTPN22 appears to put people at higher risk of a wayward T-cell response. The group has since gone on to use modern genetic methods to search for single nucleotide polymorphisms, or SNPs, to identify players that have fallen under the radar of older methods. The group has discovered another signaling molecule that seems to increase a person's risk for rheumatoid arthritis by 30 percent. (The paper reporting the gene is in press.)
In collaborations with other scientists worldwide, Dr. Gregersen has also been able to show that certain markers are strongly linked to certain ethnic groups and others are not. "This will help us in figuring out what exactly is going on in this illness," he said. "It's pretty exciting." Early on in the rheumatoid arthritis research game, when HLA popped out as a major genetic player in the condition in the 1980s, Dr. Gregersen discovered that there was a shared bit of DNA that traveled in the disease. What took two years to identify in the laboratory - shared bands of genetic material - would take two days today. And that speed is what excites Dr. Gregersen. "We have the tools to get at these genes rather quickly now," he said. "The more patients and controls that we have, the more power we will have to pull out new genes and make associations." In another major breakthrough, scientists have discovered the importance of a substance called citrulline as a target for immune attack in rheumatoid arthritis (RA). This immune system antibody associated with rheumatoid arthritis recognizes citrulline, which seems to be a key player in the condition. Indeed, the HLA associations with RA have now been shown by Dr. Gregersen and others to directly regulate the immune response to proteins containing citrulline. Citrulline is formed when a specific enzyme comes in contact with arginine, one of 20 common amino acids in proteins. When one of the enzymes is present, nitrogen is removed from the chemical structure of arginine and it converts into citrulline. Laboratories have developed a test to measure for anti-cyclic citrullinated peptide antibody, or anti-CCP. It is now being used as a diagnostic for rheumatoid arthritis. Scientists are now finding that patients have CCP antibodies months or years prior to the illness, suggesting a way to identify the disease before it starts and perhaps offer treatments to stave off the symptoms. It turns out that those with these antibodies who also have a particular variety of HLA, a complex of genes that regulate immune function, have a 30 times higher risk of developing rheumatoid arthritis than those without these genetic risk factors. Scientists at the University of Colorado are now analyzing the genes from 2,500 first degree relatives of rheumatoid arthritis patients and testing CCP levels to see whether there is a way to predict, based on these measurements, who will go on to develop rheumatoid arthritis. Ultimately, understanding how the genes work to confer illness will help in the development of new treatments.Normal Control Genetic DatabaseIn addition, The Feinstein Institute is participating in a groundbreaking effort to release large amounts of genetic data on normal subjects for use by the scientific community. A key barrier to progress for many geneticists is the costs of obtaining genetic data from normal control populations to use for comparison to the genetic variation seen in people with disease.
In collaboration with the Children's Hospital of Philadelphia, The Feinstein will release genetics data on approximately 6,000 normal volunteers. A company that designs new genetic testing technology, Illumina, Inc. will maintain the database and make it available to scientists. The data will not include personal identifiers but scientists will have information on age and ethnicity to best match their groups to study.
About The Feinstein Institute for Medical Research: Headquartered in Manhasset, NY, and part of the North Shore-LIJ Health System, The Feinstein Institute for Medical Research is home to international scientific leaders in Parkinson's disease, Alzheimers disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma, neuroimmunology, and medicinal chemistry. Feinstein investigators rank in the top 6th percentile of all grant awards funded by the National Institutes of Health. Feinstein Researchers are developing new drugs and drug targets, and producing results where science meets the patient. For more information, please visit www.FeinsteinInstitute.org.
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Autoimmune, rheumatic diseases linked to deeper aortic inflammation and risk of aneursym.

Autoimmune, rheumatic diseases linked to deeper aortic inflammation and risk of aneursym.
Rheumatoid arthritis, lupus, and other inflammatory rheumatic diseases are associated with a high rate of death from heart disease. One explanation is a greater susceptibility to atherosclerosis. Although atherosclerosis is linked to inflammation in healthy individuals as well, the mechanism of inflammation and the reason for accelerated atherosclerosis in patients with inflammatory rheumatic disease remain unclear. Does atherosclerosis result from systemic inflammation, a hallmark of these rheumatic diseases, or from local inflammation of vessels?
To shed light on the link between chronic inflammation and atherosclerosis, a team of researchers in Norway and the United States, affiliated with the Cleveland Clinic Foundation and Brigham and Women’s Hospital in Boston, focused on the aortas of recent recipients of coronary artery bypass graft (CABG) surgery, comparing biopsy specimens from patients with inflammatory rheumatic disease to those from patients without it. Their study, presented in the June 2007 issue of Arthritis & Rheumatism, affirms inflammatory rheumatic disease and smoking as independent predictors of vessel wall inflammation. The vascular inflammation might be a factor that promotes atherosclerosis and the formation of aneurysms.
Aortic samples were obtained during CABG surgery, performed at two cardiac centers in Norway, from 66 patients with inflammatory rheumatic disease and 51 control patients. The inflammatory rheumatic disease group included patients with rheumatoid arthritis, psoriatic arthritis, lupus, ankylosing spondylitis, polymyalgia and other diseases. Age, body mass index, family history of heart disease, and other traditional cardiovascular risk factors were similar in both groups. All specimens were evaluated, by light microscope, for evidence of chronic inflammatory cell infiltration in the aortic wall. This was achieved by counting and measuring the mononuclear cell infiltrates (MCI) in the aorta, with particular attention to the adventitia, the deepest layer of vascular tissue. Using statistical analysis, the relationship between these inflammatory infiltrates and established lifestyle risk factors for heart disease was also assessed.
In the adventitia (the deepest layer of the blood vessel wall), MCIs occurred more frequently in patients with inflammatory rheumatic disease — 47 percent of this group, compared with 20 percent of the control group. Along with greater prevalence, these inflammatory cells were larger in size. In the middle layer of the vessel wall (the media), MCIs were detected only in patients with inflammatory rheumatic disease. What’s more, MCIs were observed in 6 of 7 patients with a history of aortic aneurysm. In addition to inflammatory rheumatic disease, current smoking was independently associated with more pronounced chronic inflammatory infiltration in the inner adventitia.
In summary, inflammatory rheumatic diseases (many of which involve autoimmune mechanisms) are associated with much higher white blood cell infiltration in the middle and deepest layers of the blood vessel walls, and cigarette smoking worsens inflammation in the inner adventitia. Despite the limitations of its small sample size, this groundbreaking study of aortic inflammation in patients with inflammatory rheumatic disease indicates the need for further investigation into an inflammatory process that may increase vulnerability to dying from a heart attack or aneurysm (Courtesy of EurekAlert!, a service of AAAS).

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MS, more common among women

MS, or multiple sclerosis, is a chronic inflammatory disease that affects the central nervous system. In 1940, two out of three with the condition were women but by the year 2000, that figure went up to four out of five. "We also need to ask the general questions about what women do differently than men, such as use of hair dye and cosmetics that may block vitamin D absorption," said Dr Gary Cutter, from the University of Alabama in Birmingham. In another study, researchers also found the largest increase in the ratio of women to men has been for those whose MS started at younger ages. MS can cause a variety of symptoms, including changes in sensation, visual problems, muscle weakness, depression, difficulties with coordination and speech, severe fatigue, cognitive impairment, problems with balance, overheating and pain. MS will cause impaired mobility and disability in more severe cases. MS is the most common disabling neurological condition affecting young adults; it is an autoimmune condition - meaning the immune system mistakes the body's own tissue for an infectious foreign body, and attacks it. MGP/SF/BGH
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JAMA report on transplant treatment for newly diagnosed type 1 diabetes patients

New York, NY, April 11, 2007 — The Journal of the American Medical Association reported on April 11, 2007, that a procedure similar to a bone-marrow transplant was able to reverse type 1 diabetes in a small clinical trial in South America.
An editorial in the JAMA called the report “provocative.” It is that, and might some day have an important impact on understanding the autoimmune attack that causes type 1 diabetes and reversing it in newly diagnosed patients.
The treatment involves taking blood from the patient and isolating the hematopoietic stem cells that give rise to bone marrow and blood cells, destroying the patient’s existing immune system and other cells, then returning the patient’s own hematopoietic stem cells to the body to develop a new immune system. In the trial, the immune system was apparently reset or retrained, and after the procedure, the symptoms of diabetes were reversed.
The procedure—called autologous nonmyeloablative hematopoeitic stem cell transplantation—carries some significant risks and has usually been reserved for patients with either life-threatening disease, like leukemia, or organ-threatening autoimmune diseases. Because of those risks, it is not clear whether this trial would be approved in the U.S.
The trial presents a number of positives. It indicates that the immune system of people with type 1 diabetes can be retrained or reset, at least for a period of time. And it suggests that when the autoimmune response is interrupted, patients with some insulin-producing cells remaining (common in many newly diagnosed patients) can begin to regenerate enough additional beta cells to reduce or even eliminate their insulin requirements.
As with any early clinical trials involving new treatments or procedures, there are a number of issues that will need to be addressed before this approach can become widely available to patients with type 1 diabetes. The risks associated with a highly invasive treatment need to be better quantified, mitigated, and weighed against the benefits of the procedure. What exactly happens in the treatment—whether the immune system is “re-trained,” or just reset, with the risk of diabetes returning at some point—needs to be better understood. And the potential patient universe that could benefit from such a procedure needs to be outlined (as the trial involved just the recently diagnosed, who may have significant insulin-producing cells remaining) and the long-term effects have not been defined at this time.

Source- JDRF

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Gene Behind Autoimmune Diseases Identified by Researchers

Newswise — A report in the March 22 issue of the New England Journal of Medicine reveals that a pinpointed region of chromosome 17, a gene named NALP1, could be a new target of treatment for autoimmune diseases. This is a particularly exciting discovery because NALP1, a gene known to control part of the immune system that serves to alert the body to viral and bacterial attacks, has not previously been specifically implicated in autoimmune diseases, affirms the American Autoimmune Related Diseases Association (AARDA), a national nonprofit patient advocacy organization. The discovery was the result of collaboration between St. George University of London, the University of Colorado at Denver and Health Sciences Center (UCDHSC), and the Barbara Davis Center for Childhood Disorders.
Why does the body choose the misdirected path of attacking itself, in an autoimmune process, when it sets out to eliminate invaders, such as bacteria or viruses, thus resulting in autoimmune diseases--for example, lupus, multiple sclerosis, rheumatoid arthritis, vitiligo, thyroiditis (Graves', Hashimoto's), juvenile (type 1) diabetes, or any one of the more than 100 such diseases?
The findings of this latest research study, which followed 656 persons from 114 extended families in the United States and the United Kingdom who had multiple autoimmune diseases, give the researchers a clue as to why the immune system attacks one of the body's own tissues. "If the sensor NALP1 is overreactive, it could trigger a response to the wrong stimulus," said Professor Dorothy Bennett, Professor of Cell Biology at St. George's University of London, investigator for the UK arm of the study. She added, "We hope to study exactly how this works and to learn even more from the other genes that we are working to identify."
Lead investigator Dr. Richard Spritz, director of the Human Medical Genetics Program at UCDHSC, was quoted as saying, "Since NALP1 appears to be part of our body's early-warning system for viral or bacterial attack, this gives us ideas about how to try to discover the environmental triggers of these diseases." Dr. Spritz said, "This finding may also


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Congress Designates May 2007 as Autoimmune Disease Awareness Month !

The month of May has been named national Autoimmune Disease Awareness Month (ADAM) by Congress in order to call increased attention to a family of diseases that are still not well-known or well-understood by the medical and research communities and the general public.
The National Coalition of Autoimmune Patient Groups, facilitated by the American Autoimmune Related Disease Association (AARDA), has spearheaded
this advocacy effort. The Congressional resolution is sponsored by Senator Joseph Biden (D-DE) and Congressman Steve Israel (D-NY).
“By declaring May as Autoimmune Disease Awareness Month, Congress is sending a clear message that autoimmune disease is a national health concern that must be paid attention,” explained Senator Biden.
“While many aspects of autoimmune disease are not well-known, we do know that the family of these diseases is under-recognized, and that they post a major healthcare problem in the United States, particularly to women,” added Congressman Israel.
There are more than 80 known autoimmune diseases including multiple sclerosis, juvenile diabetes, Crohn’s disease, scleroderma, polymyositis, lupus, Sj`gren’s disease and Graves’ disease. Autoimmunity is the underlying cause of these diseases. It is the process whereby the immune system mistakenly recognizes the body’s own proteins as foreign invaders and begins producing antibodies that attack healthy cells and tissues, causing a variety of diseases.
According to the National Institutes of Health (NIH), there are 24.5 million Americans who suffer from autoimmune diseases and that the prevalence of these diseases is on the rise. Collectively, autoimmune disease is one of the top 10 leading causes of death in children and women under 65 and represents some $100 billion in annual direct health care costs, yet less than six percent of Americans surveyed in a recent Roper poll could identify an autoimmune disease.
AARDA is asking those interested in being a part of the advocacy effort for Autoimmune Disease Awareness Month to contact their congressional representatives to request that they sign onto the resolution as co-sponsors. Contact information for all U.S. senators and congressmen can be found on AARDA’s website at http://www.aarda.org and clicking on “Congress Connect.”
To view the resolutions, , please visit www.thomas.gov and search for H. Res # 258 and S. Res. # 116. For more information, contact AARDA at www.aarda.org

Scientists Pinpoint Gene Behind Autoimmune Diseases

Published: Wednesday, March 21, 2007 9:40 PM ET
Canadian Press: AMANDA GARDNER, HEALTHDAY REPORTER


WEDNESDAY, March 21 (HealthDay News) - Variations in one specific gene appear to be behind several different autoimmune and auto-inflammatory diseases.
The pinpointed region of chromosome 17, called NALP1, could be a new target for treatment, said the authors of a study in the March 22 issue of the New England Journal of Medicine.
"This part of the immune system may respond to triggers coming from the environment, like bacteria or viruses, and there are indications that you can turn it off. So, we're very, very hopeful that there may be drugs that allow us to do that," said the study's senior author, Dr. Richard A. Spritz, who directs the Human Medical Genetics Program at the University of Colorado at Denver and Health Sciences Center.
Spritz added, "That's not going to help people with childhood diabetes, where the damage is already complete. But, for a number of chronic autoimmune disorders, like lupus and vitiligo, if you turn off the autoimmune process, the body could repair itself."
Some 80 autoimmune and auto-inflammatory disorders, which occur when the immune system malfunctions and starts destroying normal tissue, affect between 15 million and 25 million people in the United States, particularly women.
A few of the autoimmune diseases are caused by mutations in single genes, but most appear to be more complex. Scientists suspect that some genes may predispose individuals to one or more diseases, whereas other genes may predispose individuals to autoimmune and auto-inflammatory diseases in general.

"There has been a feeling for decades that autoimmune diseases are somehow related," said Dr. Peter Gregersen, author of an accompanying editorial in the journal and director of the Robert S. Boas Center for Genomics and Human Genetics at the Feinstein Institute for Medical Research in Manhasset, N.Y.
Interactions between gene variants and environmental factors also play a role in triggering the onset of a disease.
Spritz and his colleagues have long focused on patients with vitiligo, a disorder in which pigment cells are destroyed, resulting in white patches on the skin and sometimes the hair. Individuals with vitiligo tend also to have other autoimmune and auto-inflammatory diseases, as do their relatives. But the combinations of diseases are not very consistent.
"They probably have genes that predispose more toward autoimmunity in general and not specific disorders," Spritz said.
The team did a systematic genetic analysis of 656 persons from 114 extended families in the United States and United Kingdom who had multiple autoimmune diseases, including vitiligo. This led them to a number of genetic possibilities, but the "hottest" signal was a region on chromosome 17, which had shown up previously as possibly harboring a lupus gene in families who also had vitiligo.
A closer examination revealed a collection of variations in a specific gene, NALP1.
"We don't really know which one causes the disease, but we can use the variations that we see as flags or markers of variations," Spritz explained. "These could be the ones that cause the disease or tell us about the ones that do."
But NALP1 is probably only part of the picture.
"This can't be the whole story," Spritz said. "This is one of probably many genes that predispose to autoimmunity, but it looks like it may be involved in a pretty big way, which is why we were able to find it."
The gene is connected to the body's primitive immune system, which is involved with the earliest responses to outside attacks.
"It probably has a big effect, and it probably interacts in some complex way with other genes and other risk factors," Spritz pointed out. "We know a lot about this gene. It was not an anonymous gene that you would have to start from ground zero studying. We know that it's part of the surveillance system for attack by bacteria or viruses, part of the innate immune system."
"This work is really nice and elegant, and it's also provocative," Gregersen said. "It raises the issue of whether this gene might be involved in more common disorders."
He added that the research was a good example of "a successful, family-based approach to gene identification and an example of how new genes identified that way can raise new connections among different diseases."

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Stem cell finding could help fight autoimmune disease

HEALTHDAY
In a finding that could help researchers better understand autoimmune disease, scientists say a process called autophagy prompts dying embryonic stem cells to send out "eat me" and "come and get me" signals to ensure their elimination by healthy cells."Our findings also suggest that defects in autophagy might trigger autoimmune diseases and, if so, reversing the defects could potentially help treat such diseases," Dr. Beth Levine, chief of the division of infectious diseases at the University of Texas Southwestern Medical Center, in Dallas, said in a prepared statement.Her team described its findings in a study published in the March 8 online issue of Cell.In mouse embryos incapable of activating autophagy, dying cells aren't able to produce the chemical signals that instruct healthy cells to remove them, the study found. An accumulation of dead cells can result in abnormal development, inflammation and autoimmune disease."The activation of autophagy in cells destined to die may serve to clear dead cells and prevent detrimental inflammation during normal development or when cell death occurs in certain diseases," Levine explained.

Successful Islet Cell Transplant Without Immunosuppressive Therapy in Mice with Type 1 Diabetes

Newswise — Scientists at Weill Cornell Medical College may have reached a breakthrough in the search for a lasting cure for type 1 diabetes.Reporting in the Feb. 20 issue of the Proceedings of the National Academy of Sciences, the team greatly boosted the number of immune T-cells able to shield transplanted pancreatic islet cells from attack by the immune system. Insulin-producing islet cells are deficient in type 1 diabetes."If we can replicate this in humans, we might someday do away with the lifelong use of powerful immunosuppressive drugs that patients must take after islet cell transplant -- drugs that we believe also do harm to islet cells over time," explains the study's senior author Dr. Manikkam Suthanthiran, chief of the Division of Nephrology and Hypertension at Weill Cornell Medical College and chief of the Department of Transplantation Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.Type 1 diabetes is an inherited disorder in which the body's immune cells attack islet cells in the pancreas, reducing or eliminating the body's ability to produce the blood-sugar hormone. It is distinct from the much more common type 2 form of diabetes, where obesity and other factors cause a gradual decline in cells' sensitivity to insulin. Scientists have sought to reverse type 1 diabetes by transplanting new islet cells. The procedure has met with some success -- in fact, Dr. Suthanthiran's team at NewYork-Presbyterian/Weill Cornell performed the first successful islet transplantation in the tri-state area in patients with type 1 diabetes in 2004.However, problems remain. "To stave off the destruction of transplanted cells, patients must be placed on lifelong immunosuppressive therapy," Dr. Suthanthiran explains. "Besides having powerful side effects, we're learning that these drugs can be toxic to islet cells, too."Now, an innovative biochemical manipulation of immune cells may get around that problem. Working in collaboration with researchers at The Rockefeller University, the research team focused on immune system regulatory T-cells (T regs). These cells help the immune system decide which entities are "enemies" and which are "friendly" and should be left alone. "Specifically, there are a subset of T-cells with cell-surface proteins CD4 and CD25, which are called natural regulatory T-cells," Dr. Suthanthiran explains. "These cells express a key factor called Foxp3, and the CD4+CD25+Foxp3+ regulatory T-cells suppress the runaway immune response to islet cells. Without Foxp3, the suppression of the islet destructive response cannot take place."Unfortunately, Foxp3-positive T-cells make up a paltry 2 to 5 percent of the total T-cell population, so they have little impact in shielding transplanted islet cells from harm.However, working with the standard mouse model for type 1 diabetes, the researchers were able to convert the much more common form of CD4+ CD25- T-cells into CD4+CD25+ T-cells that did express protective Foxp3. "We did so by a two-pronged approach," Dr. Suthanthiran says. On the one hand, the research team exposed the much more common form of CD4+ CD25- T-cells to transforming growth factor-beta (TGF-b), which helps switch the T-cell over to a Foxp3 expressing cell.But TGF-b on its own is too blunt an instrument. "If we turn all of these T-cells into random immune suppressors, that could lead to more cancers and other problems," the researcher explains. "So, we used another immune system signaler, the dendritic cell, to target Foxp3 activity much more specifically and shield only the islet cells from immune system attack." Study co-researcher Dr. Ralph Steinman of The Rockefeller University actually discovered the dendritic cell and its role in immune system signaling, and was instrumental in this research, Dr. Suthanthiran says. Dr. Steinman's group has shown that dendritic cells are highly efficient in turning on natural regulatory cells into islet protective cells."When CD4+ CD25- T-cells came into contact with both TGF-b and the specific antigen-presenting dendritic cells, they switched over to the immunosuppressive Foxp3 variety," he says. "The dendritic cells made sure that this protective immunosuppression was targeted to islet cells, specifically."The result: successful islet transplantation in diabetic mice without any pharmacologic immunosuppression; the transplanted islet cells stayed healthy and produced insulin over the full nine weeks of the study. And there was a bonus: "We also determined that this approach shields the pancreas' own islet cells from harm," the researcher says. "That's important, because newly diagnosed type 1 diabetes patients often have some percentage of working islet cells remaining. This strategy might protect those cells, as well as the transplanted cells."According to Dr. Suthanthiran, there's no reason to believe this approach wouldn't also protect other types of transplanted cells or organs, including lung, kidney and hearts transplants. "It's also important to note that we were treating established diabetes in this mouse model," Dr. Suthanthiran says. "Most of the success so far has been in preventing disease before it sets in, but this is akin to going into a house and putting out the fire after it has already started." Of course, it remains to be seen if success in mice will translate to success in human type 1 diabetes. But Dr. Suthanthiran says he is optimistic. "We want to create a transplant situation where we don't have to deliver any outside immunosuppressive drugs," he says. "That would truly be the best kind of cure."This work was funded by the American Society of Transplantation, the Juvenile Diabetes Research Foundation and the U.S. National Institutes of Health.Co-researchers include lead author Dr. Xunrong Luo, formerly at Weill Cornell Medical College, now at Northwestern University, Chicago; Dr. Hua Yang and Dr. Ruchuang Ding of Weill Cornell Medical College; Samantha L. Bailey and Kathryn Pothoven of Northwestern University; and Dr. Kristin V. Tarbell (co-lead author) and Dr. Ralph M. Steinman of The Rockefeller University, New York City. For more information, patients may call (866) 697-6397.


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Researchers Discover New Molecular Path to Fight Autoimmune Diseases

Newswise — Multiple sclerosis, diabetes, and arthritis are among a variety of autoimmune diseases that are aggravated when one type of white blood cell, called the immune regulatory cell, malfunctions. In humans, one cause of this malfunction is when a mutation in the FOXP3 gene disables the immune cells’ ability to function. In a new study published online this week in the Proceedings of the National Academy of Sciences, researchers at the University of Pennsylvania School of Medicine have discovered how to modify enzymes that act on the FOXP3 protein, in turn making the regulatory immune cells work better. These findings have important implications for treating autoimmune-related diseases.
“We have uncovered a mechanism by which drugs could be developed to stabilize immune regulatory cells in order to fight autoimmune diseases,” says senior author Mark Greene, MD, PhD, the John Eckman Professor of Pathology and Laboratory Medicine. “There’s been little understanding about how the FOXP3 protein actually works.” First author Bin Li, PhD, a research associate in the Greene lab has been working on elucidating this process since FOXP3’s discovery almost five years ago.
Li discovered that the FOXP3 protein works via a complex set of enzymes. One set of those enzymes are called histone deacetylases, or HDACs. These enzymes are linked to the FOXP3 protein in association with another set of enzymes called histone acetyl transferases that modify the FOXP3 proteins.
Li found that when the histone acetyl transferases are turned on, or when the histone deacetylases are turned off, the immune regulatory cells work better and longer. As a consequence of the action of the acetylating enzyme, the FOXP3 protein functions to turn off pathways that would lead to autoimmune diseases.
“I think this simple approach will revolutionize the treatment of autoimmune diseases in humans because we have a new set of enzymatic drug targets as opposed to the non-specific therapies we now use,” says Greene. Non-specific therapies include the use of steroids and certain chemotherapy-like drugs that act on many cell types and have significant side effects.
“Before this work, FOXP3 was thought essential for regulatory T-cell function, but how FOXP3 worked was not known,” says Li. “Our research identifies a critical mechanism. Based on this mechanism, treatments could be developed to modulate this regulatory cell population.”
“In this line of investigation, we have learned how to turn on or off this regulatory immune cell population – which is normally needed to prevent autoimmune diseases – using drugs that are approved for other purposes, but work on these enzymes” notes co-author Sandra Saouaf, PhD, a research associate at Penn.
Li, Greene, Saouaf and Penn colleagues Wayne Hancock and Youhai Chen are now extending this research directly to several mouse models of autoimmune diseases.
Additional co-authors are Arabinda Samanta, Xiaomin Song, Kathryn T. Iacono, Kathryn Bembas, Ran Tao, Samik Basu, and James Riley, all from Penn.

Preventing unwanted side effects of treatment for autoimmune diseases

Treatment for autoimmune and inflammatory disorders such as multiple sclerosis often includes blocking a special cell surface attachment molecule known as alpha4 integrin to prevent migration of white blood cells (WBCs). However, this therapy can cause adverse side effects, such as impaired immunity and hematopoiesis [the process of development of new WBCs in the thymus (T cells) and bone marrow (B cells)]. Now, researcher Mark H. Ginsberg and colleagues at the University of California in San Diego have identified a mechanism to selectively reduce WBC recruitment while sparing hematopoiesis. The study appears online on February 9 in advance of print publication in the March issue of the Journal of Clinical Investigation. The authors created mutant mice known as "alpha4(Y991A) mice," in which the alpha4 integrin can no longer bind to a signaling protein inside the cell called paxillin. Previously generated alpha4 integrin mutant mice died at birth because too many aspects of alpha4 function were changed. The new alpha4(Y991A) mice have an impairment only in the interaction between alpha4 and paxillin, and thus have fewer side effects from the mutation. The authors noticed that, in contrast to wild-type mice, alpha4(Y991A) mice exposed to an inflammation-inducing compound called thioglycollate recruited fewer circulating T and B cells to the region of exposure. However, the development of new B and T cells was unaffected. The authors suggest that these mice are an important model for the identification of signaling mechanisms specific to inflammation, and that a new class of pharmaceutical agents that target the specific interaction of paxillin and alpha4 integrin could be important future treatments of inflammatory disease. TITLE: Blocking the alpha4 integrin-paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory siteAUTHOR: Mark H. GinsbergUniversity of California San Diego, La Jolla, California, USAView the PDF of this article at: https://www.the-jci.org/article.php?id=26091

CLAIMS OF SMITH’S LUPUS NOT SURPRISING SAYS AUTOIMMUNE DISEASES ASSOCIATION

Newswise — Claims that Anna Nicole Smith suffered from lupus are not surprising, according to the Autoimmune Diseases Association, a national voluntary health organization. Many of the reports of how Smith was affected by her newly disclosed condition are consistent with a diagnosis of lupus. Lupus is a chronic inflammatory autoimmune disease in which the immune system becomes misdirected and attacks the body’s healthy tissues and organs. In lupus, any part of the body can be affected and common symptoms include painful or swollen joints, skin rashes, unexplained high fever, kidney problems and severe fatigue.
Although a diagnosis of lupus for Smith has not yet been confirmed, it is not uncommon for celebrities to try to keep their autoimmune diseases hidden from the public. “People who suffer from lupus, as with the more than 80 autoimmune diseases, often keep their disease hidden from their family and friends because they fear that their disease will be misunderstood,” explains Virginia Ladd, Autoimmune Diseases Association president.
A lack of awareness of autoimmune disease often leads to this misunderstanding. A study conducted by the group found that 29% of Americans mistakenly think autoimmune disease is AIDS and only 5% of respondents could even name an autoimmune disease. While the National Institutes of Health have estimated that 24.5 million Americans have one or more autoimmune diseases.
According to the Autoimmune Diseases Association, it is not unusual for autoimmune disease patients to spike a high fever, as has been reported in Smith’s case. Symptoms of autoimmune disease can be very confusing to both patients and their physicians.
“Smith gave birth to her daughter last fall and if she had lupus, the symptoms of the disease can really flare up three months after delivery,” explains Robert G. Lahita, M.D., P.h.D., Chairman of Medicine at Jersey City Medical Center and author of the book, Women and Autoimmune Disease. “Her symptoms were consistent with a diagnosis of lupus.”
Smith’s rapid weight gain could likely be explained as a side effect of her medications. Corticosteroids are commonly prescribed for multiple autoimmune diseases including lupus.
“Autoimmune diseases have been cited in the top ten leading causes of all deaths among U.S. women younger than 65,” says Stanley M. Finger, PhD, chairman of the Autoimmune Diseases Association. “The public is always surprised to learn this.” Autoimmune diseases strike women more often than men. In lupus, women are affected nine times more often than men.
The Autoimmune Diseases Association is the only national organization dedicated to addressing the problem of autoimmunity, the major cause of chronic illness. It is leading the effort to have Congress declare the month of May as Autoimmune Disease Awareness Month (ADAM). For more information, please visit the association’s website at http://www.aarda.org or call 586-776-3900 or 888-856-9433.

New insights into autoimmunity and depression

Novel experiment links depression with a specific autoantibody and central nervous system dysfunction in lupus
Systemic lupus erythomatosus (SLE), often simply called lupus, is a complex autoimmune disease marked by joint pain, skin rashes, extreme fatigue, and depression, among other symptoms. Some studies have described a possible link between SLE’s most severe psychiatric manifestation, psychosis, and a protein autoantibody associated with the central nervous system, anti-ribosomal P.
To investigate how an autoantibody could stimulate behavioral changes by interaction with the brain, researchers at Tel Aviv University set out to induce depressive hallmarks in mice. Their findings, presented in the March 2007 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), shed light on the brain pathways of depression in general and in central nervous system dysfunction in SLE in particular.
Healthy female mice received injections, directly into the brain, of human anti-ribosomal P antibodies extracted from the blood sample of an SLE patient. For control purposes, equal numbers of mice were injected with normal human immunoglobin G. All the mice were then subjected to a series of tests: a forced swimming test in a glass beaker partially filled water to evaluate escape-oriented behaviors, such as rearing and jumping; rotarod and grip strength tests to gauge motor function; a staircase test; a swim T-maze test to assess cognitive function; and a passive avoidance test to measure the ability of mice to remember a foot shock delivered 24-hours earlier.
Depression-like behavior was strongly observed in the performance of anti-ribosomal P antibody-injected mice on the forced swimming test. The immobility time of these mice was twice as high as that of the control group, indicating a state of despair. In the remaining tests of cognitive and motor functions, there were no significant differences detected between the mice in each group, ruling out neurological damage.
In an additional experiment, the "depressed" mice were randomly divided into treatment groups. Some mice were treated with fluoxetine, the antidepressant marketed as Prozac, and some mice were treated with haloperidol, a psychotropic drug used to treat anxiety, addiction, and depression. To determine the effectiveness of each therapy, mice were subjected to repeating the forced swimming, staircase, and rotarod tests. Depression-like behavior was significantly blocked by long-term treatment with fluoxetine, but not by short- or long-term treatment with haloperidol.
At the culmination of the experiments, the brains of mice were sectioned and scrutinized through immunostaining. The staining pattern delineated the limbic system, which regulates the automatic nervous system’s response to stress. It also highlighted areas of the brain associated with the sense of smell.
These findings provide a novel line of research into the mechanisms underlying the limbic and olfactory pathways in depression. Imaging studies both in patients with clinical depression and patients with SLE could help determine whether these pathways are similarly affected in humans.
"The relevance of the results to the involvement of the central nervous system in SLE is another intriguing aspect of the present study," notes its leading author, Yehuda Shoenfeld, M.D., while emphasizing the need for further investigation through large-scale clinical studies. "Elucidating the mechanisms by which anti-ribosomal P induces behavioral changes may lead to novel therapeutic advances for SLE patients with depression," Dr. Shoenfeld reflects.
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Article: "Induction of Autoimmune Depression in Mice by Anti-Ribosomal P Antibodies via the Limbic System," Aviva Katzav, Inna Solodeev, Ori Brodsky, Joab Chapman, Chaim G. Pick, Miri Blank, Wei Zhang, Morris Reichin, and Yehuda Shoenfeld, Arthritis & Rheumatism, March 2007, (DOI: 10.1002/art.22419).

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Scientists Learn the Origin of Rogue B Cells

February 08, 2007 - Doctors have long wondered why, in some people, the immune system turns against parts of the body it is designed to protect, leading to autoimmune disease. Now, researchers at the National Institutes of Health’s (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), in collaboration with the Oklahoma Medical Research Foundation, have provided some new clues into one likely factor: the early development of immune system cells called B cells. B cells are formed in the bone marrow and produce antibodies. Antibodies are generated from the cutting and splicing of immunoglobulin genes early in B-cell development, and have the potential to develop strong and highly specific affinity for different pathogens. When an infectious pathogen (a disease-causing agent) enters the body, B cells are activated and release antibodies into the bloodstream to combat the pathogen. When antibodies encounter the pathogen, they bind to it, rendering it incapable of causing further harm. Antibody molecules also serve as receptors on the surface of B cells.The problem occurs when the random cutting and splicing of immunoglobulin genes results in an antibody that recognizes a component of one’s own body.

While the body has a built-in mechanism to correct these errant cells, the NIAMS researchers discovered this doesn’t always work the way it was intended. “What happens is that, if the body ever produces a cell with a self-reactive antibody molecule, that cell will get arrested in development at the point where it is actually combining and creating an antibody receptor,” says Rafael Casellas, Ph.D., an investigator in NIAMS’s Genomic Integrity and Immunity Group. Often, rather than killing off the cell, the body edits — or corrects — the receptor, like one might edit a paper, he says. In normal circumstances, this new, good receptor replaces the bad one, but what Casellas and Dr. Patrick C. Wilson of the Oklahoma Medical Research Foundation found was that about 10 percent of the body’s B cells retain both receptors: a good, useful one and the faulty self-reactive one that the good receptor was designed to replace. This means that the aberrant B cells have escaped the body’s mechanism to correct them. “Our research goes against the theory that B cells should only express a single receptor,” says Casellas.Using a technique in which they inserted a piece of human gene into the cells of laboratory mice, the researchers created a model for visualizing the process in live animals. “Most of what scientists do is to create systems to visualize complex phenomena, then to allow nature to give you the answers to your questions,” says Casellas.Their new findings raise the question of how this knowledge might eventually help people with autoimmune disease. That question, says Casellas, is one that will take time to answer. “This is only one step,” he says. “We all carry these cells around, but not all of us develop autoimmunity. Our work provides one explanation for the origin of these self-reactive B cells.”“If you understood the system extremely well and were able to delete the editing cells during development, for instance, then you would only have lymphocytes that don’t express self-receptors at all,” he says.For now, the step forward to understand where these self-directed cells are coming from is a big one. “Our objective is to understand the ins and outs of this process,” says Casellas.

The research was also funded by the NIH’s National Center for Research Resources as part of its Institutional Development Award Program (IDeA). The program fosters health-related research and improves the competitiveness of investigators in states that historically have not received significant levels of research funding from NIH.The National Institutes of Health (NIH)

For more information on autoimmune diseases go to www.aarda.org

New Treatment For Psoriasis Is Highly Effective

Newswise — A new treatment for psoriasis that targets its key inflammatory mediators (IL-12 and IL-23) is highly effective, according to a study by University of Utah researchers to be published in the Feb. 8 issue of The New England Journal of Medicine.
Current treatments for psoriasis include topical medicines and UV light therapy to treat the symptoms of the disease. Many of these treatments are messy, time consuming, have cumulative toxicities, and are not very effective, according to Gerald Krueger, M.D., principal investigator for the study. Krueger is a professor of dermatology and a Benning Presidential Endowed Chair at the University of Utah School of Medicine.
He says the results of the study are especially intriguing because of what it may mean for other immune mediated diseases that share the same signaling pathways, specifically inflammatory bowel disease (IBD).
In 2005 another team of researchers (Mannon et al for the anti-IL-12 Study Group) showed that a different human monoclonal antibody to p40 was effective in the treatment of IBD. “These results suggest that therapeutics that target the IL-12 and IL-23 signaling pathway appear to effectively treat both psoriasis and IBD,” he said.
According to Krueger, the story of the link between psoriasis and IBD gains intrigue by events independent of these reports of treatment success. In October of last year the University of Utah and Celera Group of Applera Corporation reported at the American Association of Human Genetics annual meeting that psoriasis patients carry a common polymorphism in the gene for p40 (IL12B) more often than control subjects. Further exploration led to a discovery of a second polymorphism in the receptor for IL-23 that also associates with psoriasis. These results were recently published in the American Journal of Human Genetics (Cargill et al. 2007). Duerr and colleagues (2006) have reported that the same variant in the IL-23 receptor is associated with IBD. The common forms of these polymorphisms are associated with risk of both psoriasis and IBD, while the uncommon forms are protective, according to Krueger.
“This is really an alignment of the stars. It’s unusual that targeting a new inflammatory pathway in two different diseases provides patients with dramatic improvement,” he said. “And then, almost simultaneously, we find disease-associated genetic variants in this same pathway.”
Krueger and colleagues at Celera predict that refinement of disease association patterns to specific genetic variants within IL-12/23 and the IL-23 receptor will play an important role in the elucidation of the causes of psoriasis, and IBD.
Krueger says that, “Further studies should help determine whether any of the identified differential risk polymorphisms are also associated with response to therapy and possible toxicities and thereby help determine the most effective dosage of these new monoclonal antibody therapies.”
About Psoriasis:
Psoriasis is a chronic (long-lasting) skin disease of scaling and inflammation that affects 2 to 2.6 percent of the United States population, or between 5.8 and 7.5 million people. Although the disease occurs in all age groups, it primarily affects adults. It appears about equally in males and females. Psoriasis occurs when skin cells quickly rise from their origin below the surface of the skin and pile up on the surface before they have a chance to mature. Usually this movement (also called turnover) takes about a month, but in psoriasis it may occur in only a few days. In its typical form, psoriasis results in patches of thick, red (inflamed) skin covered with silvery scales. These patches, which are sometimes referred to as plaques, usually itch or feel sore. They most often occur on the elbows, knees, other parts of the legs, scalp, lower back, face, palms, and soles of the feet, but they can occur on skin anywhere on the body. About 25% of patients who develop psoriasis go on to develop psoriatic arthritis.
Information courtesy of: http://www.niams.nih.gov/hi/topics/psoriasis/psoriasis.htm#1

Autoimmune information
www.aarda.org

New Score Helps Spot Rheumatoid Arthritis

By Jeffrey Perkel, HealthDay Reporter
TUESDAY, Jan. 30 (HealthDay News) -- Dutch researchers may have a new method of predicting whether patients with arthritic symptoms will progress to the autoimmune form of the disease, rheumatoid arthritis.
By differentiating those patients who will develop full-blown rheumatoid arthritis from those who will not, the new formula could speed earlier treatment of rheumatoid arthritis patients, reducing damage to their joints while sparing those who will not develop the disease the side effects sometimes associated with rheumatoid arthritis drugs.
"You don't want to give treatment to patients who will spontaneously remit, because they will not get the benefit," explained lead researcher Dr. Annette van der Helm-van Mil, a rheumatologist at Leiden University Medical Center in the Netherlands. "You want to give it only to the patients who have a high chance of progressing to rheumatoid arthritis."
The findings are published in the February issue of Arthritis and amp; Rheumatism.
According to the Arthritis Foundation, rheumatoid arthritis is an autoimmune disease that affects some 2.1 million Americans, most of them women. The disease often presents first as "undifferentiated arthritis," a condition that lacks the criteria for a more definitive diagnosis. Up to 50 percent of patients with undifferentiated arthritis will spontaneously go into remission, while another third will progress to rheumatoid arthritis.
The problem, said van der Helm-van Mil, is that treatment of rheumatoid arthritis with the rug methotrexate at this point can reduce future joint damage but is also potentially toxic. That's why spotting patients with true rheumatoid arthritis early is so important.
In their study, the Dutch group studied a cohort of 570 patients who presented to the Leiden Early Arthritis Clinic with undifferentiated arthritis, 177 of whom progressed to rheumatoid arthritis within one year.
They identified nine variables, including gender, age, the number and distribution of stiff and swollen joints, and three laboratory tests. When factored into an algorithm, these factors could predict the likelihood of developing rheumatoid arthritis with nearly 90 percent accuracy.
Scores from this "prediction rule" ranged from zero to 14. Patients who score six or below have a 91 percent chance of not developing rheumatoid arthritis, the researchers said, while those who score above 8 have an 84 percent chance of progressing to the autoimmune disease. Those who score seven (about 25 percent of patients) have a 50/50 chance of developing rheumatoid arthritis, while those who score above 10 have a 100 percent chance of developing the disease.
"Using information like this can be extremely helpful in managing patients," said Dr. Clifton Bingham III, assistant professor of medicine in the divisions of rheumatology and allergy and clinical immunology at the Johns Hopkins Arthritis Center in Baltimore, Md. "One of the large questions we face in patients who present with undifferentiated arthritis is knowing which of those patients should receive more aggressive therapy to minimize the long-term consequences of the disease or to decrease the likelihood of going on to develop rheumatoid arthritis," he explained.
Bingham noted, however, that this information may be more useful in the United States for primary care physicians than for rheumatologists. The formula already reflects common practice among rheumatologists, he said. Plus, health care differences between the Netherlands and the United States mean that rheumatologists in the U.S. may be less likely to see patients with undifferentiated arthritis than their counterparts in Leiden, because in the U.S., these patients are more likely to present to primary care doctors first. By the time the patient gets to a rheumatologist, he or she has often already developed more-definite rheumatoid arthritis, Bingham said.
"So, it provides a decision tool for primary care doctors to use in determining which patients are most appropriate for early referral to a rheumatologist," he said.
Bingham cautioned that several caveats must be considered before implementing this prediction score in the United States. First, it needs to be validated in other locales and with other patient populations. Second, he cautioned against using this test to produce strict cutoff values for treatment, since what might be true in a population isn't always true for an individual patient. Finally, he noted that the study doesn't address which treatment regimen is most effective once a patient actually develops rheumatoid arthritis.
"We face that question [of treatment] perhaps more often than the question being raised in this study," Bingham said. "We don't yet know how to answer that question."
The methods used in this study could possibly be used to help solve that puzzle, he added.
More information
For more information on rheumatoid arthritis, visit the Arthritis Foundation.
SOURCES: Annette van der Helm-van Mil, M.D. Ph.D., rheumatologist, Leiden University Medical Center, Leiden, the Netherlands; Clifton Bingham III, M.D., assistant professor, medicine, division of rheumatology and allergy, Johns Hopkins University, Baltimore, Md.; February 2007, Arthritis & Rheumatism

Autoimmune Disease Breakthrough Gained by Identification of 30 Errant Genes

A report in the January issue of Nature magazine announces that one more step in understanding what may cause the body to attack itself in its war against autoimmune disease has been discovered by researchers at the Massachusetts Institute of Technology's Whitehead Institute, says the Autoimmune Related Diseases Association (AARDA), a national nonprofit patient advocacy organization.
Newswise — A report in the January issue of Nature magazine announces that one more step in understanding what may cause the body to attack itself in its war against autoimmune disease has been discovered by researchers at the Massachusetts Institute of Technology's Whitehead Institute, says the Autoimmune Related Diseases Association (AARDA), a national nonprofit patient advocacy organization.What happens in certain cases to cause the body's immune system to go wild with an over reaction when it encounters invading viruses or bacteria, thus resulting in one or more autoimmune diseases--such as rheumatoid arthritis, lupus, multiple sclerosis, thyroid disease (Graves', Hashimoto's), juvenile (type 1) diabetes?
Researchers Richard Young and Alexander Marson, an M.D./Ph.D. student working in Young's laboratory, have reported discovering 30 genes that go awry in autoimmune diseases. According to Young, the regulatory T cells (called “T regs”) that normally control the immune system may have genetic defects. In that case, the T regs protective powers are weakened.
The "brain" of the T regs is a protein called Foxp3. It can send the message to increase or decrease the production of other genes. Dr. Marson, study lead author, said, "We identified a set of roughly 30 genes that are clearly regulated by Foxp3 and, surprisingly, a lot of them are suppressed by Foxp3." Mutation in more of the genes, PTPN22, is associated with a number of autoimmune disorders. It is speculated that altering the Foxp3 gene might be one way to reach a cure of autoimmune diseases.
Two significant implications have emerged from this research. Marson commented, "One is that we've identified this core set of genes that are probably likely to play key roles in preventing autoimmune more disease." He added, "The second implication, which is maybe more long-term, is that we hope that identifying these targets will allow us to screen for drugs to mimic the function of Foxp3 and, thus, treat autoimmune disease."
Autoimmune disease pioneer Noel R. Rose, M.D., Director of the Johns Hopkins Center for Autoimmune Disease Research, says that treating autoimmune disorders will require enhancing either the number or effectiveness of regulatory T cells. He remarked that the MIT study is "certainly important in trying to understand how these regulatory T cells work." He cautions, "Whether this will have important functional implications, only time will tell."
Commenting on the study results, Virginia Ladd, AARDA president and executive director, observes, “The discovery adds weight to the reason why autoimmune diseases should be considered a disease category similar to the way that cancer is viewed rather than as singular diseases.” She adds, “It also lends proof to the genetic connection among these diseases and an understanding as to why these diseases run in families.”
Ms. Ladd points out that the public is unaware of the genetic connection among various autoimmune diseases, and patients are seldom queried by healthcare professionals regarding the family history in autoimmune disease. AARDA is pressing for federal legislation that would bring more awareness to autoimmune diseases and the fact that collectively they affect millions of Americans.
The American Autoimmune Related Diseases Association is the only national organization dedicated to addressing the problem of autoimmunity, the major cause of chronic illness. For more information, please visit AARDA’s Web site at http://www.aarda.org or call 586-776-5903 or 888-856-9433.

Scientists Spot Key Autoimmune Disease Genes

MONDAY, Jan. 22 (HealthDay News) -- The identification by U.S. scientists of genes thought to be key to autoimmune disorders could be a big step toward new treatments for these illnesses, which include lupus, rheumatoid arthritis and type 1 diabetes.
Cells called regulatory T-cells are supposed to help keep the immune system in check, but in autoimmune disease, these mechanisms can fail.
Now, researchers reporting this week in the journal Nature have identified a set of genes closely linked to regulatory T-cell function. The finding could have important implications for research into autoimmune disease and even cancer, experts say.
"This is certainly important in trying to understand how these regulatory T-cells work," said Dr. Noel Rose, director of the Johns Hopkins Center for Autoimmune Disease Research in Baltimore. "Whether this will have important functional implications, only time will tell," said Rose, who was not involved in the study.
Though it is meant to shield our bodies from all pathogens foreign and domestic, the immune system can be frustratingly temperamental. For example, when presented with cancer, the system basically shrugs. In other cases, the cell's defense department can sometimes go into overdrive, leading to autoimmune disorders like systemic lupus erythematosus and Graves' disease, where the body attacks its own cells.
Both of these situations are linked to the immune system's fundamental purpose: to distinguish the body's own cells (and related entities) from foreign invaders. So, cancer cells are ignored by the immune system because they are determined to be the body's own cells. Autoimmune disorders arise when the immune system gets confused and attacks healthy tissues.
In this study, researchers from Harvard Medical School, the Dana-Farber Cancer Institute, the Massachusetts Institute of Technology, and the Whitehead Institute for Biomedical Research focused on genes that help direct these processes via regulatory T-cells.
They focused on a protein that is found only in regulatory T-cells, called Foxp3. Foxp3 is a transcription factor -- that is, it dials up or down the production of other genes. Its significance in controlling the immune system is underscored by the fact that people with mutant Foxp3 genes develop IPEX, a syndrome marked by massive autoimmune disorders and early mortality.
Using sophisticated gene microarray technology, the team scanned the entire T-cell genome. "We identified a set of roughly 30 genes that are clearly regulated by Foxp3 and, surprisingly, a lot of them are suppressed by Foxp3," said study lead author Alexander Marson, a graduate student at Harvard Medical School and MIT.

· Autoimmune properties of nucleus pulposus: an experimental study in pigs.

· Geiss A,
· Larsson K,
· Rydevik B,
· Takahashi I,
· Olmarker K.
Department of Orthopaedics, Sahlgrenska University Hospital, Goteborg University, Goteborg, Sweden.

STUDY DESIGN: Assessment of activated T and B cells in a subcutaneous chamber filled with autologous nucleus pulposus using flow cytometry and immunohistochemistry. OBJECTIVES: To examine if subcutaneously placed autologous nucleus pulposus may attract activated T and B cells in an animal model. SUMMARY OF BACKGROUND DATA: Nucleus pulposus has been suggested to trigger an autoimmune response if exposed to the immune system, for example, in association with disc herniation. T-cell activation represents a hallmark in the generation of an autoimmune response, subsequently leading to the differentiation of B cells, but a causal association between the exposure of nucleus pulposus to the systemic circulation and T and B cell activation is still lacking. METHODS: Autologous nucleus pulposus was harvested from the intervertebral disc of 9 pigs and placed subcutaneously in perforated titanium chambers. In order to control for the effect of the titanium chamber, an additional empty chamber was placed subcutaneously in each pig. After 7 days, the pigs were killed and the chambers were harvested. Flow cytometry and immunohistochemistry were used for analysis of T-helper cells (CD4+), cytotoxic T cells (CD8+), and B cells (Igkappa) in the chamber exudates and T cells (CD45RC) in the remaining blood clot tissue of the chamber. RESULTS: As compared with the empty chambers, the proportion of activated T cells (CD4+ and CD8+) was significantly higher in the exudate of the nucleus pulposus filled chamber. The proportion of activated B cells expressing immunoglobulin kappa (Igkappa) was also significantly elevated in the exudate of the nucleus pulposus chambers. The analysis of the remaining chamber tissue revealed a significantly higher amount of T cells (CD45RC) in the nucleus pulposus chambers than in the empty chambers. CONCLUSIONS: The present findings indicate that nucleus pulposus attracts activated T and B cells. However, since the cell population in the nucleus pulposus of young pigs may differ from that of adult humans, the obtained data may not be directly transferred to the human situation of a disc herniation. The observations in the present study may nevertheless explain some of the local tissue reactions occurring in association with disc herniation and nerve root involvement, thereby providing further insight into the pathophysiology of sciatica.

Regulatory T cells require WASp if they are to prevent self-destruction.

In humans, mutation of the gene encoding a protein known as WASp leads to susceptibility to infections and systemic autoimmunity. Most studies have focused on understanding the defects in T cell activation caused by the WASp deficiency, but researchers at the University of Washington in Seattle have now found that in mice and humans a population of T cells known as regulatory T cells (Treg), which keep other immune cells from attacking the body's own tissues and causing autoimmunity, are also impaired in the absence of WASp.
In the study, which appears online on January 11 in advance of publication in the February print issue of the Journal of Clinical Investigation, David Rawlings and colleagues show that like WASp-deficient humans, WASp-deficient mice develop systemic autoimmune disease. This was not due to a defect in the number of Treg that developed in the mice, but due to a defect in their ability to control autoimmunity. Consistent with this, the peripheral blood of a WASp-deficient patient in whom a spontaneous revertant mutation occurred had substantial numbers of WASp+ Treg. These cells were able to ameliorate this individual's recurrent episodes of autoimmune hemolytic anemia, indicating that a defect in Treg function is likely to contribute to the systemic autoimmunity from which individuals lacking WASp suffer.
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TITLE: Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis
AUTHOR CONTACT:David J. RawlingsUniversity of Washington School of Medicine, Seattle, Washington, USA.Phone: (206) 987-7450; Fax: (206) 987-7310; E-mail: drawling@u.washington.edu.
Jennifer SeymourMedia Relations ManagerChildren's Hospital and Regional Medical Center, Seattle, Washington, USA.Phone: (206) 987-5207; Fax: (206) 987-5215; E-mail: jennifer.seymour@seattlechildrens.org