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.

A more tolerant immune system?? The future for autoimmune diseases?

Montana State University researchers have found a new way to fool the immune system into becoming more tolerant.David Pascual, MSU professor of veterinary molecular biology, said the process will let people tolerate instead of over-react to certain antigens. Antigens are foreign substances that cause the immune system to respond, but some immune systems respond too strongly.The discovery is good news for people with allergies, autoimmune diseases and inflammatory diseases like arthritis and multiple sclerosis, Pascual said. The discovery will let people use a nasal spray or take a pill to keep their bodies from overreacting to specific antigens. Their immune system will become non-responsive instead of producing allergic reactions or painful inflammations."We are pretty excited about it," said Pascual who noted that MSU has been working on the project for five years. The biotechnology is available now to companies or entrepreneurs that want to license it and develop it further.The key to the biotechnology is a protein that can be fused to a broad range of antigens, Pascual said. By fusing the protein to a specific antigen, researchers can target diseases. The approach is effective at extremely low doses, Pascual said. In some cases, tolerance is produced after only one dose.MS is one of many diseases that the new biotechnology could target. Becky Wiehe, regional program manager for the Montana Division, All America Chapter, National Multiple Sclerosis Society, said she is encouraged every time she hears about research projects that can help people with MS. She didn't used to hear such reports."There are many investigations in the research pipeline," Wiehe said. "That, to me, is exciting. It suggests we have new places to go, and we will get there."At least 1,600 Montanans have multiple sclerosis, and much about the neurological disease of the brain and spinal cord is a mystery, Wiehe continued. Common symptoms are fatigue, tingling, numbness, and inflammation of the nerve to the eye, but symptoms come and go unpredictably in many people. Montana also has a relatively high number of cases which are related, it seems, to genetic tendencies and the state's distance from the equator.MS becomes more common the farther you are from the equator, Wiehe said, theorizing that, "It might be a viral issue in colder climates."She added that Montana's level of MS is comparable to those in other states and countries along the 48th parallel. She said it might also reflect the large number of Montanans whose ancestors came from Scandinavia and Norway. Those areas have MS levels similar to Montana's . www.aarda.org

Systemic Lupus Erythematosus : Safety concern regarding Rituxan in systemic lupus erythematosus

The Food and Drug Administration (FDA) is alerting health care professionals and patients treated with Rituxan (rituximab) to reports of an emerging risk of a serious side effect in patients receiving or who have used Rituxan.
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FDA recently learned that two patients who were treated with Rituxan for systemic lupus erythematosus (SLE) developed progressive multifocal leukoencephalopathy (PML), a fatal viral infection of the central nervous system. This side effect has been reported in patients as late as 12 months after their last dose of Rituxan.SLE is not an approved indication for Rituxan. Rituxan is approved only for the treatment of patients with non-Hodgkin's lymphoma and patients with rheumatoid arthritis whose disease no longer responds to other common treatments. "Rituxan is used in both approved and off-label settings, and therefore it is very important for prescribers as well as patients to be aware of these new reports of the risk of PML," said Dr. Steven Galson, director of FDA's Center for Drug Evaluation and Research. "Patients who are being treated or have been treated with Rituxan who experience any major changes in vision, balance, or coordination, or who experience confusion, should promptly call their doctor."

Type 1 Diabetes May Be Caused By Disruption of Link Between Nerve Cells and Beta Cells

New York, NY, December 15, 2006 — Researchers in Canada have found evidence in mice that the autoimmune attack causing type 1 diabetes may be triggered by abnormal nerve endings in the pancreatic beta cells. The scientists found that in mice that usually develop type 1 diabetes spontaneously, removing these defective nerve endings prevented the mice from contracting the disease. The study was led by Hans Michael Dosch, a scientist at the Hospital for Sick Children in Toronto, and published in the latest issue of the journal Cell.The researchers identified a “control circuit” between islet cells and the sensory nerves surrounding them. The nerve cells normally produce a neuron-peptide that keeps this circuit functioning. But since defective neurons can’t produce the substance, the circuit is disrupted. This led to inflammation around the islets and eventually to their destruction—and type 1 diabetes in the mice. Conversely, the researchers found that infusing the animals with the neuron-peptide actually reversed early diabetes.This is an intriguing finding that could lead to increased focus on the role nerve cells play in the initiation of type 1 diabetes. It has long been assumed that the misguided autoimmune attack that causes type 1 diabetes is aimed at pancreatic beta cells from the very beginning. But the new findings suggest that the connection between nerve cells and beta cells is where the disease process begins. (The new research is preliminary and was conducted in mice, so it is far from certain whether human type 1 diabetes is triggered by the same events.)If research in humans supports these findings, it could provide a possible new therapeutic target for diabetes prevention and a strategy for diagnostic tests to detect diabetes risk earlier. It also could offer a way to produce conditions that allow beta cell regeneration. And it would shed light on a possible link between type 1 diabetes and autoimmune attacks on nervous tissue.Although JDRF did not fund the new study in Cell, it supported earlier research by Dr. Dosch into a possible connection between nerve cells and type 1 diabetes. In 2003, Dr. Dosch and colleagues found that the autoimmune destruction in type 1 diabetes was not limited to beta cells, but destroyed nerve cells as well. JDRF funded that research, which was published in Nature Medicine, and the human islets used were provided by a JDRF research center in Pittsburgh.

Protalex Lead Compound, PRTX-100, Inhibits Platelet Phagocytosis In Vitro

Data Presented at American Society of Hematology Conference

NEW HOPE, Pa.--(BUSINESS WIRE)--Protalex, Inc. (OTCBB: PRTX) announced today that it has unveiled pre-clinical data showing that PRTX-100, the company’s lead compound in development for various autoimmune disorders, inhibits the phagocytosis (ingestion) of platelets in vitro. The data from the study entitled, PRTX-100 Inhibits Platelet Phagocytosis In Vitro, were presented Saturday, December 9, 2006, by Chris Yatko, Research Scientist at Protalex, at the American Society of Hematology’s 48th Annual Meeting and Exposition in Orlando, Florida. Platelet phagocytosis is the effector limb of Idiopathic Thrombocytopenic Purpura (ITP), a rare blood-clotting disorder. As such, the results of the study indicate the potential of PRTX-100 for the treatment of patients with ITP.
“Prevention of platelet phagocytosis is an important step in the treatment of ITP. This study confirms our belief that PRTX-100 may be a promising therapy for this indication and we look forward to continued development of this compound,” said Steven H. Kane, President and Chief Executive Officer of Protalex.
About Idiopathic Thrombocytopenic Purpura (ITP)
ITP is an autoimmune disease in which platelets are misidentified as foreign objects by the immune system and are subsequently targeted for elimination. Normal proteins found on the surface of the platelets act as antigens in ITP-affected patients, thus signaling the body’s white blood cells to remove the platelets from the bloodstream. As a result, patients with ITP have an abnormally low platelet count, ranging from zero (most severe) to about 100,000 per cu/ml of blood (milder case). A healthy person usually has a platelet count of between 150,000 and 400,000 per cu/ml of blood. A count of 30,000 is generally considered safe (i.e., protecting against spontaneous bleeding). Patients with ITP therefore often bruise easily, suffer from bleeding gums as well as nosebleeds, gingival, gastrointestinal, and/or central nervous system bleeding.
Two types of ITP exist: (1) Acute ITP, usually lasting less than six months and mainly occurring in children, typically caused by a viral infection (often not requiring treatment and not recurring), and; (2) Chronic ITP, which is longer-term and chiefly affects adults, specifically women over 40 years of age.
According to the Platelet Disorder Support Association, ITP currently affects approximately 200,000 people in the U.S., with women suffering from the disorder at a rate about 3 times greater than men. About 50% of new cases occur in children and roughly 30,000 new cases occur annually. At present, there is no known cure and only a limited number of treatments are available, including chemotherapy, various biologics, hormones, small molecule immunosuppressants or splenectomy. Corticosteroids are currently the standard first-line therapy, however, these are associated with significant short- and long-term side effects, including swelling of the face, neck, and/or shoulders, fluid retention, heartburn, osteoporosis, premature atherosclerosis, cataracts, glucose intolerance, thinning of the skin and increased risk of infections, among others.
About PRTX-100
PRTX-100 is a highly-purified form of Staphylococcal Protein A. PRTX-100 binds directly to monocytes and a subset of B-cells that are involved in the development and progression of various autoimmune diseases, enabling the compound to modulate the function of these cells and restore the balance of the immune system.

Autoimmune disease triggered if T cells miss a single protein early on

Public release date: 21-Nov-2006[
Contact: Wallace Ravvenwravven@pubaff.ucsf.edu415-476-2557University of California - San Francisco
Autoimmune disease triggered if T cells miss a single protein early on
Scientists have discovered that autoimmunity can be triggered in the thymus, where the immune system's T cells develop, if T cells fail to recognize just one of the body's thousands of proteins as "self." The research confirms an emerging view that autoimmunity can start in this cradle of the immune system, and not only at the sites where autoimmune diseases emerge, such as the pancreas in the case of type 1 diabetes, or the joints in rheumatoid arthritis.
The discovery, from a mouse model of a human autoimmune condition, suggests that effective strategies to treat autoimmune disease should target not only the "peripheral" sites where autoimmune disease is active, but also the thymus -- the organ where T cells and self-proteins, or self-antigens, first interact.
The research was led by investigators at the University of California, San Francisco (UCSF). It was published online November 20 by the Journal of Experimental Medicine and will appear in the journal's print edition November 27.
T cell soldiers encounter the body's full array of proteins in the thymus, and those T cells with receptors that recognize "self" proteins, or antigens, normally are purged to avoid autoimmune attacks in the body later on. The new research showed that if just one of the body's antigens is not recognized as "self," this single failure can lead to a severe autoimmune disease in the retina.
"The thymus is like a filter," said Mark Anderson, MD, PhD, assistant professor of medicine at the UCSF Diabetes Center, and senior author of a scientific paper describing the discovery. "It is removing or pulling out autoreactive T cells. What this new study shows is if just one self-antigen is missing as the T cells go through the filter, it looks like this alone can lead to an autoimmune disease."
"The finding supports the promise of treatments targeting individual body proteins or antigens since we have shown that a single self-antigen can trigger disease," he added.
A similar mechanism may be at play involving other autoimmune diseases such as type 1 diabetes, Anderson said. Immunologists have demonstrated that insulin is expressed in the thymus – not just in the pancreas. Studies have shown that people who are protected from diabetes express high levels of insulin in the thymus, while those who are predisposed express lower levels of insulin in this organ.
"What we think is that 'more is better' in the thymus," Anderson says. "If you have more insulin in the thymus, then there is a better chance that potentially destructive insulin-specific T cells will encounter insulin as self and be filtered out."
In the thymus, immature T cells display on their surface many thousands of unique receptors, generated by random gene rearrangements. This strategy allows the receptors to recognize the tremendous diversity of invading pathogens. In the process, however, they also develop receptors that bind to the body's own proteins. These T cells are normally eliminated, avoiding the plague of autoimmunity.
A clue to how the elimination process is controlled came from previous work involving a protein in the cell nucleus called Aire (for autoimmune regulator), which regulates the expression of some 300 to 1,000 antigens in the thymus. Humans and mice lacking the normal Aire gene suffer from multiple autoimmune diseases including diseases that target the thyroid, adrenal, ovary, and eye.
In 2002, Anderson, then at Harvard Medical School, and colleagues there demonstrated that knocking out the Aire gene in the mouse thymus led to failures of expression of a number of genes in peripheral tissues, resulting in autoimmune diseases in those tissues -- the first direct evidence linking gene knockouts in the thymus to autoimmune defects in body tissues. The study, however, did not link a specific organ autoimmune attack with a specific protein missing in the thymus.
In the new study, the researchers carried out a detailed analysis of the autoimmune attack that is directed against the eye in Aire-deficient mice. What the team found was that the immune system was mainly targeting a single eye protein called IRBP despite the fact that several eye-specific proteins were missing in the thymus of Aire knockout mice. The team then went on to show that IRBP was expressed in the thymus under the control of Aire and that knockout mice lacking the IRBP protein were protected from the disease because they don't express the protein that the immune system is targeting.
In a key, final part of the new study, Anderson and his colleagues showed that if mice without a thymus gland – so-called "nude" mice – received a normal thymus lacking only IRBP, they developed the autoimmune eye disease. The autoimmune attack occurred even though the mice had normally functioning IRBP in their retinas. The final finding demonstrated that failure of T cells in the thymus to recognize IRBP as a self-protein was sufficient to cause the autoimmune disorder in the retina.
The scientists hope that better understanding of interactions in the thymus can lead to earlier, more effective treatment of autoimmune diseases.
"When we see autoimmune disease in the clinic, we are usually looking at it in a relatively late stage. Tissue is already damaged, antigen expression is ramped up and the immune response is spreading to other self-antigens," Anderson said. "If we can also train our focus on the thymus, where we know at least some of the autoimmune disease is triggered, we may be able to determine just what self-antigens are important and shut down the autoimmune process targeting those self -antigens."
The team is collaborating with Jeffrey Bluestone, PhD, director of the UCSF Diabetes Center, in preclinical studies to see if T cell autoimmune attacks on IRBP can be modulated to prevent the autoimmune eye disease.
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Lead author is Jason DeVoss, PhD, a postdoctoral scientist in Anderson's laboratory.
Co-authors include Lawrence Fong, MD, PhD, UCSF assistant professor of hematology and oncology; Yafei Hou, PhD, a postdoc in Fong's lab; Wen Lu, BS, and Kellsey Johannes, BA, both research assistants in Anderson's lab.
Also: Gregory Liou, PhD, associate professor of ophthalmology at the Medical College of Georgia; Howard Chang, MD, PhD, assistant professor dermatology at Stanford University School of Medicine; John Rinn, PhD, a postdoctoral scientist in Chang's lab; and Rachel Caspi, PhD, section head, Laboratory of Immunology, National Eye Institute.
The research is supported in part by the National Institutes of Health.
UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.