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.