Work supported by the National Institute of Arthritis and Musculoskeletal Skin Diseases has led to the discovery of two genes responsible for ankylosing spondylitis (AS), an inflammatory and potentially disabling disease of the spine.
The discovery of the two genes – ARTS1 and IL23R – brings the scientific community closer to fully understanding AS, says John D. Reveille, M.D., professor and director of the Division of Rheumatology and Clinical Immunogenetics at the University of Texas (UT) Medical School at Houston, who led the study with Matthew A. Brown, M.D., professor of immunogenetics at Australia's University of Queensland.
In earlier studies of identical twins, Dr. Brown and his colleagues found that the cause of ankylosing spondylitis is more than 90 percent genetic. With the discovery of the newly identified genes, a large proportion of the genetic risk for AS has now been identified.
The IL23R gene, says Dr. Brown, plays a role in the immune system's response to infection. ARTS1 is involved in processing infectious agents into "bite-size chunks" that can be seen – and fought – by the body's immune system.
The recent discovery is based on work from the largest and most comprehensive genome-wide association scan conducted to date. In this part of the research project, investigators were searching for genetic information related to AS, as well as autoimmune thyroid disease/Graves' Disease, breast cancer and multiple sclerosis.
"This discovery, to me, is the most important since 1973, when HLA-B27 was discovered," says Reveille colleague Frank C. Arnett, M.D., professor of internal medicine and pathology and laboratory medicine at the UT Medical School. HLA-B27 is a powerful predisposing gene that increases the risk of getting AS by more than 100 times.
Dr. Arnett says the location of the genes and the fact they don't coincide with those of autoimmune diseases, such as rheumatoid arthritis, lupus or juvenile diabetes, helps refute the long-held notion that AS is an autoimmune disease. "It is looking more like AS is not an autoimmune disease, but really an unusual response to infection. These genes working together probably impair the immune system's ability to rid the body of some of these bacteria or their products."
He also believes this discovery could eventually lead to ways to immunize people against AS. "I think these give us the genetic handles to identify the pathways that are involved in AS. Once you know the dysregulated pathway, you can find a drug to either strengthen or inhibit the pathway."
In the meantime, Dr. Reveille says the two genes, along with HLA-B27, could also help physicians identify patients who are at the highest risk for developing AS. "For example, if you have a family member with AS, a simple blood test would be able to tell us if you are also at risk," he says. "We could offer screenings for people with inflammatory back pain. In the past, [testing for the HLA-B27 gene] was all we had. Now we potentially have more tests."
"This is a success story for genetics work," says Dr. Reveille. "I think it will lead the way for other work to be done."
AS is a chronic inflammatory arthritis characterized by joint stiffness, pain and extra bone growth that can result in partial or complete fusion of the spine. It typically strikes adolescent and young adult males. Currently there is no cure for the disease.
Friday, March 14, 2008
Discovery of a new switch of the immune response
At the Institut Curie, Inserm researchers, in collaboration with collegues from Dynavax(1), have discovered a new mechanism controlling the choice in humans between two lines of defence in the event of attack. In the presence of viruses or bacteria, the immune system can trigger a response that is rapid but devoid of memory – innate immunity – or a response that takes longer to put in place but is more specifically targeted – adaptive immunity.
The essential prerequisite to the proper functioning of innate immunity is the “turning on” of the protein PI3-kinase. Once PI3-kinase is activated, the immune response is triggered, leading to the production of type I interferons, the spearhead of innate immunity, which destroy the body’s invaders. This discovery opens up new therapeutic prospects since it may suggest ways of restoring the function of innate immunity, which is overactivated in autoimmune diseases and inhibited in certain cancers. This work is published in the 18 February 2008 issue of the Journal of Experimental Medicine.
The body is often faced with attacks from outside (viral or bacterial infection) and sometimes from inside, because of the dysfunction of its own cells (cancer), and defends itself by activating its immune system. There are two types of defence. The first is innate immunity: this has no memory, and is permanently on guard to detect and destroy abnormal cells, tumor cells, or virus-infected cells. The second, which takes longer to initiate, is adaptive immunity, which specifically targets an invader. This response requires a education phase during which the cells of the immune system learn to recognize their enemy.Dendritic cells, the body’s “sentinels”, are the first line of defence against invading pathogens: they recognize viruses and bacteria and then trigger an immune response, which, depending on the case, may be innate or adaptive. In response to an intruder, the so-called plasmacytoid dendritic cells can either produce large amounts of interferons, molecules that trigger a rapid response against viral infections, or “specialize” and become cells able to teach the immune system to recognize the pathogens. At the Institut Curie, Vassili Soumelis(2) and his team have discovered how the dendritic cells choose between the two types of immune response. First, whatever the response, the presence of an intruder stimulates the TLR receptor inside the dendritic cells. Only then is the choice made between the two types of response. The PI3-kinase signaling pathway is activated, and the innate response is triggered. Kinase PI3 is the switch that turns on a whole cascade of proteins inside the cell. Information on the presence of an intruder in the body is thus transmitted to its final destination, in the cell’s nucleus, where the protein IRF-7 (transcription factor) modifies the expression of specific genes and so alters the cell’s behavior. In this specific case, IRF-7 induces the production of type 1 interferons (interferon-alpha, for example), which will bring about the destruction of the viruses and strongly activate various cells of the immune system. Vassili Soumelis MD, PhD at the Institut Curie explains: “Activation of the protein PI3-kinase is one of the very first steps needed for the production of large quantities of type 1 interferons, leading to the triggering or strengthening of the innate immune response.” In certain autoimmune diseases, like systemic lupus erythematosus(3) or Sjögren’s syndrome(4), this innate response overstimulated, leading to an abnormal defense reaction of the immune system, which attacks its own cells, tissues, or organs. In some cancers, on the other hand, the innate response is virtually absent. It may be that the cancer cells are able to block the PI3-kinase signaling pathway. Through this discovery, Vassili Soumelis and his collaborators hope, in time, to develop new treatments for use in autoimmune diseases and oncology. By acting on PI3-kinase, it may be possible to adapt the innate response, so as to inhibit it in the treatment of autoimmune diseases and boost it in cancer treatment.
For more information on autoimmune diseases visit www.aarda.org
The essential prerequisite to the proper functioning of innate immunity is the “turning on” of the protein PI3-kinase. Once PI3-kinase is activated, the immune response is triggered, leading to the production of type I interferons, the spearhead of innate immunity, which destroy the body’s invaders. This discovery opens up new therapeutic prospects since it may suggest ways of restoring the function of innate immunity, which is overactivated in autoimmune diseases and inhibited in certain cancers. This work is published in the 18 February 2008 issue of the Journal of Experimental Medicine.
The body is often faced with attacks from outside (viral or bacterial infection) and sometimes from inside, because of the dysfunction of its own cells (cancer), and defends itself by activating its immune system. There are two types of defence. The first is innate immunity: this has no memory, and is permanently on guard to detect and destroy abnormal cells, tumor cells, or virus-infected cells. The second, which takes longer to initiate, is adaptive immunity, which specifically targets an invader. This response requires a education phase during which the cells of the immune system learn to recognize their enemy.Dendritic cells, the body’s “sentinels”, are the first line of defence against invading pathogens: they recognize viruses and bacteria and then trigger an immune response, which, depending on the case, may be innate or adaptive. In response to an intruder, the so-called plasmacytoid dendritic cells can either produce large amounts of interferons, molecules that trigger a rapid response against viral infections, or “specialize” and become cells able to teach the immune system to recognize the pathogens. At the Institut Curie, Vassili Soumelis(2) and his team have discovered how the dendritic cells choose between the two types of immune response. First, whatever the response, the presence of an intruder stimulates the TLR receptor inside the dendritic cells. Only then is the choice made between the two types of response. The PI3-kinase signaling pathway is activated, and the innate response is triggered. Kinase PI3 is the switch that turns on a whole cascade of proteins inside the cell. Information on the presence of an intruder in the body is thus transmitted to its final destination, in the cell’s nucleus, where the protein IRF-7 (transcription factor) modifies the expression of specific genes and so alters the cell’s behavior. In this specific case, IRF-7 induces the production of type 1 interferons (interferon-alpha, for example), which will bring about the destruction of the viruses and strongly activate various cells of the immune system. Vassili Soumelis MD, PhD at the Institut Curie explains: “Activation of the protein PI3-kinase is one of the very first steps needed for the production of large quantities of type 1 interferons, leading to the triggering or strengthening of the innate immune response.” In certain autoimmune diseases, like systemic lupus erythematosus(3) or Sjögren’s syndrome(4), this innate response overstimulated, leading to an abnormal defense reaction of the immune system, which attacks its own cells, tissues, or organs. In some cancers, on the other hand, the innate response is virtually absent. It may be that the cancer cells are able to block the PI3-kinase signaling pathway. Through this discovery, Vassili Soumelis and his collaborators hope, in time, to develop new treatments for use in autoimmune diseases and oncology. By acting on PI3-kinase, it may be possible to adapt the innate response, so as to inhibit it in the treatment of autoimmune diseases and boost it in cancer treatment.
For more information on autoimmune diseases visit www.aarda.org
There’s something uniquely frightening about autoimmune disorders, diseases that occur when the body attacks itself. But there’s increasing evidence t
Source (HealthNewsdigest.com) - Multiple sclerosis. Lupus. Type 1 Diabetes. What links these three afflictions, which exact a devastating toll on people who would otherwise be in the prime of their lives? They are all autoimmune diseases, and the 23.5 million Americans who suffer from these and nearly a hundred other chronic autoimmune illnesses signal a frightening trend. In
THE AUTOIMMUNE EPIDEMIC: Bodies Gone Haywire in a World Out of Balance—And the Cutting Edge Science That Promises Hope (Touchstone/Simon & Schuster; February 5, 2008; $25.00/hardcover; 0-7432-7775-9), author and lecturer Donna Jackson Nakazawa—herself afflicted with several autoimmune diseases—sounds a call to arms, taking readers inside today’s most prestigious scientific labs to show how “autogens” (heavy metals, toxins, pesticides, viruses, and everyday chemicals that can play a role in triggering autoimmunity) are putting an often unbearable load on the human immune system.
THE AUTOIMMUNE EPIDEMIC combines up-to-the-minute research from leading universities and hospitals, including Harvard University, Johns Hopkins Medical Institutions, and the National Institutes of Health, with the frontline perspective of Nakazawa and other autoimmune sufferers to explore vital topics including:What role chemicals, heavy metals, viruses, diet, and genes play in developing autoimmune disease The connection between autoimmune disease and allergies, the rates of which are likewise skyrocketing The disturbing fact that 75% of autoimmune sufferers are women—and one in nine women will be afflicted with these diseases Ways in which readers can lessen the multitude of exposures that threaten their immune systems and their overall health Why scientists now believe that even people who are not genetically predisposed to autoimmunity may fall ill The groundbreaking interventions from today’s top labs that promise to help halt the disease process THE AUTOIMMUNE EPIDEMIC calls for a halt in the proliferation of these debilitating, and often fatal, diseases—and provides the knowledge and the means to make a difference. As Dr. Douglas Kerr, director of the Johns Hopkins Transverse Myelitis Center states in the book’s foreword, “Reading The Autoimmune Epidemic is a necessary first step. Reading The Autoimmune Epidemic is a life-altering event. It needs to be.”ABOUT THE AUTHORDonna Jackson Nakazawa is an author and lecturer who specializes in family life and health issues. She has contributed to Parade and AARP The Magazine, and has appeared on ABC News and NPR radio. Nakazawa is also the author of Does Anybody Else Look Like Me? She lives in Maryland with her family
For more information on autoimmune diseases visit www.aarda.org
THE AUTOIMMUNE EPIDEMIC: Bodies Gone Haywire in a World Out of Balance—And the Cutting Edge Science That Promises Hope (Touchstone/Simon & Schuster; February 5, 2008; $25.00/hardcover; 0-7432-7775-9), author and lecturer Donna Jackson Nakazawa—herself afflicted with several autoimmune diseases—sounds a call to arms, taking readers inside today’s most prestigious scientific labs to show how “autogens” (heavy metals, toxins, pesticides, viruses, and everyday chemicals that can play a role in triggering autoimmunity) are putting an often unbearable load on the human immune system.
THE AUTOIMMUNE EPIDEMIC combines up-to-the-minute research from leading universities and hospitals, including Harvard University, Johns Hopkins Medical Institutions, and the National Institutes of Health, with the frontline perspective of Nakazawa and other autoimmune sufferers to explore vital topics including:What role chemicals, heavy metals, viruses, diet, and genes play in developing autoimmune disease The connection between autoimmune disease and allergies, the rates of which are likewise skyrocketing The disturbing fact that 75% of autoimmune sufferers are women—and one in nine women will be afflicted with these diseases Ways in which readers can lessen the multitude of exposures that threaten their immune systems and their overall health Why scientists now believe that even people who are not genetically predisposed to autoimmunity may fall ill The groundbreaking interventions from today’s top labs that promise to help halt the disease process THE AUTOIMMUNE EPIDEMIC calls for a halt in the proliferation of these debilitating, and often fatal, diseases—and provides the knowledge and the means to make a difference. As Dr. Douglas Kerr, director of the Johns Hopkins Transverse Myelitis Center states in the book’s foreword, “Reading The Autoimmune Epidemic is a necessary first step. Reading The Autoimmune Epidemic is a life-altering event. It needs to be.”ABOUT THE AUTHORDonna Jackson Nakazawa is an author and lecturer who specializes in family life and health issues. She has contributed to Parade and AARP The Magazine, and has appeared on ABC News and NPR radio. Nakazawa is also the author of Does Anybody Else Look Like Me? She lives in Maryland with her family
For more information on autoimmune diseases visit www.aarda.org
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