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.
###
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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Wednesday, February 28, 2007
Friday, February 9, 2007
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
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
Thursday, February 8, 2007
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
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
Friday, February 2, 2007
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
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
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