Scientists Find a Key Element of Lupus, Suggesting Better Drug Targets
Feb. 4, 2013 — A team led by scientists at The Scripps Research Institute (TSRI) has identified specific cellular events that appear key to lupus, a debilitating autoimmune disease that afflicts tens of millions of people worldwide. The findings suggest that blocking this pathway in lupus-triggering cells could be a potent weapon against the disease.
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In the new study, described in an online Early Edition of the Proceedings of the National Academy of Sciences the week of February 4, 2013, the researchers determined that the absence of a certain type of immune cell, or of a key signaling molecule within the cell, greatly reduces the development of autoimmunity in mouse models of lupus. Mice with these protective changes showed little impairment of their normal immune functions.
"We are excited about the potential of such an inhibitor as a new kind of treatment for lupus, as well as other autoimmune conditions," said Argyrios N. Theofilopoulos, chair of TSRI's Department of Immunology and Microbial Science and a senior author of the new study.
A Case of Mistaken Identity
While there are therapies for lupus, also known as systemic lupus erythematosus (SLE), none of these tightly targets its underlying causes. The condition appears to arise from both genetic and environmental factors, and involves complex autoimmune processes. A key feature is the activity of antibodies -- "autoantibodies" -- that attack the patient's own nucleic acids (DNA, RNA) and other cellular proteins. Lupus's signs and symptoms include rashes, joint pain, anemia and kidney damage. Untreated complications, such as kidney failure and blood clots, can be fatal. Physicians typically treat lupus with broadly immunosuppressive drugs, which raise patients' risks for some infections and cancers.
Theofilopoulos and his laboratory have long been at the forefront of lupus research. In recent years, they and other researchers have found evidence that a powerful class of immune-stimulating chemicals, known as type I interferons, are essential to the vicious cycle of lupus autoimmunity.
The cycle apparently begins when certain immune cells mistakenly detect self-proteins and nucleic acids as "foreign" and begin pumping out type I interferons. This mobilizes other elements of the immune system, including the antibody response, and soon autoantibodies are attacking self-molecules in healthy cells. The autoantibodies in turn present these "foreign" molecules to type I interferon-producing cells, adding fuel to the autoimmune fire.
Lab-dish evidence has suggested that the key producers of type I interferons in lupus are a relatively sparse class of immune cells known as plasmacytoid dendritic cells (pDCs). In the new study, Theofilopoulos and his colleagues sought more conclusive evidence of pDCs' role, using mouse models of lupus.
In Search of Evidence
The experiments were led by first author Roberto Baccala, an associate professor in the TSRI Department of Immunology and Microbial Science who has worked with Theofilopoulos on lupus-related research for the past two decades. To help determine whether lupus can develop in the absence of pDCs, the TSRI scientists collaborated with Keiko Ozato, an expert on immune cell genetics at the National Institutes of Health. Ozato has developed a strain of mice that have no pDCs due to lack of a key gene (IRF8) needed for these cells' development.
The team knocked out this gene in another strain of mice that normally succumbs to a lupus-like autoimmune disease with age. These mice grew up without pDCs and, as a result, were largely protected from the disease.
"When we injected a standard inducer of interferons into these mice, they didn't produce detectable interferons," said Baccala. "And when we watched the animals for the usual development of lupus, we found that autoantibodies were practically non-existent, and all the other lupus-like manifestations were drastically reduced."
Next, the researchers sought to highlight specifically how pDCs promote lupus autoimmunity. For this they used a different mouse gene knockout, based on a mouse strain developed in the TSRI laboratory of Bruce Beutler, a long-time collaborator who has since moved to become the director of the Center for Genetics of Host Defense at the University of Texas Southwestern Medical Center.
Beutler's special mice lack a working gene for a protein called SLC15A4, and as a result of this mutation, the pDCs in these mice develop normally, but are largely unable to produce type I interferons in response to the usual stimuli. Such cells normally produce large amounts of interferons after detecting viral or bacterial genetic material. For this detection, they use a class of internal receptors called TLRs (toll-like receptors). Beutler received the 2011 Nobel Prize in Physiology or Medicine for his work on TLRs. His SLC15A4-mutant mice specifically lack the ability to respond to stimuli that would normally be detected by two of these receptors, TLR7 and TLR9. These same TLRs have been implicated in lupus -- they apparently mistake self-nucleic acids for viral nucleic acids.
Working with Beutler, the TSRI team applied the SLC15A4 mutation to a strain of lupus mice to see if it would protect them from autoimmunity. And it did. "The usual lupus-like signs significantly decreased, and survival was extended," said Baccala.
A Potential Target
Baccala and Theofilopoulos now see SLC15A4 as a potential target for a lupus drug -- a drug that, in principle, would prevent flare-ups of autoimmunity without suppressing other parts of the immune system as much as current therapies do. "The SLC15A4-mutant mice seem to be otherwise almost normal immunologically," said Baccala. "They can clear common viral infections, for example."
"We are now trying to find pharmacologic inhibitors of type I interferon production, and in particular, inhibitors of SLC15A4," said Theofilopoulos.
Emerging evidence indicates that TLR-based detection of self-molecules and production of interferons contribute to other autoimmune conditions, too. Thus, inhibitors of these specific immune signaling pathways might have use beyond the treatment of lupus. "We think that our findings have implications for rheumatoid arthritis, diabetes, neuroinflammatory diseases and many other diseases in which TLRs appear to play a role," Theofilopoulos said.
Other contributors to the study, "Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus," were TSRI researchers Rosana Gonzalez-Quintial, Amanda L. Blasius, Ivo Rimann and Dwight H. Kono.
The research was supported by the National Institutes of Health (grants AR53228, AR31203, AR39555, 1U19-AI100627-01 and 2P01-AI070167-06A1).
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The above story is reprinted from materials provided by Scripps Research Institute.
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Roberto Baccala, Rosana Gonzalez-Quintial, Amanda L. Blasius, Ivo Rimann, Keiko Ozato, Dwight H. Kono, Bruce Beutler, and Argyrios N. Theofilopoulos. Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. PNAS, February 4, 2013 DOI: 10.1073/pnas.1222798110
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Scripps Research Institute (2013, February 4). Scientists find a key element of lupus, suggesting better drug targets. ScienceDaily. Retrieved July 13, 2013, from http://www.sciencedaily.com /releases/2013/02/130204184634.htm
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New genetic findings expected to accelerate autism testing and development of treatments
Results of International Autism Genome Project - Phase 2 are unveiled
TORONTO – Canadian and international scientists have uncovered key changes in DNA in individuals with autism. The Phase 2 results of the multinational Autism Genome Project Consortium published in the June 9 advance online edition ofNature, substantiate the importance of genes as susceptibility factors in autism spectrum disorders.
This study is the largest of its kind, involving 1,500 families and more than 120 scientists and clinicians from across North America and Europe. The team was led by Dr. Stephen Scherer, corresponding author of the study, Senior Scientist at The Hospital for Sick Children (SickKids), Director of The Centre for Applied Genomics at SickKids and the McLaughlin Centre at the University of Toronto and Dr. Peter Szatmari, co-principal investigator, Director of the Offord Centre for Child Studies and Professor at McMaster University. Dr. Dalila Pinto, Postdoctoral Research Fellow at SickKids, was lead author.
Using microarrays (or gene-chip technology) in the highest-resolution testing to date, researchers investigated individuals with autism spectrum disorders (ASDs). ASDs, diagnosed in one in 110 children, are a group of neurodevelopmental conditions resulting in challenges connected to communication, social understanding and behaviour.
The researchers reported that individuals with ASDs tended to carry more insertions and deletions affecting their genes – called copy number variants (CNV) – than did people in the control group. Some of these CNVs appeared to be inherited, while others are considered new, because they are found only in offspring with autism and not in the parents. Dozens of new “autism risk genes” were discovered, including some that might be helpful in early diagnosis.
“We now know several of the genes involved in autism and for the first time, we are able to tie many of these genes into the same biological pathways involved in brain function,” says Scherer. “Knowing these autism genes are linked, we can begin to develop therapies to target the common pathways involved.”
Szatmari adds, “This study will lead to a paradigm shift when it comes our understanding of the root causes of autism and indeed other neurodevelopmental disorders. Previously it was believed that autistic individuals share common genetic variations in a few genes. This research points to the fact that genetic variations are actually rare, meaning individuals with autism are genetically quite unique. But as we discover more and more of these variants, the number of cases of ASD we can explain increases substantially. ”
According to Pinto, “Another surprising discovery was the significant overlap between autism susceptibility genes and those genes that were previously thought to be implicated in intellectual disability. This suggests that at least some genetic risk factors are shared at the pathway level by different mental health disorders and developmental disabilities, providing insights into possible common pathogenic mechanisms”.
The study found that for about 10 per cent of the families studied, there are some genetic clues that may assist in the early diagnosis of autism or related complications. The Canadian researchers say the next step a goal is to set up mechanisms and processes so that all families who are interested can have access to this testing.
“Guided by these massive genomic data sets, we can start to see the forest through the trees, offering answers and hope for families with autism," says Scherer.
The Autism Genome Project consists of 120 scientists from more than 50 institutions representing 12 countries who formed a first-of-its-kind autism genetics consortium. The Project began in 2002, when researchers from around the world came together to share their samples, data and expertise to facilitate the identification of autism susceptibility genes.
The funding to the Canadian team which provided leadership in the identification and analysis of these genes came from public and private partners including major awards and support from Genome Canada through the Ontario Genomics Institute, the McLaughlin Centre, the Canadian Institutes of Health Research, the Canadian Institute for Advanced Research, the Canada Foundation for Innovation, the Ministry of Research and Innovation, the Ontario Innovation Trust, the Catherine and Maxwell Meighen Foundation, the Premier's Summit Award in Medical Research, Autism Speaks, The Centre for Applied Genomics, the Chedoke Health Corporation, the Mayberry Family Fund, the Hamilton Health Sciences Foundation andSickKids Foundation.
Pinto was supported by fellowships of the Netherlands Organization for Scientific Research and the Royal Netherlands Academy of Arts and Sciences.
About The Hospital for Sick ChildrenThe Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision of Healthier Children. A Better World.™ For more information, please visit www.sickkids.ca.
About SickKids Research & Learning TowerSickKids Research & Learning Tower will bring together researchers from different scientific disciplines and a variety of clinical perspectives, to accelerate discoveries, new knowledge and their application to child health — a different concept from traditional research building designs. The Tower will physically connect SickKids science, discovery and learning activities to its clinical operations. Designed by award-winning architects Diamond + Schmitt Inc. and HDR Inc. with a goal to achieve LEED® Gold Certification for sustainable design, the Tower will create an architectural landmark as the eastern gateway to Toronto’s Discovery District. SickKids Research & Learning Tower is funded by a grant from the Canada Foundation for Innovation and community support for the ongoing fundraising campaign. For more information, please visitwww.buildsickkids.com.
About the University of Toronto
Established in 1827, the University of Toronto has one of the strongest research and teaching faculties in North America, presenting top students at all levels with an intellectual environment unmatched in depth and breadth on any other Canadian campus. With more than 75,000 students across three campuses (St. George, Mississauga and Scarborough) and over 450,000 alumni active in every region of the world, U of T’s influence is felt in every area of human endeavour.www.utoronto.ca
About McMaster University
McMaster University, one of four Canadian universities listed among the Top 100 universities in the world, is renowned for its innovation in both learning and discovery. It has a student population of 23,000, and more than 140,000 alumni in 128 countries.
For more information, please contact:
Matet Nebres
The Hospital for Sick Children
416-813-6380matet.nebres@sickkids.ca
The Hospital for Sick Children
416-813-6380matet.nebres@sickkids.ca
Suzanne Gold
The Hospital for Sick Children
416-813-7654, ext. 2059suzanne.gold@sickkids.ca
The Hospital for Sick Children
416-813-7654, ext. 2059suzanne.gold@sickkids.ca
Paul Cantin
University of Toronto Faculty of Medicine
416-978-2890paul.cantin@utoronto.ca
University of Toronto Faculty of Medicine
416-978-2890paul.cantin@utoronto.ca
Veronica McGuire
McMaster University
905-525-9140, ext. 22169vmcguir@mcmaster.ca
McMaster University
905-525-9140, ext. 22169vmcguir@mcmaster.ca
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Magic Tricks Reveal Surprising Results About Autism
Also Included In: Psychology / Psychiatry
Article Date: 22 Oct 2010 - 0:00 PDT
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Autism Treatment Tools - Training, Curriculum, & Data Tracking in the Classroom. - www.rethinkautism.com
Autism game therapy - EASe games, a fun listening program to help your autistic child learn - www.easecd.com
Magicians rely on misdirection - drawing attention to one place while they're carrying out their tricky business somewhere else. It seems like people with autism should be less susceptible to such social manipulation. But a new study in the U.K. finds that people with autism spectrum disorder are actually more likely to be taken in by the vanishing ball trick, where a magician pretends to throw a ball in the air but actually hides it in his hand.
In the vanishing-ball illusion, a magician throws a ball in the air a few times. On the last throw, he merely pretends to throw it, making a tossing motion and looking upwards while the ball remains concealed in his hand. But observers claim to "see" the ball leaving the hand. This misdirection depends on social cues; the audience watches the magician's face. People with autism are known for having trouble interpreting social cues, so Gustav Kuhn of Brunel University and his coauthors Anastasia Kourkoulou and Susan R. Leekam of Cardiff University thought they could use magic tricks to understand how people with autism function.
For this experiment, 15 teenagers and young adults with autism spectrum disorder and 16 without autism watched a video of a magician performing the vanishing-ball illusion. Then they were asked to mark where they last saw the ball on a still image of the magician. The last place it appeared was in the magician's hand, but many people mark a position higher up and say that he threw the ball. "We strongly suspected that individuals with autism should be using the social cues less than typically developing individuals," says Kuhn - that people with autism would watch the ball rather than the magician's face, and thus have a better idea of what happened.
But the exact opposite happened. People with autism were much more likely to think the magician had thrown the ball. Kuhn speculates that this is because the people in the study were all students at a special college for autism, where they would have been taught to use social cues. When he examined where their eyes had looked, he found that, like normally-developing people, they looked first at the magician's face - but their eyes took longer to fix there. They also had more trouble fixing their eyes on the ball. The results are published in Psychological Science, a journal of the Association for Psychological Science.
"What we suggest is that individuals with autism have particular problems in allocating attention to the right place at the right time," Kuhn says. This may cause trouble in social situations, when you have to be able to pay attention to the right thing at the right time. Kuhn would like to repeat the experiment in children with autism, who may not yet have been educated in social cues, to see if they are also taken in by the illusion.
*Gustav Kuhn describes his study, "How Magic Changes Our Expectations About Autism" in this SciVee PubCast: (click on "video + document")
Source:
Keri Chiodo
Association for Psychological Science
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Study Links Immune Protein To Abnormal Brain Development
Also Included In: Schizophrenia; Neurology / Neuroscience; Immune System / Vaccines
Article Date: 15 Oct 2010 - 3:00 PDT
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UCLA scientists have discovered that exposing fetal neurons to higher than normal levels of a common immune protein leads to abnormal brain development in mice.
Published Oct. 14 in the online Journal of Neuroimmunology, the finding may provide new insights into factors contributing to human neurological disorders like schizophrenia and autism.
The researchers studied a protein called major histocompatibility complex, or MHC. The protein plays a dual role in the body: It helps the immune system to identify infected cells, and it enables neurons to make the right connections with each other in the brain.
"When neurons sense infection or damage to the brain, they produce more MHC," said Daniel Kaufman, professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA. "We wanted to explore whether higher levels of MHC affect how the brain develops."
Kaufman and his colleagues studied the development of mice whose neurons were genetically engineered to produce more MHC than normal.
Focusing on two key regions of the brain, the researchers looked at neurons that process vision and neurons involved in learning and memory. Next, the team compared these cells with their counterparts in normal mice.
What the scientists saw confirmed their hunch.
"The mice whose neurons produced extra MHC showed subtle changes in the connections between those neurons and other neurons in both brain regions," Kaufman said.
The UCLA finding could be of relevance in unraveling the origins of schizophrenia and autism, he noted.
"Infections in pregnant women have been associated with slightly higher risks for schizophrenia and autism in their children," he said. "Subtle changes in brain development due to excess MHC may explain this relationship."
Kaufman noted that female mice that contract infections during pregnancy also often give birth to offspring with behavioral abnormalities similar to autism and schizophrenia.
"We suspect that infection stimulates the mother's immune system to produce molecules that act like distress signals they circulate through her blood and then enter the developing brain of the fetus," he said. "There, they alert neurons to make more MHC, which our study shows can lead to altered neuronal circuitry."
"This finding gives us greater insight into the role that MHC plays in the nervous system and may enhance our understanding of the factors that can contribute to neuropsychiatric disorders like autism and schizophrenia," Kaufman said.
Source: University of California, Los Angeles (UCLA)
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Diagnosing Autism With MRI Is One Step Closer
Also Included In: Neurology / Neuroscience; MRI / PET / Ultrasound
Article Date: 13 Oct 2010 - 1:00 PDT
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University of Utah (U of U) medical researchers have made an important step in diagnosing autism through using MRI, an advance that eventually could help health care providers identify the problem much earlier in children and lead to improved treatment and outcomes for those with the disorder.
In a study published on Oct. 15, 2010 in Cerebral Cortex online, researchers led by neuroradiologist Jeffery S. Anderson, M.D., Ph.D., U of U assistant professor of radiology, used MRI to identify areas where the left and right hemispheres of the brains of people with autism do not properly communicate with one another. Those areas are in "hot spots" associated with functions such as motor skills, attention, facial recognition, and social functioning behaviors that are abnormal in autism. MRI's of people without the disorder did not show the same deficits.
"We know the two hemispheres must work together for many brain functions," says Anderson. "We used MRI to look at the strength of these connections from one side to the other in autism patients."
Other than increased brain size in young children with autism, there are no major structural differences between the brains of people with autism and those who do not have the disorder that can be used to diagnose autism on a routine brain MRI. It has been long believed that more profound differences could be discovered by studying how regions in the brain communicate with each other. The study, and other work U of U researchers are doing using diffusion tensor imaging (measures microstructure of white matter that connects brain regions), reveals important information about autism. The advances highlight MRI as a potential diagnostic tool, so patients could be screened objectively, quickly, and early on when interventions are most successful. The advances also show the power of MRI to help scientists better understand and potentially better treat autism at all ages.
"We still don't know precisely what's going on in the brain in autism," says Janet Lainhart, M.D., U of U associate professor of psychiatry and pediatrics and the study's principal investigator. "This work adds an important piece of information to the autism puzzle. It adds evidence of functional impairment in brain connectivity in autism and brings us a step closer to a better understanding of this disorder. When you understand it at a biological level, you can envision how the disorder develops, what are the factors that cause it, and how can we change it. "
An increasing number of studies have shown abnormalities in connectivity in autism, but this study is one of the first of its kind to characterize functional connectivity abnormalities in the entire brain using MRI rather than in a few specific pathways. The research involved about 80 autism patients between the ages of 10-35 and took about a year and a half to complete. The results will be added to an existing autism study following 100 patients over time. "The longitudinal imaging data and associated knowledge gathered forms a unique resource that doesn't exist anywhere else in the world," says Lainhart.
In addition to someday using MRI as a diagnostic tool for autism, researchers also hope to use the data to biologically describe different subtypes of autism. "This is a complex disorder that doesn't just fall into one category," says Lainhart. "We hope the information can lead us to characterizing different types of autism that may have different symptoms or prognoses that will allow us to identify the best treatment for each affected individual."
The collaborative autism imaging research group led by Lainhart is working together to develop methods to use brain imaging to better understand autism and improve the lives of affected individuals. It includes researchers in the departments of psychiatry, radiology, and pediatrics, the Neurosciences Program, the Scientific Computing and Imaging Institute, and The Brain Institute at the U of U, as well as collaborators at Brigham Young University, the University of Wisconsin, and Harvard University.
Source: University of Utah Health Sciences
