NIAMS Scientists Discover New Genetic Immune Disorder in Children
DIRA patient Jacob (center) and his parents, Kevin and Joyce, visit with Raphaela Goldbach-Mansky, M.D., M.H.S. Jacob has been undergoing treatment in a NIAMS research protocol at the NIH Clinical Center.
NIAMS researchers and an international team of investigators recently discovered a new autoinflammatory syndrome, a rare genetic condition that affects children around the time of birth. The scientists have termed the new syndrome DIRA (deficiency of the interleukin-1 receptor antagonist). Children with the disorder display a constellation of serious and
potentially fatal symptoms that include swelling of bone tissue, bone pain and deformity, inflammation of the periosteum (a layer of connective tissue around bone) and a rash that can span from small individual pustules to extensive pustulosis that covers most of the patient’s body. Most of the children with DIRA begin to have symptoms from birth to 2 weeks of age.
“The beauty of this discovery is that the symptoms of this devastating disease can now be treated,” said NIAMS director and immunodermatologist Stephen I. Katz, M.D., Ph.D. “The abnormal inflammatory pathways seen in this disease may also help us understand other common diseases that share clinical features, such as psoriasis, as well as other autoinflammatory disorders.”
Raphaela Goldbach-Mansky, M.D., M.H.S., NIAMS researcher and lead author, added, “We knew when we saw these children that we were dealing with a previously unrecognized autoinflammatory syndrome. The clinical characteristics were distinct from other diseases we had seen before.” When her colleague, Ivona Aksentijevich, M.D., tested the first patient for genetic abnormalities, their suspicions were confirmed, and ultimately abnormalities were found in a number of other cases.
All the children had inherited mutations in IL1RN, a gene that encodes a protein known as interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra binds to the same cell receptors as the inflammatory protein interleukin-1 and acts as a brake on this inflammatory protein. Without IL-1Ra,
the children’s bodies cannot control systemic inflammation that can be caused by interleukin-1.
The scientists identified nine patients from six families with DIRA in the Canadian province of Newfoundland, the Netherlands, Lebanon and Puerto Rico. Those who were alive at the time of diagnosis – six in all – were treated with anakinra, a synthetic form of human IL-1Ra that is normally used in people with rheumatoid arthritis. Although the patients were resistant to other medications such as steroids, most responded successfully and immediately to anakinra. “Our first patient had been unresponsive to several treatments, and his health care team had almost given up. But with anakinra, he was out of the hospital in 10 days and his symptoms resolved,” Dr. Goldbach-Mansky said.
Although the mutation that causes DIRA is rare, as many as 2.5 percent of the population of northwest Puerto Rico are carriers. Because DIRA is recessively inherited, these data suggest that it may be present in about 1 in 6,300 births in this population. Because the mutation was found in three independent Dutch families, newborn screening for DIRA in this population, as well as that of northwest Puerto Rico, may be warranted, Dr. Goldbach-Mansky said. Since these findings first appeared in the New England Journal of Medicine, several new cases have been identified.
“The DIRA discovery can be attributed to an innovative and collaborative effort between clinicians and laboratory researchers at NIAMS and an international team of dedicated investigators,” said NIAMS clinical director and coauthor Daniel L. Kastner, M.D., Ph.D. “Moreover, the unveiling of this novel autoinflammatory syndrome provides us with a tool to further dissect the role of interleukin-1 in human biology and disease.”
In addition to NIAMS, support came from the National Cancer Institute; the National Institute of Allergy and Infectious Diseases; the NIH Clinical Center; the National Human Genome Research Institute; Memorial University of St. John’s,
Newfoundland; the University of Iowa, Iowa City; the University of Utrecht, Netherlands; the University of Toronto, Canada; Lund University, Malmo, Sweden; Shafallah Medical Genetics Center, Qatar; Feinstein Institute, Manhasset, N.Y.; and Erasmus Medical School, Rotterdam, Netherlands.
From the Scientific and Clinical Directors
Welcome to the fall/winter 2009 issue of IRPartners. In this issue’s lead story, you’ll learn about a new genetic immune disorder recently discovered by NIAMS intramural scientists. We also provide a brief snapshot of the Institute’s involvement with nanobiology and nanomedicine, two emerging and exciting areas of research.
We welcome new staff members to NIAMS, including our new group of clinical fellows, and celebrate the accomplishments of others. Our HPP Spotlight features the Barney Neighborhood House, an organization that provides social services to senior residents in Washington, D.C.
Lastly, we provide you with a synopsis of recent intramural research highlights and introduce you to several NIAMS health information products.
Enjoy this issue!
John O’Shea, M.D.
Intramural Research Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Daniel Kastner, M.D., Ph.D.
Intramural Research Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Nanomedicine at NIAMS
Dennis Winkler (left) of Alasdair Steven’s Laboratory of Structural Biology Research, conducts a lab tour during NIH Nanoweek 2009.
Nanomedicine is receiving increased attention at NIH, and NIAMS scientists are playing an important role. Nanomedicine refers to highly specific medical interventions at the molecular scale for treating disease or healing damaged tissues, such as muscles and bones. Nanomedicine gets its name from nanometer – a measurement equal to one-billionth of a meter and too small to be seen with a conventional lab microscope. Because of their small size, nanoparticles can easily interact with molecules on the surface and inside of cells. They are believed to have enormous potential for detecting disease and delivering treatments.
Kuan Wang, Ph.D., chief of the NIAMS Laboratory of Muscle Biology and section head of the Muscle Proteomics and anotechnology Section, was one of the organizers of NIH Nanoweek 2009, a weeklong meeting at the Bethesda campus that highlighted various nano-related research activities from both the intramural and extramural programs. The event featured research from Dr. Wang’s lab and the Institute’s Laboratory of Structural Biology Research lab, led by Alasdair Steven, Ph.D.
Dr. Wang was one of several presenters during Nanoweek. He and Jeffrey Forbes, Ph.D., are studying how molecules handle mechanical stress with nanotools such as an atomic force microscope, single molecule fluorescence, and molecular modeling of stressed molecules.
“All molecules are elastic to some degree and would fail at some point when they are pushed too far, so it is very important to understand how nature designs the stress-handling capability,” said Dr. Forbes. “This is a fun place to do research. We developed and fabricated many of the nanotools we use.”
Dr. Wang added, “Since force is the most important function of muscles, the mechanical strength of the proteins that are used to assemble the contractile machinery is critical from a structural engineering point of view. This is an emerging field called mechanobiology that is propelled by nanotechnology.”
Also during Nanoweek, Dennis Winkler, Ph.D., an instrumentation specialist in Dr. Steven’s lab, demonstrated how his group uses cryo-electron microscopy and cryo-electron tomography techniques to study biological complexes such as viruses and cellular components. By using powerful computers to analyze the images from the electron microscopes, researchers can produce
highly detailed models of the specimens they are investigating, allowing them to explore life on the nano scale.
HPP Spotlight Barney Neighborhood House, Senior Program
Barney Neighborhood House (BNH), an institution in Washington, D.C., serves as the lead agency to deliver social services to
elderly residents in Wards 1 and 4.
One critical element of BNH services is the daytime care of the District’s seniors, many of whom are bused from their residences to spend the day at the center. The BNH Senior Program is housed in an unassuming building in northwest Washington. Inside, activities coordinator James Thompson engages the seniors and organizes activities to stimulate their minds and bodies. These activities include literacy and fitness classes, health promotion sessions and trips to local attractions.
BNH collaborates with private and public organizations to provide free services to seniors. Some of these services include free hot lunches delivered to isolated and homebound seniors, nutrition counseling, and home visits and assistance for caregivers at locations throughout the city.
The care and services provided by BNH staff keep to the spirit of its founders, Charles F. Weller, Eugenia Winston Weller and John B. Sleman, Jr. Originally established in 1901 as the Neighborhood House, the name later changed to the Barney Neighborhood House and Social and Industrial Settlement to recognize Alice Pike Barney and her daughters, who were active volunteers and patrons of the institution. In April 1981, BNH was designated the head agency for senior services in its selected wards.
NIAMS IRP Research in the News
Gene Expression Findings a Step Toward Better Classification and Treatment of Juvenile Arthritis
Robert Colbert, M.D., Ph.D., chief of the NIAMS Pediatric Translational Research Branch and a team of NIAMS-funded extramural researchers, have discovered gene expression differences that could lead to better ways to classify, predict outcome, and treat juvenile idiopathic arthritis (JIA). Their work, reported in Arthritis & Rheumatism, supports the notion that there is more variability in JIA than the four or five major subtypes currently recognized. Eventually such findings could enable doctors to target more aggressive treatment to children at risk of more severe arthritis, while those likely to have milder disease could be spared the stronger treatments that carry a greater risk of side effects.
Barnes MG, Grom AA, Thompson SD, Griffin TA, Pavlidis P, Itert L, Fall N, Sowders DP, Hinze CH, Aronow BJ, Luyrink LK, Srivastava S, Ilowite NT, Gottlieb BS, Olson JC, Sherry DD, Glass DN, Colbert RA. Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis. Arthritis & Rheumatism. 2009;60(7):2102-12. DOI 10.1002/art.24601.
Griffin TA, Barnes MG, Ilowite NT, Olson JC, Sherry DD, Gottlieb BS, Aronow BJ, Pavlidis P, Hinze CH, Thornton S, Thompson SD, Grom AA, Colbert RA, Glass DN. Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets. Arthritis & Rheumatism. 2009;60(7):2113–23. DOI 10.1002/art.24534.
Scientists Discover New Genetic Immune Disorder in Children
Raphaela Goldbach-Manksy, M.D., M.H.S., Ivona Aksentijevich, M.D., and their colleagues in the NIAMS Genetics and Genomics Branch recently discovered a new autoinflammatory disease dubbed DIRA (deficiency of the interleukin-1 receptor antagonist). Their findings were published in the New England Journal of Medicine. Children with the disorder display a constellation of serious and potentially fatal symptoms and have inherited mutations in IL1RN, a gene that encodes a protein known as interleukin-1 receptor antagonist (IL-1Ra). As expected, treatment with anakinra, a synthetic form of human IL-1Ra, resulted in the resolution of symptoms in all of the children.
Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgård U, Cowen EW, Pham TH, Booty M, Estes JD, Sandler NG, Plass N, Stone DL, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee CC, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen PM, Hak AE, Huizing M, Rahman P, Douek DC, Remmers EF, Kastner DL, Goldbach-Mansky R. An autoinflammatory disease with deficiency of the interleukin-1 receptor antagonist. New England Journal of Medicine. 2009;360:2416-27.
NIAMS Researchers Identify Protein That Helps Govern Immune Cell Differentiation
Juan Rivera, Ph.D., and his colleagues in the NIAMS Laboratory of Molecular Immunogenetics have discovered that the protein Lyn kinase, expressed in immune cells called basophils, helps control the way immune cells called T helper cells differentiate in mice. This ability to govern cell differentiation makes basophils and their cell-signaling pathways possible targets for future therapeutic strategies in systemic lupus erythematosus (SLE) and other immune-mediated diseases. Dr. Rivera and his team published their findings in the journal Immunity.
Charles N, Watford WT, Ramos HL, Hellman L, Oettgen HC, Gomez G, Ryan JJ, O’Shea JJ, Rivera J. Lyn kinase controls basophil GATA-3 transcription factor expression and induction of Th2 cell differentiation. Immunity. 2009 Apr 17;30(4):533-43.
NIAMS Researchers Investigate FMF in People With Only One ME FV Gene Mutation
Ivona Aksentijevich, M.D., and her colleagues in the NIAMS Genetics and Genomics Branch have challenged a widely held belief that familial Mediterranean fever (FMF) is a recessively inherited autoinflammatory disease occurring in people with two Mediterranean fever gene mutations (MEFV) – one from each parent. Investigators used a standard genetic sequencing technique, capillary electrophoresis, to screen samples from 46 FMF patients with only 1 severe MEFV mutation, and a more thorough and expensive method, hybridizationbased chip technology, to scan a subset of these samples. As reported in Arthritis & Rheumatism, in no case did any technique result in the detection of a second MEFV mutation. The team concluded that identification of a single MEFV mutation in people with typical FMF symptoms is sufficient evidence for doctors to diagnose FMF and start treatment.
Booty MG, Chae JJ, Masters SL, Remmers EF, Barham B, Le JM, Barron KS, Holland SM, Kastner DL, Aksentijevich I. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis & Rheumatism. 2009;60(6):1851-61.
New Genetic Risk Factor for Rheumatoid Arthritis Identified
Daniel Kastner, Ph.D., and Elaine Remmers, Ph.D., of the NIAMS Genetics and Genomics Branch and their collaborators in the North American Rheumatoid Arthritis Consortium, have identified a new genetic risk factor for rheumatoid arthritis (RA). The team identified a gene dubbed REL as being involved in the signaling pathway that can lead to RA. The researchers analyzed samples from two groups, which included both RA patients and controls. The product of the REL gene plays a key role in the immune system and the RA-associated REL variant is found in about one half of the population of North America. The scientists will continue to study how it increases a person’s risk for RA.
Gregersen PK, Amos CI, Lee AT, Lu Y, Remmers EF, Kastner DL, Seldin MF, Criswell LA, Plenge RM, Holers VM, Mikuls TR, Sokka T, Moreland LW, Bridges SL Jr, Xie G, Begovich AB, Siminovitch KA. REL, encoding a member of the NF-kB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nature Genetics. 2009 June 7;41:820-23.
NIAMS’ O’Shea Receives Irish Society Honors
John O’Shea, M.D.
John O’Shea, M.D., NIAMS scientific director, recently received the 2009 Irish Society for Immunology Public Lecture Award in
Dublin, Ireland. Each year, the society honors an outstanding immunologist in recognition of his or her contribution to the
understanding of immunology and health improvement.
As part of the award, Dr. O’Shea was invited to deliver a talk about his research. Sponsored by the Royal Society of Dublin, the Irish Society of Immunology, and the Irish Times, the lecture was titled “Learning from Patients: How Rare Diseases
Inform Immunology.” Dr. O’Shea discussed two rare immunodeficiency diseases and how studying the molecular basis of these diseases has offered new insights into immunoregulation. He also explained how one of these disorders led to the generation of a new class of immunosuppressant drugs.
Dr. O’Shea came to NIAMS in 1994 and currently leads the Molecular Immunology and Inflammation Branch in conducting basic and
clinical investigations on the molecular mechanisms underlying immune and inflammatory responses in rheumatic and autoimmune diseases.
NIAMS Welcomes New Round of Clinical Fellows
From left to right, new NIAMS fellows Maria Alba, Siddharth Bethi, and Nadia Habal
NIAMS welcomes three new clinical fellows – Maria Alba, Siddharth Bethi, and Nadia Habal – to its Rheumatology Fellowship Program. This program provides a balance of both academic and practical training for physicians wishing to pursue a career in academic rheumatology medicine. Program participants tend to be recent graduates of 3-year internal medicine residency programs and work as NIAMS clinical fellows for 2 or more years. The fellows gain practical knowledge by completing clinical rotations in consultative practice, pediatric rheumatology, and community-based rheumatology practice. They spend a good deal of time working at the NIAMS Cardozo Community Health Center in Washington, D.C., which offers them an opportunity to enhance their clinical skills in a community setting.
“The time spent at the NIH helped me realize that I wanted to pursue further training in rheumatology and participate in clinical research,” notes Dr. Alba, who first came to NIH as a clinical research fellow for the Sjörgren’s Syndrome Clinic of the National Institute of Dental and Craniofacial Research. A native of the Dominican Republic, Dr. Alba received her medical degree from the Instituto Tecnológico de Santo Domingo before coming to the United States to complete her internal medicine training at Lincoln Medical Center and Lenox Hill Hospital in New York.
New NIAMS clinical fellow Dr. Bethi recognizes the great opportunity to learn from NIH faculty members. He grew up in India where he received his medical degree, graduating from Mahatma Gandhi Mission Medical College at Aurangabad in 2000. After
completing his residency in India, Dr. Bethi came to the United States to pursue his master’s degree in public health at the University of Michigan in Ann Arbor, graduating in 2004. Before joining NIH as a fellow, he completed his internal medicine residency at the Long Island College Hospital in Brooklyn, N.Y.
“I feel quite privileged to be working at NIH,” states Dr. Habal, who aspires to become a rheumatology teaching and attending physician. She comes to NIAMS after serving as chief resident of the Internal Medicine Residency Program at Texas Health
Presbyterian Hospital of Dallas. Dr. Habal grew up in Sherman, Texas, and completed her postsecondary education at Baylor University.
In 2004, she traveled to the Texas-Mexico border to complete her third year of medical school at the Regional Academic Health Center in Harlingen. The following year she received her medical degree from the University of Texas Health Science Center
at San Antonio where she also completed her preliminary internship.
NIAMS looks forward to working with this talented group of young physicians!
Cardozo Clinic Bids Farewell to Its Nurse Practitioner
Heather Greysen, N.P.
The NIAMS Cardozo Community Health Center (CHC) recently bade farewell to Heather Greysen, N.P., as she left Washington, D.C., for New Haven, Conn. Ms. Greysen joined CHC in 2007 after she moved to the area from San Francisco. Always with a smile on her face, she took on many responsibilities, serving both as the primary care provider and a liaison between physician and patient. Ms. Greysen was instrumental in developing several operational procedures that improved patient care, assisted patient management and enhanced the facility. During her tenure, she helped launch a new research project to improve the quality of the patient referrals to the clinic from the underserved community.
Mark Gourley, M.D., and Ms. Greysen visited several sites in the referring provider community to give information and support literature to community physicians to assist them in referring patients to the clinic. To date, CHC has analyzed approximately 300 referrals that were received in the past year. The clinic hopes these research efforts will add to the quality of care that its patients receive. Although CHC staff members are sad to see Ms. Greysen go, they are excited for her new career in Connecticut and are hopeful that the new nurse practitioner will be able to fill her shoes.
NIAMS Features Audio Materials
In an effort to extend the reach of the Institute’s materials about bone, joint, muscle and skin diseases, NIAMS is now offering health information in audio format. The Institute maintains about 20 MP3 files on the NIAMS Web site. Users can download these files to their computers or their hand-held MP3 players and listen to recordings on a variety of health topics. These recordings were created from the health information in NIAMS Fast Facts, an easy-to-read series of publications for the public.
Additional titles may be added in the future. Web visitors may view the list of topics and access the audio files at http://www.niams.nih.gov/Health_Info/audio_pubs.asp.
Updated Bone Health CD-ROM Now Available
NIAMS recently released a CD-ROM, Bone Health Information for You and Your Patients. This CD was initially created to give health professionals and the general public easy access to the latest information on bone health and diseases. In the last decade, medical research has influenced a rapid advancement in treatment options for many diseases of bone. Through this CD, NIAMS hopes to expand awareness and understanding of bone diseases and strategies to optimize bone health.
The CD-ROM includes:
- a collection of more than 120 print-friendly PDF files of selected patient education materials, many also in Spanish and Chinese
- professional educational resources, including the full text of Bone Health and Osteoporosis: A Report of the Surgeon General
- Web links to current clinical trials and numerous useful resources from NIH, other Federal agencies, and nonprofit organizations.
One free copy is available to anyone on request. Health professionals, patients and family members, faculty at health professions schools, and nonprofit organizations serving individuals and their families will find this CD particularly useful.
To order the free CD-ROM, contact the NIAMS Clearinghouse by phone at 877-22-NIAMS (877-226-4267) or by e-mail at firstname.lastname@example.org or visit the Web site at http://www.niams.nih.gov.
National Resource Center Offers 2010 Pocket Planner
Due to the enthusiastic response to the 2009 Pocket Planner With Tips and Resources for Healthy Bones for Life, the NIH Osteoporosis and Related Bone Diseases ~ National Resource Center (NRC) has launched a new edition of this resource for 2010. The planner provides simple tips for improving bone health and provides links to federal resources and more detailed information on the NRC Web pages.
Each month of the planner offers a unique strategy for enhancing bone health, such as:
- Getting enough calcium and vitamin D.
- Staying active for strong bones.
- Talking to your health care provider about your bones.
- Preventing falls that break bones.
The planner includes space to schedule activities for optimizing bone health, as well as a list of selected calcium-rich foods and their calcium content.
Free planners are available in quantities up to 15. To order, please contact NRC at 800-624-2663 or use the order form online at http://catalog.niams.nih.gov.
Need an NIH Speaker?
The NIH Speakers Bureau is a service that lists NIH researchers, clinicians, and other professionals who are available to speak to school groups and other local and national organizations. Speakers have expertise in such areas as arthritis, osteoporosis, autoimmunity, and several dozen other topics covered by NIH. To find out more about this service, sponsored by NIH ’s Office of Science Education, visit its Web site at http://science.education.nih.gov/spkbureau.nsf.
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Stephen I. Katz, M.D., Ph.D., Director
John O’Shea, M.D., Scientific Director
Daniel Kastner, M.D., Ph.D., Clinical Director
Janet S. Austin, Ph.D., OCPL Director
Marcia Vital, M.S., Editor
Trish Reynolds, R.N., M.S., Managing Editor
Mimi Lising, M.P.H., Candice Williams, Sara Rosario Wilson