NIH Clinical Center

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Backgrounder


Clinical Center
National Institutes of Health

FOR RELEASE: July 27, 1995

Contact: Laura Bradbard
Communications
NIH Clinical Center
(301) 496-2563

NOTE TO MEDIA:

Researchers at the National Institutes of Health have identified a new genetic disease, Autoimmune Lymphoproliferative Syndrome (ALPS). The unique setting of the NIH Clinical Center allowed clinicians and researchers to collaborate and make this exciting discovery.

What follows is a feature story describing ALPS and the process of collaboration that led to the discovery. The story also describes how identifying the underlying genetic mutation that causes ALPS will contribute to our understanding of other diseases. This is the message we hope to convey to your audiences.

Researchers are available for additional interviews; their names and numbers appear at the end of the article.

From time to time, we will be sending you additional story ideas that illustrate the Clinical Center's unique ability to advance biomedical breakthroughs.

Clinical Center Researchers Discover ALPS

She was a vivacious little girl, but baby-sitters were afraid to touch her. With a massively swollen belly and neck glands the size of baseballs, it was hard for her to attend school with the other children. She had kidney disease that resembled lupus and rashes that flared and subsided. Her immune system destroyed her red blood cells and platelets, and then sometimes, it didn't. She was a mystery in medicine, until her doctors called the Clinical Center at NIH for help.

The Clinical Center works like no other hospital. A unique combination of experts from the various research groups at NIH work under one roof, share information, and collaborate with physicians referring patients from outside the government. In this exceptional medical arena the base for referral is the entire world. For that reason, a physician's question to colleagues led to the collaborative discovery of Autoimmune Lymphoproliferative Syndrome (ALPS), a new genetic disease.

Drs. Stephen Straus and Michael Lenardo of the National Institute of Allergy and Infectious Disease (NIAID), Dr. Jennifer Puck, National Center for Human Genome Research (NCHGR), and other NIH researchers, studied five children with massive lymph node enlargement and increases in a rare subset of immune cells called "double negative T cells."

"The collaboration worked rapidly and effectively, not just because of the strengths of each of its components, but because of unique aspects of the Clinical Center, which combines the proximity of cutting-edge research groups with the ability to provide without charge specialized evaluations for patients with rare disorders," said Dr. Straus.

ALPS is the first disease clearly due to an abnormality in apoptosis, or programmed cell death. Scientists are learning increasingly that the body possesses powerful mechanisms that help decide when certain cells are no longer needed. The scheduled, or "programmed" death of these cells helps control many critical normal processes.

In the case of the immune system, certain lymphocytes must die to keep immune responses focused properly on foreign substances. Interference with the apoptosis of lymphocytes has been found to underlie this child's illness and that of others recently evaluated. This accumulation of unneeded lymphocytes due to abnormal apoptosis sets the stage for a number of autoimmune diseases--where the immune system attacks its own tissues-- including rheumatoid arthritis, lupus, and several types of kidney disease.

"Researchers at the Clinical Center are predisposed to wanting to know the why of medicine not just the how of it. That's the beauty of the Clinical Center." Dr. Straus explained. "All I had to do was introduce my research colleagues to the children with ALPS. Then it was not an abstract concept any longer--the children's appearances and their clinical histories were too compelling to ignore."

The children's problems included skin rashes, anemia, bleeding, and kidney diseases. Blood tests indicated exorbitant numbers of T lymphocytes, disease-fighting cells, and no ability to destroy cells when they are no longer needed. T cells come in two types, those with CD4 protein on their surface and those with CD8. These children had large numbers of cells with neither and that is what was so rare.

The collaborative research, including Clinical Center labs and those of NIAID, the National Cancer Institute (NCI), and NCHGR, began in 1990 with a physician's phone call to Dr. Straus. After studying the referred child's medical history, he approached Dr. Tom Fleisher of the Clinical Center's immunology lab to perform specific blood tests. Dr. Fleisher, an expert in lymphocyte analyses, had never seen results like those of this first little girl.

"She had a massive expansion of cells that we normally have very few of. " Dr. Fleisher explained. "Her lymphocyte profile was strikingly abnormal because she had a dramatic increase in double-negative T lymphocytes."

After the surprising blood tests, Dr. Elaine Jaffe's pathology lab at NCI performed similar immunohistochemical analyses of lymph nodes from the child and verified Dr. Fleisher's results in the tissues as well. The disease continued to baffle the scientists.

"Chance favors the prepared mind," Dr. Straus noted. "So when a Michigan physician called to discuss a child with the same puzzling set of symptoms, I knew we had found another instance of this disease. Now, we had two children. And I could only assume there were more out there."

And he was right. Before long, there were 11 patients with a disease that in 1992 was unrecognized. The first child has been admitted almost 30 times in 4 years, and thanks to the Clinical Center, the visits have all been free to her family. Without the networking and the collaboration, Clinical Center doctors wouldn't know about these children and couldn't bring them to the labs.

One small discovery grows from a broad base of research--a rare disease provides clues to other diseases and leads to new science. About the time Dr. Straus and his colleagues were studying these children, scientists elsewhere were discovering a new lymphocyte protein called Fas. It and related proteins became the subject of international research. Fas is a key element of the system that results in lymphocyte apoptosis. The whole field of apoptosis was exploding and further Clinical Center investigation would show that these children had defective Fas protein on their lymphocyte cells.

NIAID Drs. Warren Strober and Michael Sneller, recognized the overall clinical and immunologic similarities of the children to a special research breed of mice that have the same lymph node swelling and spleen enlargement as the children and a marked increase in the double negative T lymphocytes. It turns out that these mice have defective genes and can not make the Fas protein.

In 1994, Dr. Straus obtained test materials to determine if his patients had Fas protein defects as well. Dr. Michael Lenardo, an NIAID immunologist and apoptosis expert, was enlisted to test the patients' cells for their ability to die.

when substances that can bind to Fas proteins are added to them in tissue cultures. Dr. Jennifer Puck brought her expertise in medical genetics to the search. Her lab was perfect for determining whether the patients had normal Fas genes.

Within a matter of weeks the research team knew they had the answer--a new autoimmune disease caused by a genetic flaw that prevents apoptosis--the natural suicide mechanism that removes damaged cells.

The team ran full tilt--they pulled the data and brought it all together. They brought the patients back to the Clinical Center. They brought the siblings and family members in for further testing.

"The Fas protein was not signaling the cells to die," Dr. Straus explained. "The gene responsible for making it was mutated."

This gene, because it sits at the crux of an important cellular pathway, may be important not only to our understanding of other autoimmune diseases, but may have implications for cancer research. Dr. Albert Lin of the NCI has been studying the family of one of the ALPS children because there are several members with Hodgkin's disease. Could there be a connection? NIH scientists working at the Clinical Center, through their search for a diagnosis for a single child's illness, have found the molecular basis for a previously unrecognized clinical problem.

"The discovery of ALPS will provide answers to a number of other science questions," Dr. Straus said. "The things that will come together, what we will learn, will expand way beyond the question at hand. We haven't figured out the complete story yet, but we will. It's very exciting."

Physicians available for media questions:
Stephen Straus NIAID 301-496-5221
Elaine Jaffe NCI 301-496-0183
Michael J. Lenardo NIAID 301-496-6754
Jennifer M. Puck NCHGR 301-402-2194
Warren Strober NIAID 301-402-2208


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