National Institute of Neurological Disorders and Stroke
A report describing this research, led by scientists at the National
Institutes of Health (NIH), appears in the December issue of Nature
"This finding is a major advance for Lyme disease researchers and their
patients," notes Anthony S. Fauci, M.D., director of the National Institute
of Allergy and Infectious Diseases (NIAID). "We now have a powerful new
tool to investigate what role autoimmune mechanisms play in the development
of chronic symptoms associated with Lyme disease. We also can use this
strategy to study other infectious and immunologic diseases."
Adriana Marques, M.D., of NIAID's Laboratory of Clinical Investigation,
heads one of the Institute's two large studies of chronic Lyme disease and
co-authored the new report.
The new technique, developed by Roland Martin, M.D., of the National
Institute of Neurological Disorders and Stroke (NINDS), Richard Simon,
Ph.D., of the National Cancer Institute (NCI), together with Clemencia
Pinilla, Ph.D., of the Torrey Pines Institute for Molecular Studies, San
Diego, was tested on a sample taken from a patient in the NIAID study. The
patient has chronic central nervous system disease and a strong immune
response against the Lyme agent, Borrelia burgdorferi, in both his spinal
fluid and blood. Their technique identified the specific bits of the Lyme
agent his T cells recognized when they mounted an immune response against
the bacterium. Equally important, it pinpointed candidate self-antigens,
snippets of his own cells that mimicked those recognition sites on the
The existence of these microbial mimics does not prove they cross-react with
the immune system and cause the body to turn on itself, but it is a major
step in investigating that possibility. Dr. Marques and her collaborators
at NIH and Tufts University's Mark Klempner, M.D., leader of the other large
NIAID-supported chronic Lyme disease study, are now planning to use this
method to check samples from other patients to see if they have similar
autoantigen profiles. If those results look promising, further
investigations can be done, including trying to recreate the autoimmune
disease model in small animals.
According to the study team, their strategy opens up new avenues for
understanding the immune response involved in a variety of diseases where
the causative agent has not yet been identified, such as rheumatoid
arthritis, diabetes or inflammatory bowel disease. It also can be used to
help design novel vaccines against infectious agents and tumors, and to
identify candidate self-antigens and develop ways to turn off unwanted
immune responses they might generate. "We are already using this technique
in our study of multiple sclerosis," notes Dr. Martin.
For the research reported here, the scientists used the T cells found in the
patient's spinal fluid to probe for what might be triggering the immune
response causing his disease. First, they grew T cells that reacted against
a mixture of all the bacterium's proteins. Then they tested that T-cell
clone against a library of 200 mixtures of peptides, small pieces of
proteins made from combinations of the 20 known amino acids. Each peptide
was 10 amino acids in length; one amino acid was held constant while the
other nine were randomized. Next, they numerically ranked each amino acid
according to the strength of the immune response it generated at each
position in the peptide. Finally, they performed a computer search of three
databanks-the human genome, B. burgdorferi and all known viral proteins-to
find any peptide sequences that matched their most reactive peptides. This
search enabled them to identify candidate antigens and self-antigens
potentially implicated in the disease.
The team found that the T-cell clone recognized multiple peptides, including
some derived from viruses, as well as human autoantigens potentially
important in the chronic Lyme disease process. While the response of the
T-cell clone to B. burgdorferi peptides was strongest, its reactivity with
multiple human proteins indicates that these T cells may be continuously
stimulated either by the bacterium or by the human proteins, possibly
leading to autoimmune tissue damage.
The report's other co-authors are Dr. Bernhard Hemmer (now at the University
of Marburg, Germany); Drs. Bruno Gran, Abraham Tzou, Takayuki Kondo, Irene
Cortese, Bibiana Bielekova and Henry F. McFarland from NINDS; Dr. Yingdong
Zhao from NCI; Dr. Stephen Straus from NIAID; and Drs. Jeannick Pascal and
Richard Houghten from Mixture Sciences and the Torrey Pines Institute for
NIAID, NINDS and NCI are components of the National Institutes of Health
(NIH). NIAID conducts and supports research to prevent, diagnose and treat
illnesses such as HIV disease and other sexually transmitted diseases,
tuberculosis, malaria, asthma and allergies. NINDS is the nation's leading
supporter of research on the brain and nervous system, and a lead agency in
the congressionally designated Decade of the Brain. NIH is an agency of the
U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.
MS Klempner and BT Huber. Is it thee or me?-autoimmunity in Lyme disease.
Nature Medicine 5(12):1346-7 (1999).