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Molecular Immunologic Strategies to Identify Antigens and B-Cell Responses Unique to Multiple Sclerosis
Donald H. Gilden, MD;
Mark P. Burgoon, PhD;
B. K. Kleinschmidt-DeMasters, MD;
R. Anthony Williamson, PhD;
Omar Ghausi, BS;
Dennis R. Burton, PhD;
Gregory P. Owens, PhD
Arch Neurol. 2001;58:43-48.
Identification of the causative agent of multiple sclerosis (MS) has
long eluded investigators and has become the "Holy Grail" of researchers in
the field. The immune response in cerebrospinal fluid of patients with MS,
indicated by an increased IgG level and the presence of specific oligoclonal
bands after electrophoresis, strongly parallels that found in various infectious
diseases of the central nervous system. To understand the nature of B-lymphocyte
activation in MS, 4 laboratories studied the antigen-binding regions of antibodies
found in MS brain demyelinative plaques and cerebrospinal fluid. Each analysis
revealed (1) limited germline expression, results not expected for a random
bystander response; (2) features consistent with a specific antigen–targeted
process; and (3) the clonal expansion of populations of B lymphocytes in MS.
The screening of libraries expressing protein products derived from chronic
MS plaque messenger RNA with antibodies purified from plaques, cerebrospinal
fluid, or serum of patients with MS has thus far not revealed the antigenic
target(s) of the MS antibody response. Because putative MS antigens could
be in low abundance, the screening of large libraries of random peptides expressed
on phage surfaces might offer an alternative approach to identify peptide
sequences recognized by MS antibodies. New sophisticated molecular immunologic
techniques described herein should enhance our ability to identify putative
antigen(s) targets in MS.
From the Departments of Neurology (Drs Gilden, Burgoon, Kleinschmidt-DeMasters,
and Owens and Mr Ghausi), Microbiology (Dr Gilden), and Pathology (Dr Kleinschmidt-DeMasters),
University of Colorado Health Sciences Center, Denver; and the Department
of Immunology, Scripps Research Institute, La Jolla, Calif (Drs Williamson
and Burton).
Corresponding author and reprints: Donald H. Gilden, MD, Department
of Neurology, University of Colorado Health Sciences Center, 4200 E Ninth
Ave, Mail Stop B182, Denver, CO 80262 (e-mail: don.gilden{at}uchsc.edu).
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