Multiple sclerosis (MS) is the most common inflammatory demyelinating condition of the CNS, and affects about 400,000 people in the United States. In most patients the condition begins with a relapsing/remitting course, but then evolves to a progressive phase in which earlier successful therapies are no longer effective for treating disease. The most consistent biochemical marker for MS is increased antibody in the CNS, antibody that is produced from cells within the nervous system and is more clonally restricted than the antibody found in the blood. Yet the targets of the antibody and the specific immunopathogenic mechanisms in MS are not known. Previous studies have identified repertoires of antibody sequences expressed in the demyelinating lesions, and developed methods to synthesize functional recombinant antibodies that replicate the in vivo functions. This application will examine the specificity of the intrathecal antibodies produced by resident B and plasma cells in the lesions of relapsing/remitting MS brains, using state-of-the-art immunologic techniques that include staining, precipitation and immunopanning techniques developed in this lab. The proposal will also microdissect individual B and plasma cells from postmortem lesions in secondary progressive MS brains to examine their antibodies and targets. These parallel studies may uncover differences in the antibody profiles produced in progressive MS patients compared to relapsing remitting disease, or shifts in the targets or mechanisms by which the progressive course of disease is refractory to B cell therapies. This proposal always examines the antibody that is expressed in the affected brain lesions of MS patients, and is most likely to provide clues to the disease process. The pathogenic B cell response in MS may operate by antibody- independent mechanisms such as production of pro-inflammatory cytokines or activation of harmful T cells, but activation of the pathogenic B cells requires antibodies on their surfaces to bind to their targets. This proposal uses innovative research strategies to discover the underlying nature of the immune response in MS, the fundamental targets of antibody that is expressed from first diagnosis throughout the worsening of disease. Knowledge of these targets would provide new strategies for therapies, and potential biomarkers for diagnosis and prevention of disease.

Public Health Relevance

Multiple sclerosis (MS) is a common devastating neurologic disease of unknown cause that cripples young people in the prime of life and affects about 400,000 Americans every year. A major clue to the nature of the disease is the increased amount of antibody detected in the brains of MS patients, which persists for the lifetime of the disease. Building on previous work from this lab that identified the sequences of antibodies produced in the affected brain areas of MS patients, this individual research grant proposes to identify the targets of those antibodies, and whether patients with a later progressive disease course differ in those antibody characteristics. These findings will have wide application as diagnostic tools, and for redirecting therapeutic strategies to treat and possibly prevent disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041549-10
Application #
8534288
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2001-04-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$293,605
Indirect Cost
$103,621
Name
University of Colorado Denver
Department
Neurology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Yu, Xiaoli; Burgoon, Mark; Green, Miyoko et al. (2011) Intrathecally synthesized IgG in multiple sclerosis cerebrospinal fluid recognizes identical epitopes over time. J Neuroimmunol 240-241:129-36
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Owens, Gregory P; Bennett, Jeffrey L; Lassmann, Hans et al. (2009) Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann Neurol 65:639-49
Yu, Xiaoli; Barmina, Olga; Burgoon, Mark et al. (2009) Identification of measles virus epitopes using an ultra-fast method of panning phage-displayed random peptide libraries. J Virol Methods 156:169-73
Bennett, Jeffrey L; Haubold, Kurt; Ritchie, Alanna M et al. (2008) CSF IgG heavy-chain bias in patients at the time of a clinically isolated syndrome. J Neuroimmunol 199:126-32
Yu, Xiaoli; Burgoon, Mark P; Shearer, Andrew J et al. (2007) Characterization of phage peptide interaction with antibody using phage mediated immuno-PCR. J Immunol Methods 326:33-40
Owens, Gregory P; Winges, Kimberly M; Ritchie, Alanna M et al. (2007) VH4 gene segments dominate the intrathecal humoral immune response in multiple sclerosis. J Immunol 179:6343-51

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