EXCEED THE SPACE PROVIDED. Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the Central Nervous System (CNS) which likely involves an autoimmune mechanism directed against self-myelin associated antigens. There is substantial evidence suggesting that B cells are involved in at least one mechanism of MS pathogenesis. However, both functional and molecular analysis of the immunoglobulins (Ig's) produced by clonally expanded CSF B cells has been limited. We hypothesize that a subset of clonally expanded B cells in the CSF of MS patients is involved in at least one mechanism of MS pathogenesis by producing antibodies that bind to myelin associated antigens. In order to identify complete Ig rearrangements that may play a role in the autoimmune activities evidenced in MS patients and test for their antigenic specificity, we intend to define the Ig repertoires in the CSF of MS patients in order to identify Ig's from clonally expanded B cells. We then plan to determine the antigenic specificity of these unique Ig rearrangements by cloning both the heavy and light chain segments into an expression vector, isolating the resultant Fab fragments, and testing them for their antigenic specificity. We can also use PCR to track the persistence of these clones in the original MS patients. Moreover, we can determine if other MS patients have the same clonally expanded B cells in their CSF. These studies provide the necessary foundation to initiate and assess the potential role of B cells in at least one mechanism of MS pathogenesis, and ultimately will allow us to explore whether generating specific immunotherapies directed against these clonally expanded B cells in the future is warranted. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040993-03
Application #
6837606
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Utz, Ursula
Project Start
2002-12-15
Project End
2005-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
3
Fiscal Year
2005
Total Cost
$222,300
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Neurology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Chen, Ding; Blazek, Monica; Ireland, Sara et al. (2014) Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms. J Immunol 193:4823-32
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Stuve, Olaf; Cravens, Petra D; Singh, Mahendra P et al. (2007) High incidence of post-lumbar puncture headaches in patients with multiple sclerosis treated with natalizumab: role of intrathecal leukocytes. Arch Neurol 64:1055-6
Stuve, Olaf; Marra, Christina M; Bar-Or, Amit et al. (2006) Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol 63:1383-7
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