In some patients with neuropathy and plasma cell dyscrasia there are IgM M-proteins that react with nerve components and that may cause the neuropathy. In approximately half the patients the neuropathy is demyelinating and the M-proteins bind to myelin. In the other patients there is primary axonal degeneration and the M-proteins bind to nerve axons or to endoneurium. The M-proteins that bind to myelin were initially found to bind to the myelin associated glycoprotein (MAG) but recent evidence suggest that the M-proteins bind to a carbohydrate determinant that is shared by central and peripheral MAG and by other glycoproteins and gangliosides in peripheral nerve. There is also evidence that secretion of the M-proteins may be regulated by T-lymphocytes.
The aims of the proposed project are to: 1) characterize the carbohydrate determinant to which the anti-MAG M-proteins bind in patients with demyelinating neuropathies; 2) identify and characterize the nerve antigens to which the M-proteins bind in patients with axonal neuropathies; 3) determine if the identified nerve antigens are also immunologically involved in other patients with neuropathies of unknown etiology; 4) determine whether the anti-MAG M-proteins from patients with demyelinating neuropathy or any of the M-proteins from patients with axonal neuropathies share idiotypic or heavy chain variable region (Vh) determinants; and 5) elucidate the T and B cell interactions regulating production of the M-proteins in vitro and determine if there are idiotype specific or antigen specific T-cells present which may regulate the M-protein secreting B-cells. The project is of interest and important for a number of reasons. It would help diagnose and classify patients with peripheral neuropathies and identify those who may benefit from therapeutic intervention; characterization of the target antigens will allow the development of analogues which could be used to block or remove circulating M-proteins; demonstration of shared Vh determinants between M-proteins from different patients would suggest that there may be an abnormality linked to the expression of the Vh regions, and elucidation of the T and B cell interactions regulating secretion of the M-proteins may lead to the development of more specific and effective therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS018016-04A1
Application #
3398042
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1982-01-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
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Thomas, F P; Adapon, P H; Goldberg, G P et al. (1989) Localization of neural epitopes that bind to IgM monoclonal autoantibodies (M-proteins) from two patients with motor neuron disease. J Neuroimmunol 21:31-9
Latov, N; Hays, A P; Yu, R K et al. (1988) Antibodies to glycoconjugates in human motor neuron disease. Neurochem Pathol 8:181-7
Ito, H; Latov, N (1988) Monoclonal IgM in two patients with motor neuron disease bind to the carbohydrate antigens Gal(beta 1-3)GalNAc and Gal(beta 1-3)GlcNAc. J Neuroimmunol 19:245-53
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Freddo, L; Hays, A P; Nickerson, K G et al. (1986) Monoclonal anti-DNA IgM kappa in neuropathy binds to myelin and to a conformational epitope formed by phosphatidic acid and gangliosides. J Immunol 137:3821-5
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