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Invited Article: Human natural autoantibodies in the treatment of neurologic disease

From the Departments of Immunology (M.R., L.R.P.) and Neurology (M.R., A.E.W.), Mayo Clinic College of Medicine, Rochester, MN.

Address correspondence and reprint requests to Dr. Moses Rodriguez, Department of Neurology, Mayo Medical School, Guggenheim 442B, 200 First Street, SW, Rochester, MN 55905 rodriguez.moses{at}mayo.edu

Naturally occurring autoantibodies are molecules that are part of the normal immunoglobulin repertoire. This review focuses on three distinct groups of human monoclonal antibodies (mAb). These are human natural autoantibodies that, when injected into an animal model of human disease, stimulate remyelination in CNS demyelinating diseases, protect neurons and extend neuronal processes in CNS axonal disorders, and activate immune dendritic cells to produce cytotoxic T cells to clear metastatic tumors. Natural autoantibodies react to self antigens and are of relatively low affinity. They are derived from germline immunoglobulin genes and are usually polyreactive. Our experiments demonstrated CNS entry by autoradiography of labeled mAb and by MRI. Remyelinating mAb rHIgM22 clusters beta-integrin and mouse mAb O4 recognizes sulfatide. Neuronal outgrowth mAbs sHIgM42 and sHIgM12 appear to target carbohydrates on the surface of neurons. The mAb sHIgM12 (B7-DC-Xab) also is promising as therapeutic against metastatic tumors. It functions by binding and cross-linking the antigen B7-DC on dendritic cells, inducing tumor-specific cytotoxic T cells. All these mAbs activate a transient increase in intracellular calcium, signal via NFb, and prevent apoptosis. The mAbs engage downstream signaling events that induce the primary function of the cell (that is, remyelination for oligodendrocytes, axonal preservation and neurite extension for neurons, or antigen presentation for dendritic cells). Natural human auto mAbs are a potentially important therapeutic technique in combating a wide spectrum of disease processes.

Ig = immunoglobulin; mAb = monoclonal antibodies; MS = multiple sclerosis.

Supported by grants from the NIH (R01 NS 24180, R01 NS 32129, P01 NS 38468, R01 CA104996, R01 CA096859), the National Multiple Sclerosis Society (RG 317 2-B-8, CA 1011 A8-3), the Multiple Sclerosis Society of Canada, the Applebaum Foundation, the Hilton Foundation, the Peterson Foundation, and Acorda Therapeutics, Inc. (Hawthorne, NY).

Disclosure: Patents for promotion of remyelination and stimulation of dendritic cells are issued and are owned by Mayo Foundation. Therefore, the authors have a potential financial conflict of interest.

Received October 14, 2008. Accepted in final form January 23, 2009.

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