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

Abstract

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 NFkappab, 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.

Current Concepts in Multiple Sclerosis: Autoimmunity Versus Oligodendrogliopathy

“…These results are consistent with findings in experimentally demyelinated animals in which lasting myelin debris impaired remyelination [31]. Some natural autoantibodies [32] or myelin-specific T cells [33] were also reported to be beneficial for remyelination, which also reasonably explains the necessity of inflammation after demyelination.…”

Identification of target antigens of naturally occurring autoantibodies in cerebrospinal fluid

“…Higher naturally occurring autoantibody levels against apoptosis-associated antigens correlate with protection from cardiovascular events and renal disease in patients with systemic lupus erythematosus [11]. In addition, the use of naturally occurring autoantibodies is a potentially important therapeutic technique for various neurologic and malignant diseases [12][13][14][15]. However, the repertoire of naturally occurring autoantibodies against neuronal antigens in CSF is unclear.…”

Autoimmune Versus Oligodendrogliopathy: The Pathogenesis of Multiple Sclerosis

“…This hypothesis is consistent with findings in experimentally demyelinated animals that myelin debris impairs remyelination (Kotter et al 2006) and activation of Toll-like receptor (to stimulate the phagocytosis of dead myelin) enhances remyelination (Setzu et al 2006); thus myelin-scavenging processes (or what we considered ''autoimmune demyelination'') may be beneficial for restoring neural functions through remyelination after oligodendroglial death. Some natural autoantibodies were reported to be beneficial for remyelination (reviewed in Rodriguez et al 2009), which also reasonably explains the necessity of inflammation after myelin degeneration.…”