Antibodies as Mediators of Brain Pathology

Abstract

The brain is normally sequestered from antibody exposure by the blood brain barrier. However, antibodies can access the brain during fetal development before the barrier achieves full integrity, and in disease states when barrier integrity is compromised. Recent studies suggest that antibodies contribute to brain pathology associated with autoimmune diseases such as systemic lupus erythematosus and neuromyelitis optica, and can lead to transient or permanent behavioral or cognitive abnormalities. We review these findings here and examine the circumstances associated with antibody entry into the brain, the routes of access and the mechanisms that then effect pathology. Understanding these processes and the nature and specificity of neuronal autoantibodies may reveal therapeutic strategies toward alleviating or preventing the neurological pathologies and behavioral abnormalities associated with autoimmune disease.

Figure 1

Mechanism of Action of Autoantibodies Penetrating Brain Tissue. Autoantibodies that bind to cell surface proteins on glial cells or neuronal cells can induce complement-mediated cytotoxicity (CDC), which results in the formation of the membrane attack complex (MAC) (A). By contrast, antibody-dependent cell-mediated cytotoxicity (ADCC) is induced by Fc receptor-bearing effector cells that can lyse antibody-coated target cells (B). CDC and ADCC can result in cell death. Antibodies can interfere with the crosstalk of receptor signaling by acting as agonistic, antagonistic, or co-agonistic antibodies (C). Antibodies can cause receptor internalization following binding of their cell surface antigen, which leads to altered antigen density on the cell surface (D). Some brain-reactive antibodies will have no functional effect (E).