Involvement of Fc receptors in disorders of the central nervous system

Abstract

Immunoglobulins are proteins with a highly variable antigen-binding domain and a constant region (Fc domain) that binds to a cell surface receptor (FcR). Activation of FcRs in immune cells (lymphocytes, macrophages, and mast cells) triggers effector responses including cytokine production, phagocytosis, and degranulation. In addition to their roles in normal responses to infection or tissue injury, and in immune-related diseases, FcRs are increasingly recognized for their involvement in neurological disorders. One or more FcRs are expressed in microglia, astrocytes, oligodendrocytes, and neurons. Aberrant activation of FcRs in such neural cells may contribute to the pathogenesis of major neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, ischemic stroke, and multiple sclerosis. On the other hand, FcRs may play beneficial roles in counteracting pathological processes; for e.g., FcRs may facilitate removal of amyloid peptides from the brain and so protect against Alzheimer's disease. Knowledge of the functions of FcRs in the nervous system in health and disease is leading to novel preventative and therapeutic strategies for stroke, Alzheimer's disease, and other neurological disorders.

Figure 1

The outcomes of FcR activation during ischemic injury. FCRs are activated by natural antibodies and induce JNK, p-38, NFκB and AP-1 activation in neurons, glial cells, endothelial cells, and infiltrating leukocytes. This culminates in proinflammatory cytokine and chemokine secretion. In neurons, the JNK/AP-1 pathway is activated, which promotes further lipid peroxidation and apoptosis. FcRs activation promotes leukocyte adhesion and infiltration, endothelial cell dysfunction and causes blood-brain barrier permeability. IVIG treatment activates FcγR2B which inhibits FcR activation during ischemic stroke.