Immunoglobulin G and Complement as Major Players in the Neurodegeneration of Multiple Sclerosis

Multiple Sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) and is termed as one of the most common causes of neurological disability in young adults. Axonal loss and neuronal cell damage are the primary causes of disease progression and disability. Yet, little is known about the mechanism of neurodegeneration in the disease, a limitation that impairs the development of more effective treatments for progressive MS. MS is characterized by the presence of oligoclonal bands and raised levels of immunoglobulins in the CNS. The role of complement in the demyelinating process has been detected in both experimental animal models of MS and within the CNS of affected MS patients. Furthermore, both IgG antibodies and complement activation can be detected in the demyelinating plaques and cortical gray matter lesions. We propose here that both immunoglobulins and complement play an active role in the neurodegenerative process of MS. We hypothesize that the increased CNS IgG antibodies form IgG aggregates and bind complement C1q with high affinity, activating the classical complement pathway. This results in neuronal cell damage, which leads to neurodegeneration and demyelination in MS.