Multiple Sclerosis: Antibodies Gone Awry

Multiple sclerosis is an autoimmune disease thought to be caused by T cells that attack and destroy myelin, the insulating sheath that surrounds neurons in the central nervous system and nerve cells throughout the body. If myelin is damaged, neuronal transmission can be disrupted, and communications between the brain and other parts of the body may fail.

A few years ago, researchers in California and New York suggested that T cells may not be the only culprit in multiple sclerosis. Within multiple sclerosis lesions, they identified antibodies that target myelin-associated proteins. They hypothesized that these autoreactive antibodies may contribute to the disease by binding to these proteins and attracting immune cells that destroy the myelin.

Recently, a group of scientists added another wrinkle to the story. As described in the Proceedings of the National Academy of Sciences, a team led by Alexander Gabibov, D.Sc., of the Russian Academy of Sciences and including Herbert Morse III, M.D., chief of the Laboratory of Immunopathology at NIAID and a French group from Technological University of Compiegne, examined blood samples of 24 people with multiple sclerosis and found autoreactive antibodies in 20 of them. Blood samples of 20 healthy volunteers were used as controls.

Some of these autoreactive antibodies could degrade myelin proteins. The same reaction was shown by autoantibodies isolated from mice that develop experimental allergic encephalomyelitis (EAE), a disease mirroring human multiple sclerosis.

In their paper, Drs. Gabibov and Morse and their colleagues describe how these antibodies may contribute to the symptoms of multiple sclerosis directly by catalyzing site-specific destruction of myelin basic protein (MBP) and thereby degrading the myelin sheaths. The investigation of such reaction on recombinant proteins designed to model different epitopes or pieces of MBP revealed that the antibodies have a highly pronounced catalytic specificity toward these proteins. The authors suggest that measuring the levels of these catalytic antibodies in the sera of people with multiple sclerosis may be a useful clinical marker for disease progression.

The research team also showed that copaxone—an injectable drug the U.S. Food and Drug Administration approved in 1996 for treating multiple sclerosis—effectively blocks the catalytic activity of the antibodies. This raises the possibility that new drugs for multiple sclerosis might be targeted to these destructive catalytic antibodies. One thing that should aid in the development of such drugs, says Morse, is that similar catalytic antibodies have been found in the mice with a disease mirroring human multiple sclerosis. This may provide a valuable pre-clinical model for testing the effect of potential new inhibitors.

Reference
Ponomarenko, N. et al. Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen. PNAS DOI: 10.1073/pnas.0509849103 (2006).