Oct 21, 2009
Researchers Show How Immune Attack May Directly Damage Nerve Fibers in MS
Researchers report on a protein that may engage the immune attack to target nerve fibers in MS; studies suggest that damage to nerve fibers may be the root cause of long-term disability in MS. Edgar Meinl, MD (Max Planck Institute of Neurobiology, Martinsried, Germany) and colleagues reported their findings in Proceedings of the National Academy of Sciences USA, (2009 May 19;106(20):8302-7). This study was funded by the MS Society of Great Britain and Northern Ireland, among others.
Background: Multiple sclerosis occurs when the immune system attacks and damages the brain and spinal cord, with a major target being the myelin that ensheathes nerve fibers. Recent research indicates that damage to nerve fibers themselves may occur early and contributes to long-term disability in people with MS. But it is not clear how nerve fibers are damaged in the course of the immune attack, or whether they are directly targeted by the immune system.
The Study: First, Dr. Meinl’s team used proteomics – technology that scans thousands of proteins at once – to identify antibodies (immune proteins that target specific molecules) in brain tissue from people with MS that react to nerve fiber components. This process highlighted a protein called “contactin-2/TAG-1” (transiently expressed axonal glycoprotein 1). Contactin-2/TAG-1 is active on nerve cells, in the region where myelin connects with the nerve fibers.
They then compared the reactivity of immune T cells from individuals with MS and other disorders by exposing their T cells to Contactin-2/TAG-1. They found that T cells from people with MS showed signs of “recognizing” and mounting immune responses to this molecule, and also found evidence of antibodies in MS spinal fluid that reacted to this molecule.
To determine the potential significance of these T cells, the group administered immune cells that showed reactivity to contactin-2/TAG-1 to lab rats, and they developed a mild form of EAE, an MS-like disease. In a further experiment, the investigators followed up the administration of T cells by administering antibody targeting a myelin protein. In this so-called “two-hit” model, the EAE was much more severe, resulting in widespread damage to gray matter, that is, areas of the brain where nerve cell bodies and their nerve fibers are not covered by myelin.
The results suggest that contactin-2/TAG-1 is a possible target for the immune attack in MS, and that the attack may cause direct damage to nerve fibers. In a related article, Drs. Richard Rudick and Bruce Trapp (Cleveland Clinic Foundation) note that Dr. Meinl’s two-hit model is a good one to use when teasing out why nerve fibers are damaged in MS, and for developing therapeutic approaches that target damage to nerve fibers – a key need in the treatment of MS. (The New England Journal of Medicine 2009;361(15):1505-1506).