Possible Target of Immune Attack in MS and New Therapeutic Approach Identified by National MS Society-Sponsored Investigators -- Protein produced to protect brain from harm may become target

A new study by National MS Society-supported researchers suggests a small protein (alpha B-crystallin) normally produced by cells to protect against injury may itself be the target of the multiple sclerosis immune attack. Administering the protein to mice with a similar disease countered the effect, opening the door to a potential new therapeutic approach for MS. Shalina Ousman, PhD, Lawrence Steinman, MD (Stanford University) and collaborators report their findings in the prestigious journalNature,published in advance online on June 13, 2007.

Details:

MS involves repeated attacks on myelin, the insulating and protective coating on nerve fibers that speeds nerve signals; other brain and spinal cordcomponents are also injured. Cells have built-in defenses against such attacks; one of those defenses is the release of small proteins, called heat shock proteins, that can ward off some of the harm. Alpha B-crystallin (known as “CRYAB”) is one such protective protein, and previous studies have shown CRYAB to be present in MS brain lesions, or sites of disease activity. Studies have also suggested that CRYAB may be a major target of immune T cells activated against myelin in MS.

The researchers conducted a series of experiments to investigate the mechanisms underlying this possible role of CRYAB in MS. In mice bred to be missing the gene that makes CRYAB, the MS-like disease EAE was more severe than in mice with normal CRYAB. The myelin-making cells of the normal mice were more protected from cell death, and the immune attack and inflammation were suppressed by the presence of CRYAB.

The investigators used sophisticated large scale array technology, which allows the detection of antibodies that are tested for their ability to bind to a vast numbers of nervous system molecules at once. This was used to detect immune antibodies against all or portions of the CRYAB protein in the spinal fluid from people with relapsing-remitting MS. Antibodies (which can attach to a protein and block its activity) against CRYAB were found in significant numbers in MS spinal fluid compared to that from people with other neurological disorders, suggesting that CRYAB’s protective activity might be blocked in people with MS.

To investigate CRYAB’s potential as a therapy, mice with EAE were administered CRYAB. Compared to control mice, the treated mice experienced less severe disease, due in part to decreased infiltration of immune cells into the brain and spinal cord and suppressed immune cell function, and they sustained fewer losses of myelin-making cells.

Taken together, these findings suggest that a substance produced by the body to protect against harm may itself become the target of the MS attack, blocking its ability to protect brain tissues from damage. In their paper, the authors equate the situation to “damaging the braking system of a vehicle that is already careening into danger.” Senior author Dr. Lawrence Steinman commented, “Remarkably, administration of CRYAB itself may be a potential therapy for MS. We are pushing forward to test this approach in clinical trials.”

-- Research and Clinical Programs Department