Researchers have identified a protein that may be a target of the immune attack in some people with MS, according to a new study published in The New England Journal of Medicine. An immune response to this protein – a protein called “KIR4.1,” which is found on several types of brain cells – was observed in the serum of 47% of people with MS who were tested. Further research is needed to confirm these findings, and to understand what the role of this protein may play in MS and its potential for developing new treatments. Rajneesh Srivastava, MSc and Bernhard Hemmer, MD (Technische Universität, Munich) led the international team, who are supported by grants from the German Ministry for Education and Research and the National MS Society, among others (2012;367:115-23
Multiple sclerosis involves immune system attacks that damage the brain and spinal cord, particularly myelin (the substance that surrounds and supports nerve fibers). Myelin-making cells and nerve fibers are also damaged during the course of the disease. The spinal fluid of most people with MS contains increased amounts of a type of antibody called IgG. Antibodies are immune proteins directed against an immune target, or “antigen.” IgG antibodies are present almost exclusively in infectious and inflammatory disorders and are usually directed against the disease-causing agent. However, previous attempts to identify antigens to which antibodies are targeted in MS have failed. The current study focused on the serum portion of blood samples from people with MS and from others, rather than on spinal fluid.
In a series of experiments, the authors screened serum samples from people with MS and observed that IgG antibodies were attaching themselves to specific myelin-making cells. Using “proteomics” – advanced technology that scans hundreds of thousands of proteins simultaneously – they screened numerous proteins on the cells. They identified the protein KIR4.1 as the target of the IgG reaction. KIR4.1 is an ion channel; these are proteins that are active on the surfaces of several types of brain cells and are critical for cell function.
The team then developed a method of testing people for the presence of antibodies against KIR4.1 in serum samples, and found antibodies to KIR4.1 in a substantial proportion of people with MS in comparison with others tested. In fact, the antibodies were found in serum of 186 of 397 (46.9%) people with MS, versus only 3 out of 329 people with other neurologic disorders, and in none out of 59 people without disease.
Further studies revealed that when anti-KIR4.1 antibodies that were obtained from people with MS were injected into mice, abnormalities in the nervous system occurred. In previous studies, KIR4.1 has been shown to be important in myelin formation, so the authors conclude that this protein is a plausible candidate to be a target of the immune attack in at least some people who have MS. The investigators did not observe any clinical or other differences in people with MS who had the antibodies versus those who did not. How this protein may be involved in MS, and whether this finding will lead to new approaches to treating MS, awaits further research.
In an accompanying editorial, Anne H. Cross, M.D (Washington University School of Medicine, St. Louis) and Emmanuelle Waubant, M.D., Ph.D. (University of California, San Francisco) discuss the strengths of this study. “First, the authors used an unbiased approach to search for serum antibodies specific to patients with multiple sclerosis and, once they found them, methodically sought the target,” they write.
The specific role of the protein awaits definition, especially since half of the people with MS did not have the antibodies to KIR4.1. They note that even if these antibodies arise sometime after the nervous system has already sustained damage in MS, “it is conceivable that they may perpetuate destruction of the central nervous system.”
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