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Investigators reported that serum levels of antibodies to the potassium channel KIR4.1 were higher in multiple sclerosis patients than in those with other neurologic diseases and healthy donors in independently tested cohorts.
Antibodies to a potassium channel in glial brain cells may potentially serve as a biomarker for some patients with multiple sclerosis (MS), or may indicate a subset of patients with a distinct disease process characterized by ion-channel dysfunction.
DR. JEFFREY BENNETT: “The experiment didn't reproduce the pathology of MS, but it did demonstrate that presence of these antibodies may have some role in pathogenesis. KIR4.1 could be a bystander antigen whose immune response is developed after the initial injury, or it could be a primary immune response in a fraction of MS patients.”
Serum levels of antibodies to the potassium channel KIR4.1 were higher in MS patients than in those with other neurologic diseases and healthy donors in independently tested cohorts, according to a July 12 report in the New England Journal of Medicine (NEJM).
Serum antibodies to KIR4.1 were present in 186 of 397 people with MS; three of 329 with other neurologic diseases, and none of the 59 healthy donors. Moreover, when investigators injected mice with KIR4.1 serum immunoglobulin G (IgG), they observed pathogenic changes in glial cells within 24 hours, according to the report.
But whether the antibodies are causative of MS, a secondary response to an initial causative injury, or a marker for an entirely distinct disease process in a subset of MS patients remains to be determined.
“Our study wasn't designed to look at causation,” Jeffrey Bennett, MD, PhD, a co-author of the NEJM study told Neurology Today. “But in an experiment in which we injected KIR4.1 antibodies in combination with human complement into the central nervous system of mice, we observed architectural changes in glial cells that expressed the antigen.
“The experiment didn't reproduce the pathology of MS, but it did demonstrate that presence of these antibodies may have some role in pathogenesis,” Dr. Bennett, professor of neurology at the University of Colorado Denver School of Medicine, said. “KIR4.1 could be a bystander antigen whose immune response is developed after the initial injury, or it could be a primary immune response in a fraction of MS patients.”
In the study, Dr. Bennett and colleagues screened serum IgG from MS patients to identify antibodies that are capable of binding to brain tissue, and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, they then identified the potassium channel KIR4.1 as the target of the IgG antibodies. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum.
Neurologist Bibi Bielekova, MD, who reviewed the report for Neurology Today, called the study an important one that used an unbiased approach to search for serum antibodies specific to patients with MS. The antibodies to KIR4.1 are highly specific for MS and plausibly related to the pathogenesis of MS, she said.
“This can be useful to clinicians because it appears that if a patient has these antibodies he or she has a high chance of having MS,” Dr. Bielekova, chief of the neuroimmunological diseases unit at the NINDS, told Neurology Today.
Dr. Bielekova and Francisco Quintana, PhD, who also reviewed the report, agreed that the finding opens up new lines of research related to KIR4.1, including the role of the antibody in demyelination.
“The antibodies may not be pathogenic by themselves, however in the context of neuroinflammation they may inhibit remyelination,” said Dr. Quintana, assistant professor of neurology at Harvard University. “It will be important to determine if these antibodies are associated with clinical status. Is the presence of antibodies associated with faster deterioration? If that is the case, it will be very useful to clinicians.”
Both Drs. Bielekova and Quintana noted that the finding may indicate an entirely distinct disease process for a subset of patients, similar to that which has emerged for the presence of autoantibodies to aquaporin-4 in neuromyelitis optica.
In an editorial accompanying the article Anne H. Cross, MD, and Emmanuelle Waubant, MD, PhD, noted that neuromyelitis optica was formerly believed to be a subtype of multiple sclerosis but is now considered to be a distinct disease in which autoantibodies to aquaporin-4 cause pathologic changes. “If the present findings are confirmed and extended, a subset of multiple sclerosis cases may in fact belong to a growing collection of diseases known as `channelopathies' — diseases that are caused by ion-channel dysfunction,” Drs. Cross and Waubant state in their editorial.
Whatever the precise role of KIR4.1 antibodies in MS, the finding appears to offer the promise of individualizing the diagnosis and treatment of patients. “We are good at treating the immune response against MS, but there are still many things to learn about what precisely the immune response is targeting in this disease,” Dr. Bennett told Neurology Today. “The spectrum of targets may have important implications for our ability to diagnose and better treat patients. That is, in those patients whose diagnosis may be unclear, evidence of a specific immune response can be an additional piece of evidence that would help clinicians feel more confident about the diagnosis.”
And Dr. Bennett noted that the antibody was found in patients experiencing the earliest clinical symptoms as well as in those with more progressive disease, suggesting that testing for KIR4.1 would be equally useful regardless of the stage of disease.
DR. BIBI BIELEKOVA: “This can be useful to clinicians because it appears that if a patient has these antibodies he or she has a high chance of having MS.”
“Moreover, knowing the target can lead to therapies that are target-specific as opposed to modulating the entire immune system as we do with MS therapies, and can allow for more individualized treatments,” Dr. Bennett said. “Knowing how these targets relate to various subtypes of MS and how they might correlate with the disease state of the individual can give patients useful information about their disease course and prognosis, as well as allow physicians to sequence their therapies based on knowing how aggressive the disease is.”