Possible Immune Target Identified in Multiple Sclerosis

Pauline Anderson

July 12, 2012

July 12, 2012 — Researchers believe they have identified a potential immune target specific to multiple sclerosis (MS).

It is assumed that in MS, the immune system recognizes proteins of the myelin sheath as antigenic, setting in motion an inflammatory reaction resulting in demyelination of the axons, breakdown of the blood-brain barrier, and the formation of lesions. However, the exact target of the immune response involved in MS has continually eluded researchers.

Now, investigators have determined that the response could involve the adenosine triphosphate (ATP)-sensitive inward rectifying potassium channel KIR4.1 in at least a subgroup of MS patients, on the order of about 47%. If their findings are further validated, this could represent an initial step toward development of targeted drug therapies for MS.

"The problem in MS is that while we have strong evidence that this is an autoimmune disease, we really don't know the targets of our misguided immune response," study author Bernhard Hemmer, MD, professor of neurology at Technical University, Munich, Germany, told Medscape Medical News. "If you know what the targets of the immune response are, then you can start to think about specific therapies by wiping out these cells that misbehave."

Dr. Bernhard Hemmer

Although the findings of the study are important, "as always in science, other people have to confirm our results," said Dr. Hemmer.

The research was published in the July 12 issue of the New England Journal of Medicine.

Protein Role

In a series of experiments, researchers were able to identify and characterize a specific serum immune globulin (Ig)G directed against KIR4.1. They showed that serum levels of antibodies to KIR4.1 were higher in subjects with MS than in those with other neurologic diseases or in healthy age-matched controls (P < .001 for both comparisons). They then replicated this finding in 2 independent groups of patients with MS or other neurologic diseases (again, P < .001).

The combined analysis indicated that antibodies to KIR4.1 were present in 186 of 397 MS patients (46.9%) compared with 3 of 329 patients (0.9%) with other neurologic diseases, and in none of the 59 healthy controls.

These experiments also showed that the antibody has biologic effects in vivo.

KIR4.1 is a protein that is found in the kidney and in the brain. In the brain, it is found on oligodendrocytes — cells that build the myelin sheath — and on astrocytes — cells that protect and feed neurons. According to the authors, KIR4.1 may play a role in maintenance of the electrochemical gradient across the cell membrane in perisynaptic astrocytes, which is critical to efficient potassium buffering and uptake of glutamate.

It's possible, they write, that there is a functional interaction between KIR4.1 and the water channel aquaporin-4 (AQP4), and that this interaction regulates water homeostasis. Previous animal research has shown that the development of oligodendrocytes and myelination depend on KIR4.1 expression.

How might antibodies against KIR4.1 contribute to the pathogenesis of MS? The experiments showed that serum anti-KIR4.1 antibodies from patients with MS can deplete KIR4.1 on glial cells and alter expression of glial fibrillary acidic protein (GFAP) in astrocytes. The antibodies might also induce antibody-dependent cell-mediated cytotoxicity, or interfere with the channel function of KIR4.1, resulting in disruption of potassium buffering and neurotransmitter homeostasis, leading to tissue injury or impaired remyelination.

The experiments could not determine which patients with MS carry the relevant antibodies. "We know it's only a subgroup of patients who show this reactivity," said Dr. Hemmer. Future studies should aim to determine whether this antibody is associated with a particular clinical phenotype in MS, he said.

Future research will also attempt to determine what actually happens to this protein in an MS lesion, how this antibody behaves during the course of MS, and whether there's a differential response to treatment in patients who carry this antibody, said Dr. Hemmer.

"Of course, there's a lot more to do, but this could be a first step toward understanding more about what the target is, and why immune cells go crazy in MS and target the brain," said Dr. Hemmer.

Study Relevance

The key question, he said, is how relevant the findings are. The researchers point to 2 possibilities: either KIR4.1 is an important target in MS and the immune response is directed against it, or the target is something else but patients still develop an antibody response, perhaps because the brain is damaged.

Dr. Hemmer is convinced that more than 1 immune target is involved in MS. "There's good evidence that this is not just one disease," he said. They speculate that it is instead, "a melting pot of different diseases that are possibly driven by immune responses to different antigens."

The discovery a few years ago of the AQP4 antibody in patients with neuromyelitis optica, once considered a variant of MS, appears to support this line of thinking. In that case, "you have the same picture" in that 60% to 70% of patients with neuromyelitis optica carry the AQP4 antibody, said Dr. Hemmer. "Those patients probably have another target that plays a role in this disease."

MS a "Channelopathy"?

In an editorial accompanying the publication, Anne H. Cross, MD, from the department of neurology at Washington University School of Medicine, St. Louis, Missouri, and Emmanuelle Waubant, MD, PhD, from the department of neurology at the University of California, San Francisco, say the new study has 3 major strengths.

"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. "Second, not only were antibodies to KIR4.1 highly specific for multiple sclerosis, but also this antigenic target is plausibly relevant. Third, they tested for and found short-term neuropathologic abnormalities in mice after intracisternal injection of human anti-KIR4.1 and complement, supporting the pathogenic potential in humans."

Their findings raise the question of whether there are characteristics particular to MS patients who have antibodies to KIR4.1, they speculate. In this study, no correlation was seen between affected patients and any distinguishing feature, clinical subtype, patient age, or disability level. "However, the heterogeneity of multiple sclerosis also extends to the variable responses to disease-modifying therapies," they point out. "Might patients who harbor antibodies to KIR4.1 respond differently to therapeutic agents for multiple sclerosis?"

If the antibodies are found in only half of patients, as they were in the study, this might explain why trials of therapies that reduce these antibodies, such as plasma exchange or intravenous immunoglobulins, have failed, they reason.

"Most important" is the question of whether these autoantibodies play a pathogenic role in MS, which, they write, seems unlikely since only half of patients had them. On the other hand, neuromyelitis optica, which was formerly viewed as a subtype of MS, is now considered a distinct disease caused by autoantibodies to aquaporin-4, even though only 75% of patients with this condition have antibodies to aquaporin-4 detectable by current assays, they point out.

"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. Although early-onset channelopathies are caused primarily by genetic mutations, channelopathies acquired later in life are often autoimmune in nature," Dr. Cross and Dr. Waubant write.

"In summary, putting aside a priori assumptions in the search for autoantigens in multiple sclerosis, these investigators took an unbiased approach that resulted in the identification of an unexpected but plausible antigenic target," they conclude. "The specific role of antibodies to KIR4.1 in the pathogenesis of multiple sclerosis awaits further definition."

Approached to comment on this study, Lily Jung Henson, MD, from the Swedish Neuroscience Institute, and medical director at Issaquah Neurology, Seattle, Washington, said the study represents "an important and exciting step towards understanding the pathogenesis of multiple sclerosis at a cellular level."

Dr. Jung Henson noted that the findings were "very significant statistically," and added that they "certainly do open new doors for potential therapies."

The study was funded by the German Ministry for Education and Research and Deutsche Forschungsgemeinschaft. Disclosure forms for authors and editorialists are available at www.nejm.org.

N Engl J Med. 2012;367:115-123. Abstract Editorial

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