Immune response points toward cellular pores that allow potassium passage
Using antibodies as bait in a molecular fishing expedition, researchers have hooked a protein that might be the target of an autoimmune attack in multiple sclerosis (MS). Significant amounts of antibodies to the molecule lurk in the blood of almost half of MS patients but not in healthy controls, the study reveals, suggesting an association with the disorder. The protein the investigators reeled in, a potassium channel called KIR4.1, sits in the cell membranes of astrocytes and oligodendrocytes—glial cells in the central nervous system—and antibodies against it trigger damage in the mouse brain, the investigators report. The work appeared on July 11 in the New England Journal of Medicine.
“This work is very compelling and interesting and could potentially explain a lot about the disease process,” says Leila Jackson, an immunologist at the University of Colorado, Denver. Specifically, she says, the results imply that B cells detect the antigen—KIR4.1, in this case—and respond by producing the protein-specific antibodies against it, which possibly contribute to disease.
In the new study, Bernhard Hemmer, a neurologist at Technical University Munich in Germany, and his team used the most common class of antibodies—immunoglobulin G (IgG)—as bait in their quest for MS-linked proteins. First, they purified these antibodies from the blood serum of 19 MS patients and 24 individuals with other neurological diseases. IgG from MS patients preferentially stuck to glial cells in brain-tissue sections and also bound to membrane proteins more strongly than to cytoplasmic proteins; lgG from other patients showed no such preferences. Based on this finding, the researchers searched for proteins from human brain cell membranes that glommed onto MS patient IgG. “We took what was actually hooked to the antibodies,” Hemmer says, “and that’s how we got to the protein.” KIR4.1, one of seven proteins lured with the technique, caught their attention because it turns up in oligodendrocytes and astrocytes, “the most likely targets of the autoimmune response in MS,” Hemmer says.
Hemmer’s group then measured levels of KIR4.1 IgG antibodies in MS patients’ blood. One hundred eighty-six of 397 patients, or 47%, carried a significant amount of the IgG, whereas only 3 of 329 people with other neurological diseases did; none of the 59 healthy participants tested positive. In addition, KIR4.1-specific IgG turned up in cerebrospinal fluid samples from 19 of 30 MS patients tested. To make sure previous MS treatments had not affected antibody levels, the researchers enrolled only study participants who had never received drug therapy for MS, and all patients were in the early disease phase or had clinically isolated syndrome.
The team then tested what the KIR4.1 antibodies do in the brains of live mice. The investigators took blood from MS patients with the highest antibody levels and injected mice just below the cerebellum with IgGs from those samples. Within 24 hours, KIR4.1 vanished from oligodendrocytes and astrocytes around the injection site, leaving behind evidence of immune system activity and glial cell damage, presumably triggered by the antibodies. Loss of the sodium channels might throw off neurotransmitter levels, the authors speculate, thus injuring tissue or interfering with remyelination.
Although the exact relationship between KIR4.1 and MS, if any, remains unknown, previous research has implicated potassium channels, including this one, in neuropathology. “We know from knockout animals and diseases where this channel is damaged that [it leads] to symptoms that are at least partially seen in MS,” Hemmer says, such as ataxia. Conversely, a drug called dalfampridine, approved for treating MS in 2010, aids neuronal conductance by jamming up potassium channels (see “Altered Immunity, Crippled Neurons”).
In addition to identifying a molecule that might contribute to MS, the new results could help explain how demyelinating diseases differ. Antibodies against another channel protein in the demyelination hall of fame, aquaporin 4 (AQP4), characterize neuromyelitis optica (NMO), a demyelinating disease of the optic nerves and spinal cord that used to be considered a type of MS. The distribution of the NMO-related AQP4 protein and this potassium channel might hint at their disease-specific roles, Hemmer says. The two proteins co-occur in some cell types—in astrocyte protrusions, KIR4.1 and AQP4 might jointly regulate water balance—but KIR4.1 appears on oligodendrocytes and AQP4 does not, he says. That observation parallels the observation that oligodendrocytes seem to play a role in MS but not in NMO. Jackson concurs. “If it’s real that these antibodies are pathogenic, it could explain a lot about MS as a distinct entity from NMO,” she says.
Hemmer says he’d like to develop the KIR4.1 antibody as a biomarker for diagnosing MS in the subset of patients who test positive for it. If the IgG corresponds to specific disease features, it could also be used to stratify patients, he says, adding that his group is now pinpointing characteristics of MS patients who test antibody-positive.
Jackson cautions that many steps remain between these results and clinical use. Because of overlap in antibody concentrations between MS patients and patients with other neurological diseases who are antibody-positive, researchers must do more work to identify a clear cutoff to specify only people with MS, she says. Such a test is “a big hope and a real possibility,” says Lawrence Steinman, a neuroimmunologist at Stanford University School of Medicine, adding that, in some patients, using serum could mean an end to the invasive cerebrospinal fluid testing that MS diagnosis can involve.
Hemmer also looks forward to another application of the findings: as a clue to understanding more about MS. “Behind every antibody response is a B cell response, and behind every B cell response is usually a T cell response,” he says. “This antibody … may pave the way to understanding these other components” of MS and how they unite to create the disease.
Correction (24 July 2012)
The original version of the story said in one spot that KIR4.1 rather than antibodies to KIR4.1 are abundant in MS patients.
Key open questions
- What features are shared by MS patients who make this antibody?
- What role does the potassium channel receptor play in the mechanisms of MS?
- What effect(s) do MS therapies or longer disease course have on antibody levels?
Thumbnail on landing page. A confocal immunofluorescence image of KIR4.1 channels (green), astrocytes (blue), and Müller cells (red), a type of glial cell. Courtesy of Drs. Paulo Kofuji and Eric A. Newman.